Comparison of Drug Treatments for Migraines

The main treatment for Migraine are the Triptan class of drugs, which act on 5HT₂ receptors. However, they have limited efficacy, significant side effects and cannot be used prophylactically. This project will examine and evaluate recent developments in alternative treatments

Comparison between recently developed drugs and current drugs in the treatment of migraines

Proposal Summary

A migraine is a complex disorder which is not yet fully understood. Previously, it was thought that migraines were due to the dilation of blood vessels in the brain. However, now that more research has been done on the pathophysiology of migraines, it shows migraines are a neurological disorder involving different areas of the nervous system (e.g. trigemino-vascular pathway). Current treatment of migraines are not very efficacious, have major side effects (can be fatal for those with underlying cardiac problems) and cannot be used for preventive therapy. But now, this better understanding of migraines has allowed for recent developments in alternative treatments (e.g. CGRP antagonists). These could potentially be marketed as safer and more effective drugs with a reduced number of adverse events.

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The aim of this research project is to evaluate recent developments and compare them to the current treatments to see if there are more benefits for patients. Inclusion and exclusion criteria will allow for a more focused approach so will give more reliable results.  I plan to carry out a systematic review (with possible meta-analysis) using journal articles from online databases and will refine search terms accordingly to get the most accurate information.

Background

Migraine is described as a pulsating headache which typically occurs on one side of the head and the intensity of pain is moderate or severe. It is a complex condition with an array of symptoms including nausea, vomiting, giddiness, drowsiness, photophobia and phonophobia. Migraine attacks vary in time and frequency depending on the individual, lasting on average between 4 to 72 hours. Migraines often begin in the teenage years but are most common between ages 25 to 55 and prevalence in females is greater (nhs.uk, 2018). There may be many trigger factors for migraines, some of which include hormonal changes, stress, flashing lights, lack of sleep, caffeine containing substances and drugs such as the combined oral contraceptive pill. Triggers are specific for each person but identification of a trigger factor may help in the prevention of a migraine attack (Dodick, 2018).

There are four stages of a migraine and it will depend on the type of migraine the individual has which determines the stages they go through. The stages of a migraine attack can overlap and vary. The first stage is the premonitory phase, known as the ‘prodromal’ stage and this normally takes place 1 to 24 hours before the headache commences. Around 70% of people who have prodromal symptoms (tiredness, food cravings, changes in mood, stiff neck or thirst) can use them to correctly predict the onset of migraine. This could help with initiation of drug therapy for optimal results. The next stage is aura which is experienced by around a third of migraine sufferers and normally occurs before or during the headache stage. This is characterised by neurological symptoms and is not specific to migraine sufferers. The third stage of a migraine is the headache which is felt as a throbbing pain and during this stage, individuals may feel nauseous or experience other related symptoms. The final stage of a migraine is known as the postdrome phase which is where sufferers may be extremely tired for some days as the headache stage comes to an end (Poply, Bahra and Mehta, 2016).

There are various types of migraines and the 2 main types are ‘migraine without aura’ and ‘migraine with aura’. Others include ‘migraine with typical aura, migraine with brainstem aura, hemiplegic migraine, retinal migraine and chronic migraine’. Around 7 in 10 migraine sufferers experience migraine without aura where they go through a prodromal stage (several hours or days before the headache), headache stage (4 to 72 hours), resolution stage and postdrome stage. Approximately 30% of migraine sufferers have migraine with aura which can happen before or during the onset of headache. This group of individuals can get neurological symptoms of visual disturbances (most common) such as flashing lights. Sensory disturbances can also occur, for example, tingling sensations or vertigo and these symptoms can last from anywhere between a few minutes to 1 hour. Chronic migraine is defined as someone having a headache for 15 days or more in a month over a quarter of a year period and migraine symptoms are present on 8 of those days (HCC of the IHS The International Classification of Headache Disorders, 3rd edition, 2018).

Migraines are thought to be a complicated neurological disorder as opposed to just a vascular headache but the specific cause of migraine is not known. However, knowledge of migraine pathophysiology is progressing quickly. Newer studies may provide a more comprehensive understanding of causation and drug mechanisms involved in migraines  There are many factors which can play a part in migraines such as certain medications, genetics or hormonal imbalances. Mechanisms which are involved in migraines include stimulation of the hypothalamus, changes in the thalamo-cortical loop, stimulation of the brain stem, cortical spreading depolarisation and CGRP (calcitonin gene related peptide)  and PACAP release. Depending on the factor which played a part in the onset of migraine, will determine the likely symptoms that someone will experience during an attack. Alterations in certain parts of the nervous system (central and peripheral) will give rise to particular symptoms of migraine (Charles, 2018). The pain an individual experiences during the headache phase of migraine is due to the activation of the trigemino-vascular pathway by pain signals which derive from the peripheral intracranial nociceptors. Neurones converge in the trigemino-cervical complex and this results in the release of CGRP and PACAP which can be targets for antagonists or antibodies (e.g. CGRP antagonists). The release of CGRP is responsible for other symptoms involved in migraines, not just headache so could be a very effective treatment in the future (Ong, Wei and Goadsby, 2018). Furthermore, the cortex may be involved in symptoms relating to the aura stage of migraine. The mechanism involved is cortical spreading depolarisation (CSD) which is where there is spreading of an electrophysiological wave in the cortex followed by inhibition. The excitation and inhibition wave propagates across the visual cortex which explains why visual disturbances occur during a migraine attack. Even though CSD or aura may not be the cause of headache, it could be a useful pharmacological target for a certain group of patients. For this, a neuromodulatory system could be used so perhaps electrical stimulation to neural sites in the body using transcranial magnetic stimulation. The hypothalamus is involved in the control of endocrine and autonomic activity. When stimulated, it is associated with pain during the headache stage and prodromal symptoms. Peptides could be used to target the hypothalamus to treat migraine and potentially prevent migraine onset (Charles, 2018).

Currently, acute treatment for migraines consists of NSAIDs (Ibuprofen), triptans (sumatriptan, rizatriptan, zolmitriptan) and antiemetics (metoclopramide, domperidone or prochlorperazine). The idea is to take the medication as quickly as possible upon onset of migraine for maximum efficacy. Triptans are very selective for 5HT receptors and are available in various different formulations so there is greater choice but overall, the triptan class of drugs are not effective for all patients (e.g. migraine with aura). Beta-blockers (atenolol), TCAs (amitriptyline), CCBs (verapamil) and anticonvulsants (topiramate) are the standard treatments used for migraine prevention. (Dodick, 2018).

Knowledge of migraine pathophysiology has advanced which has led to the development of potential new and improved treatments. These treatments have the ability to increase efficacy and reduce the number of adverse events of current treatments. CGRP antagonists are showing great promise, CGRP is a peptide that is released during a migraine attack and so has a very important role in the pathophysiology of migraines. CGRP is responsible for vasodilatory effects and the pain that is felt during the headache stage due to the trigeminal circuits. Earlier trials of CGRP antagonists were found to have caused liver toxicity so trials were stopped. However, now there are 4 CGRP antibodies (erenumab, eptinezumab, galcanezumab and fremanezumab)  which have potential as there is evidence of effectiveness in acute migraine, preventive treatment and less migraine attacks. Furthermore, there are studies to support the fact that these drugs are well tolerated with no signs of liver toxicity so could become the best treatment available (Grimsrud and Halker Singh, 2018). Other emerging treatments include PACAP (pituitary adenylate cyclase-activating polypeptide) antagonists, Orexin receptor antagonists, Oxytocin, nitric oxide synthase inhibitors and glutamate receptor antagonists (Ong, Wei and Goadsby, 2018).

Aims and Objectives

The aim of this project is to evaluate the most suitable treatment for migraine, focusing on recent developments such as CGRP antagonists to see if they are better than the triptan class of drugs in terms of their efficacy, side effects and if they can be used for prophylaxis.

Objectives:

• Understand the pathophysiology of migraines
• Identify the current drugs used in the treatment of migraines and recent developments in alternative treatments
• Understand the pharmacology of CGRP antagonists, triptans and the alternative treatments for migraine
• To search for relevant literature on electronic databases in regards to CGRP antagonists, triptans and the alternative treatments for migraines

Method

Search strategy

I will carry out a systematic review of current literature to find out which recently developed treatment has the biggest potential for use in migraine therapy. I will find all the information I need from journal articles through online databases or books which are evidence based. There will be a wide variety of literature available and I will use a comprehensive search strategy to make sure that I get the most relevant information. I will use databases such as PubMed, science direct, web of science and Scopus to get accurate, peer reviewed and reliable data. A Boolean search strategy will allow me to combine words like ‘AND’, ‘OR’ and ‘NOT’ to get the most compelling results and eliminate irrelevant journals. Key words I will use include ‘migraine, headache, treatment, prophylaxis, therapeutic, medication, CGRP, recent developments’. This will help me to find specific journals which relate to my research question. Once I have entered my key words into the search bar, I can then filter results by choosing literature of a certain year, document type or author.

Inclusion/exclusion criteria

To make sure that the information I obtain is relevant to my project title, I will have a list of inclusion and exclusion criteria. My inclusion criteria will include journal articles which are up to a maximum of 10 years old so that information is up to date. Only articles which are published in English will be used so will exclude foreign articles. Studies can include participants from any geographical location. Studies involving humans will be used and studies involving animals will be excluded. Also, articles which involve adult participants will be used and articles involving children or elderly participants will be excluded.

Data Quality

I will use the JADAD scale to assess the quality of data. Randomised controlled trials and blinding means that there will be no bias and data will be of a high quality and thus more reliable (Clark et al., 1999).

Outcomes

Preliminary investigation suggests that meta-analysis may not be appropriate because the data might not be able to get combined. I will be carrying out a systematic review of current literature which should enable my research to be of high statistical power and allow me to draw conclusions from it. Depending on the data that I do gather, there might be potential to carry out a meta-analysis.

GANTT Chart

Bibliography

Charles, A. (2018). The pathophysiology of migraine: implications for clinical management. The Lancet Neurology, 17(2), pp.174-182.

Cause of migraine and mechanisms involved in migraines

Clark, H., Wells, G., Huët, C., McAlister, F., Salmi, L., Fergusson, D. and Laupacis, A. (1999). Assessing the Quality of Randomized Trials. Controlled Clinical Trials, 20(5), pp.448-452.

Quality of data

Dodick, D. (2018). Migraine. The Lancet, 391(10127), pp.1315-1330.

Trigger factors for migraines

Grimsrud, K. and Halker Singh, R. (2018). Emerging Treatments in Episodic Migraine. Current Pain and Headache Reports, 22(9).

Emerging treatments for migraine, mainly CGRP

Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. (2018). Cephalalgia, 38(1), pp.1-211.

The different types of migraines

nhs.uk. (2018). Migraine. [online] Available at: https://www.nhs.uk/conditions/migraine/ [Accessed 11 Nov. 2018].

Overview of migraines including symptoms and some key facts

Ong, J., Wei, D. and Goadsby, P. (2018). Recent Advances in Pharmacotherapy for Migraine Prevention: From Pathophysiology to New Drugs. Drugs, 78(4), pp.411-437.

The role of the trigemino-vascular pathway in migraines

Poply, K., Bahra, A. and Mehta, V. (2016). Migraine. BJA Education, 16(11), pp.357-361.

The stages of migraine