Migraine: pathophysiology, recognition and management

Introduction

Headache is a common symptom associated with many different clinical conditions. The International Classification of Headache Disorders (ICHD) categorises headache into primary or secondary headache disorders^​1​.

Primary headache disorders are not associated with another underlying condition. These headache disorders include migraine, tension-type headache, trigeminal autonomic cephalalgias (TACs) and ‘other’ (e.g. cough headache, primary stabbing headache, hypnic headache).

Secondary headache disorders are caused by another condition, such as trauma or injury to the head and/or neck, cranial or cervical vascular disorders, exposure to substances or substance withdrawal and infections^​1​.

Migraine is characterised by recurrent episodes of moderate-to-severe headaches. They are usually unilateral but often bilateral in location, frequently pulsating, and aggravated by movement^​1,2​. The symptoms most strongly associated with migraine headaches are nausea, disability (needing to stop any activity) and photophobia^​2,3​. However, patients can also suffer from a wide range of different symptoms, such as phonophobia, motion sensitivity, visual disturbances, cognitive symptoms, numbness or tingling, dizziness, difficulty speaking, and fatigue^{​1,2,4–9​}. While some symptoms can vary from person to person and even between different attacks, the cardinal features — as per the ICHD diagnostic criteria — remain the same^​10​.

Migraine has two major types: migraine without aura and migraine with aura. The term ‘aura’ refers to the transient focal neurological symptoms that usually precede or sometimes accompany the headache^​1​. Migraine can start at any age but usually appears in early adulthood^​11,12​. It is a spectrum condition with severity and frequency of attacks varying throughout life, but often showing an improvement with age^​13,14​.

Epidemiology

Migraine is the third most common health condition in the world, affecting approximately one in seven people globally^{​1,15,16​}. It is more common than diabetes, asthma and epilepsy combined^​17​. It is the second highest cause of global disability in the general population but takes first place in women aged 15–49 years^​18​.

In the UK, it is estimated that approximately 10 million adults are living with migraine, with it affecting 1 in 4 adults aged 15–69 years^​19​.

There is a big gender divide in migraine — it is two to three times more prevalent in women compared with men^​20​. It is estimated that 24% of women in the UK are living with migraine compared with 12% of men^​19​. Several factors are thought to contribute to the sex/gender disparity in migraine characteristics, including hormones, brain structure and function, and environmental aspects^{​21–23​}.

Burden of migraine

Migraine can have a major negative impact on people’s work, family, and social lives^{​2,19,24,25​}. Studies have shown that people living with migraine are more likely to have a variety of other long-term health conditions^​19,26​. Emotional and mental health issues are also more prevalent in this patient group, with depression over 2.5 times and anxiety 2–5 times more likely to be present^​2,24​.

Migraine also has a significant impact on the economy nationally, owing to its impact in the workplace, as well as direct healthcare costs. Approximately 2.5 million primary care appointments are linked to headaches and migraine per year; around 100,000 of which are referred to hospital for further assessment. The number of emergency hospital admissions for headaches and migraine attacks stood at 108,711 in 2018/2019^​27​.

It is estimated that migraine costs the UK economy between £6bn and £10bn per year, with indirect healthcare costs accounting for the majority of this^​28​. Migraine-related absenteeism and presenteeism (reduced work productivity owing to being unwell) is estimated to be responsible for up to 86 million equivalent workdays lost per year in the UK. This loss of productivity equates to a cost of just under £8.8bn per annum^​29​. Direct migraine-related healthcare costs are estimated to be up to £1bn per year^​29​.

It should be understood that migraine is not ‘just a bad headache’.

Pathophysiology

Migraine is a complex condition, and its mechanisms are not fully understood. For centuries, migraine was regarded as a vascular disorder owing to the throbbing nature of the pain^​30​; however, it is now thought to originate from the trigeminovascular system and subsequently involve multiple components of both the peripheral and central nervous systems, across all phases of an attack^{​31–35​} (see Figure 1^​36​).

Reproduced with permission from Dodick, D.W. A Phase‐by‐Phase Review of Migraine Pathophysiology, Headache, Volume: 58, Issue: S1, Pages: 4-16

Four phases of a migraine attack have been identified: prodrome, aura, headache, and postdrome (30) (see Figure 2^{​1,2,5,8,13,27,35–52​}). A range of cognitive and physical symptoms have been reported before, during and after an attack^​5​. It should be noted that not all migraine sufferers will experience every stage, nor all the symptoms of each stage, and that the stages can overlap^​37​.

Visual representations of migraine aura can be seen in Box 1.^​53​

Neuropeptides

CGRP is a pain-signalling neuropeptide and potent vasodilator that is expressed throughout both the peripheral and central nervous system^​54,55​. Activation of the trigeminal system results in the release of CGRP, which acts on vascular CGRP receptors to stimulate smooth muscle adenylyl cyclase, resulting in vasodilation^​54,56​(see Figure 3^​57​).

CGRP receptors are also expressed elsewhere in the body. Inadvertently blocking CGRP at these locations could explain some of the reported adverse effects. For example, CGRP helps promote gastric acid secretion and aid gut motility, as well as having a potential role in hair growth and preventing hair loss. Inhibiting the action of CGRP in this area could explain the mechanism behind the adverse effects of constipation and alopecia, respectively^​58,59​.

Levels of CGRP have been shown to be elevated in the plasma, saliva and tears of patients during migraine attacks^{​55,60,61​}. Migraine patients also have higher background levels of CGRP than people without migraine^{​62–64​}. Studies have demonstrated that when participants are given an infusion of CGRP they go on to develop a headache^​65,66​.

Adapted from Agostoni, et al

Triggers

Whilst the exact mechanism of what initiates a migraine attack is unknown, sufferers often report different factors that they believe can trigger an attack, or at least make one more likely to occur^​11,67​. Many possible triggers have been reported, including^​9​:

• Hormonal changes — menstruation;
• Emotional triggers — stress, anxiety, tension, shock, depression, excitement;
• Physical triggers — tiredness, poor-quality sleep, shift work, poor posture, neck or shoulder tension, jet lag, hypoglycaemia, strenuous exercise;
• Dietary triggers — missed/delayed/irregular meals, dehydration, alcohol, caffeine, chocolate, tyramine-containing food (e.g., cheese, yeast extract spread);
• Environmental triggers — bright lights, flickering screens, smoking, loud noises, changes in temp/humidity, strong smells;
• Medication — some sleeping tablets, combined contraceptive pill, HRT.

Sometimes it can be difficult to decide if something is a trigger or if what is being experienced (e.g. craving chocolate or cheese, feeling tired, etc) is simply a prodromal symptom of an attack already in progress^​35​.

Diagnosis

First launched in 1988, the International Classification of Headache Disorders (ICHD) lists the standardised diagnostic criteria for the different types of migraine (see Figure 4^​1​). While resulting in a significant improvement in diagnostic accuracy and clinical research, it can be difficult to use in a clinical setting.

A thorough history is essential to diagnosing migraine. In 2003, a study by Lipton et al. demonstrated that asking headache sufferers three primary questions about the characteristics of their headache was a reliable way of diagnosing a migraine (see Box 2)^​3​. The sensitivity and specificity of the questions were similar regardless of sex, age, the presence of other comorbid headaches, or previous diagnostic status.

Other characteristics of the migraine should also be noted and recorded, such as the pattern of the headaches, characteristics of the pain, any associated symptoms, presence of an aura, any associated triggers, family history, comorbidities, and medication and other treatments already tried^{​8,11,37,68​}.

Table 1 is a comparative table to distinguish between some different headache types. It is based on the ICHD-3 diagnostic criteria^​1,2,69​.

Episodic versus chronic migraine

Migraine can be further subcategorised into episodic migraine (EM) or chronic migraine (CM) based on the frequency of attacks (see Table 2^{​1,69,70​}). 

While a threshold of 15 headache days to differentiate between episodic and chronic migraine seems somewhat arbitrary, population studies have shown that patients with chronic migraine are significantly more disabled than those with episodic migraine^​70​.

An increase in the frequency of attacks, resulting in a progression from episodic to chronic migraine, is an example of chronification. Risk factors for chronification include female gender, increasing age, frequent episodic migraine attacks, medication overuse, high caffeine consumption and poor sleep, as well as comorbidities such as obesity, anxiety, depression and temporomandibular disorders^​71,72​.

Classifying a migraine as episodic or chronic is also important from a medication management perspective. Some migraine treatments are only licensed in episodic migraine and some are only licensed in chronic migraine^​73,74​.

While there is no minimum number of migraine days required for a diagnosis of episodic migraine, patients with episodic migraine must have a minimum of four migraine days/attacks per month to qualify for prophylactic treatment with current antimigraine therapies^{​73,75–78​}.

Headache monitoring/scoring

There are several monitoring or scoring systems that can be used to record and assess migraine and its impact. Some of the more common systems are the Headache Impact Test (HIT-6) and the Migraine Disability Assessment (MIDAS), which quantify headache-related disability^​79,80​. The Hospital Anxiety and Depression Scale (HADS) identifies depression and anxiety^​81​.

An important part of migraine management is keeping a headache diary to document the frequency, duration, and severity of the headaches, any associated symptoms, what medication was self-administered and any potential triggers^​9,69​. Headache diaries are an effective way of recording and identifying baseline headache patterns, as well as monitoring the effectiveness of an intervention. Historically paper-based, there are now several migraine tracking apps available (e.g. ‘Migraine Buddy’) that can make record-keeping easier and generate migraine-related analytics.

Referrals and red flags

The majority of headaches are primary headache disorders (e.g. migraine), but others are caused by another condition or disorder^​2​. Serious causes of secondary headaches are rare (<1% of headache presentations)^​82​.

Box 3 lists several red flags that suggest a potentially serious cause of secondary headache requiring emergency admission or urgent specialist referral^​2,83​.

Patients may have concerns about the likelihood of a serious cause for their headaches, such as a brain tumour. In the UK, approximately 1 in 7 people suffer from migraine, but the incidence of brain tumours is only 7 in 100,000^​84,85​.

The likelihood of a headache having a serious underlying cause varies depending on where the patient presents. Approximately 0.1% of headaches identified in primary care, 1.0% of headaches identified in neurology clinics and 10% of headaches identified in emergency departments have a serious underlying cause^{​85–87​}.

Treatments

The treatment of migraine is focused around three specific areas: 

1. Lifestyle management;
2. Acute treatment;
3. Prophylactic agents.

After the initial diagnosis of migraine is made, it is a good idea to try and manage patients’ expectations. While migraine cannot be cured, it can be effectively managed in most cases^​2​. 

Lifestyle management

The patient should be provided with information about their migraine to empower self-management^​2​. This could be from a variety of support organisations or other reliable sources, such as the Migraine Trust, the National Migraine Centre with its ‘Heads Up’ podcast and the British Association for the Study of Headache (BASH).

In addition to identifying and avoiding migraine triggers, a change in lifestyle is an important part of migraine prevention^{​69,88,89​}. A useful mnemonic for remembering the different areas of lifestyle management is ‘SEEDS’ (Sleep, Exercise, Eat, Diary and Stress)^​90​:

• Sleep — good sleep hygiene, avoid too much or too little sleep;
• Exercise — regular exercise, at least 30 minutes three times a week;
• Eat — regular healthy meals, adequate hydration, low or stable caffeine intake;
• Diary — record frequency, duration, and severity of headaches;
• Stress — conflict avoidance, cognitive behavioural therapy, mindfulness, relaxation.

Acute treatment options

Clinicians can prescribe acute treatments in a stepped or stratified approach. In a stepped approach, treatment is slowly and only escalated after the first-line medicines have failed (i.e. simple analgesics prescribed initially, then escalated to include a triptan). With a stratified approach, the initial treatment is tailored to the severity of an attack^​2,91​. 

The first-line treatment options for a migraine attack are simple analgesics, triptans and anti-emetics. Domperidone, metoclopramide and prochlorperazine are the preferred anti-emetics owing to their multiple effects. In addition to treating the nausea and vomiting commonly associated with migraine, they also improve drug absorption by increasing gut motility, which counteracts the migraine-associated gastric stasis^{​2,92–94​}.

Medication overuse headache (MOH) is a secondary headache that can develop as a consequence of using simple analgesics (e.g. aspirin, NSAIDs, paracetamol) for ≥15 days per month, or using triptans, opioids, ergots or combination analgesic medications for ≥10 days per month^{​1,69,92​}. As a result, it is recommended that simple analgesics are limited to <15 days per month and triptans to <10 days per month^​2​. 

Opiates and compound analgesics should never be prescribed for treating a migraine attack owing to the significant risk of causing MOH and problems with dependency formation and withdrawal^​2,69​. Attention should be paid to the contents of over-the-counter preparations that are marketed for migraine as they may contain codeine^​93​. 

Going ‘cold turkey’ and stopping all overused acute headache medication for at least one month can help to resolve the MOH by itself^​1,69​, but other strategies can include starting regular prophylactic medication or offering short-term bridging treatments (e.g. nerve blocks or oral corticosteroids)^{​95–97​}. 

See Table 3 for BASH recommended acute treatment options for simple analgesics^​2​.

The Medicines and Healthcare products Regulatory Agency (MHRA) has released drug safety updates for both domperidone and metoclopramide. Domperidone is contraindicated in cardiac disease and the maximum treatment duration should not usually exceed one week^​98​. Metoclopramide should only be prescribed short-term use (up to five days) owing to the risk of neurological effects^​99​.

Abortive agents

See Table 4 for some abortive agents for migraine^{​2,100,101​}.

Triptans

Alongside simple analgesics, triptans are recommended treatment options for migraine attacks^​2​. There are seven triptans licensed for migraine in England (sumatriptan, rizatriptan, zolmitriptan, eletriptan, almotriptan, naratriptan, and frovatriptan), with sumatriptan recommended as the first-line option by NICE^​92​. 

It should be noted that if a migraine attack is not responding to the initial dose of a triptan, a second dose should not be taken for the same attack^​100​. If the triptan has not been effective within two hours, then it is unlikely to work during that attack; therefore, considering an alternative treatment option might be appropriate^​2​.

If sumatriptan has been ineffective at managing a patient’s attack, the choice of which triptan to prescribe next should be guided by which feature is most important. When compared to sumatriptan 100mg, some of the newer triptans report lower adverse events (naratriptan 2.5mg, almotriptan 12.5mg, and frovatriptan 2.5mg), a better two-hour pain response (eletriptan 80mg, rizatriptan 10mg, and almotriptan 12.5mg), or a lower recurrence rate (frovatriptan 2.5mg and eletriptan 40mg and 80mg)^​2,102​.

Triptans work by selectively binding to the serotonin receptors 5-HT_1B/D/F, inhibiting the release of neuropeptides, and acting as vasoconstrictors in extracerebral arteries^{​103–105​} (see Figure 5^​56​). 

Owing to the vasoconstrictive action of triptans, they are contraindicated in ischaemic heart disease, cerebrovascular disease, previous myocardial infarction, and uncontrolled or severe hypertension^​2​. Triptans are also unlicensed for people aged over 65 years because most of the trials excluded patients over 65 years^{​100,106​}. While studies have shown that triptans do not directly increase vascular risk, they should be used with caution in older people (individuals aged over 50 years) owing to the increasing cardiovascular risk in this age group^{​107,108​}.

Approximately 30% of patients do not respond to the triptan they are initially prescribed^​109​. Owing to this, alternative triptans should be tried, as a lack of response to one triptan does not predict non-response to another^​2​. A triptan should be trialled in at least three different attacks before being considered ineffective. A patient is deemed triptan-resistant if they are non-responsive to at least two triptans, and triptan refractory if they fail at least three triptans, including a subcutaneous formulation^​110​.

Gepants

Small molecule CGRP receptor antagonists (‘gepants’) are part of the new class of migraine treatments that target CGRP. Unlike triptans, which directly cause vasoconstriction, gepants bind to the CGRP receptor, preventing the cascade that results in vasodilation and the subsequent headache pain. Only rimegepant is currently approved for use in England as an acute agent.

Rimegepant is an oral lyophilisate that should be placed on the tongue and allowed to dissolve. It reaches maximum concentration 1.5 hours after administration. While the side-effect profile is minimal, with only nausea and hypersensitivity listed, all suspected adverse reactions must be reported as it is still under the MHRA Black Triangle scheme.

No dose adjustments are required in renal impairment, but it should be avoided in end-stage renal disease owing to a lack of data. It should also be avoided in severe hepatic impairment (Child-Pugh score C)^​101​.

Rimegepant undergoes liver metabolism by CYP3A4 and CYP2C9, and it is also a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters. As a result, it has drug interactions with several moderate or strong inhibitors or inducers of these pathways, such as macrolide antibiotics, ‘azole’ antifungals, protease inhibitors, carbamazepine, diltiazem and rifampicin^{​101,111​}.

Rimegepant has a licence for both acute usage and as prophylaxis in episodic migraine. As per NICE TA919, rimegepant is recommended as an option for the acute treatment of migraine, with or without aura in adults, only if for previous migraine attacks^​112​:

• At least two triptans were tried and they did not work well enough; or
• Triptans were contraindicated or not tolerated, and non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol were tried but did not work well enough.

The recommended dose of rimegepant is 75mg as needed (maximum 75mg per day)^​101​. It would be advisable to monitor usage and, if the patient needs more than four doses per month, they should be considered for prophylactic treatment. 

Contrary to triptans and NSAIDs, frequent use of gepants does not appear to cause MOH^​113​.

Unlike the triptans, rimegepant is not contraindicated in patients who have had a myocardial infarction or stroke; however, the evidence regarding the safety of gepants after a stroke is not clear cut. While there is no evidence that gepants have direct vasoconstrictive effects^​114​, they do prevent the CGRP-induced dilation of extracerebral arteries, which has the potential to cause a variety of cardiovascular pathophysiologies^{​104,115​}. Furthermore, the main rimegepant clinical trials excluded patients who reported a cardiovascular event (such as a stroke or myocardial infarction) within the past six months^{​114,116,117​}. Therefore, it would be prudent to avoid using rimegepant in the initial period following a stroke or myocardial infarction.

Medical devices

Alongside systemic treatment options, there are a range of medical devices available that may be beneficial in treating and/or preventing migraine symptoms^​118​.

The Cefaly device is an external trigeminal nerve stimulator (e-TNS). It connects to an adhesive electrode that is placed on the forehead and generates micro-impulses to stimulate the trigeminal nerve and produce a sedative effect^​119​. The treatment has been reviewed by NICE, which raised no major safety concerns, but stated that the evidence of effectiveness is limited for acute use and inadequate for prophylactic use^​120​.

The sTMS mini device is a single pulse transcranial magnetic stimulator (sTMS). The device is placed against the back of the head and delivers a brief pre-set magnetic pulse. The pulse depolarises neurons in the brain, inhibiting cortical spreading depression, helping to treat a migraine attack^{​118,121​}. NICE has recommended that transcranial magnetic stimulators should only be used under the care of a headache specialist, owing to a lack of evidence of efficacy, as well as uncertainty about the safety of long-term or frequent use^​122​.

Prophylactic treatment options

Preventative treatment should be considered if a patient suffers from four or more migraine attacks per month, or if their migraine is having a significant impact on their quality of life^​2,92​. The choice of prophylactic agent is patient specific. It is based on the side-effect profile and the patient’s pre-existing comorbidities. The medication is titrated slowly to effect, or to the highest tolerated dose^​2​. Treatment is considered ineffective if there has been an inadequate response to the highest tolerated dose after two to three months of treatment^​92,123​.

Table 5 provides some recommended pharmacological therapies that may be prescribed for migraine prophylaxis^​69,124​. The doses recommended by BASH are normally higher than what is listed in the British National Formulary (BNF)^​2,92​.

Some recommended non-pharmacological options include behavioural interventions (e.g. relaxation techniques or cognitive behavioural therapy), acupuncture or riboflavin 400mg daily^{​2,69,125​}.

Other preventative options for which there is evidence include: lisinopril, sodium valproate, other Beta blockers (metoprolol, nadolol, timolol, and atenolol), flunarizine (not licensed in the UK), and oral supplements (co-enzyme Q10 and magnesium)^​2​. 

After a patient has tried and failed at least three of the standard preventative treatment options, they may be able to access more advanced migraine therapies either through their GP, secondary care or a headache specialist centre (see Table 6^{​73–75,78,126–130​}).

CGRP monoclonal antibodies

Like the Gepants, the ‘anti-CGRPs’ or CGRP monoclonal antibodies (mAbs) are migraine-specific treatments that work by targeting CGRP. There are four anti-CGRPs currently available in the UK and, while they are broadly similar, they do have some interesting idiosyncrasies.

Erenumab (Aimovig; Novartis) targets the CGRP receptor, blocking CGRP from binding and preventing its action (125). Conversely, fremanezumab (Ajovy; Teva), galcanezumab (Emgality; Eli Lilly), and eptinezumab (Vyepti; H. Lundbeck) bind to the CGRP ligand itself^{​127–129​} (see Figure 5^​56​).

While there have not been any direct head-to-head studies comparing the effectiveness of different anti-CGRPs, two meta-analyses have suggested that fremanezumab is the most effective^{​131,132​}; however, the studies disagree on whether this is statistically significant.

The anti-CGRPs have all received NICE approval for use in both episodic and chronic migraine. They are approved for use in patients only if^{​75–78​}:

• They have four or more migraine days per month;
• They have tried and failed at least three preventative agents;
• The medication is provided as per the commercial agreement; 
• For erenumab specifically, only the 140mg dose should be used.

NICE has mandated stopping criteria. After 12 weeks of treatment, patients with episodic migraine must show a ≥50% reduction in the number of headache days, and patients with chronic migraine must demonstrate a ≥30% reduction^{​75–78​}. It is good practice to review the ongoing response to treatment regularly to ensure continued benefit.

Erenumab, fremanezumab and galcanezumab are all subcutaneous injections. They are normally administered once a month, although fremanezumab can be administered three-monthly when using the higher dose^{​126–128​}. They are ideal products to be supplied via a homecare service, as they can easily be self-administered by patients in their own homes. Eptinezumab is given by intravenous infusion every three months^​129​, which usually requires it to be administered in a hospital setting. As administration is only required four times per year, it means that hospital attendance for the infusion should be minimal. Another advantage is that the quarterly dosing may be beneficial in patients who struggle with treatment compliance. 

A consideration that should be made when prescribing for women of childbearing age is whether there are any plans to become pregnant. Owing to a lack of data for the anti-CGRPs and gepants in pregnancy, a washout period should be recommended before planning a pregnancy. The washout period of the mAbs would be much longer than the gepants, owing to their significantly longer half-lives, which is approximately 1 month versus 11 hours, respectively^{​101,126–129,133​}. 

As with all medication, there will be cohorts of patients who do not respond to treatment. Unfortunately, there is currently no official guidance on whether a patient who fails one anti-CGRP can be switched to another^​125​. However, some real-world studies have shown that patients who do not respond to a CGRP-receptor mAb (e.g. erenumab) may benefit from switching to a CGRP-ligand mAb (e.g. fremanezumab or galcanezumab,) and vice-versa^{​134–137​}. 

Switching between anti-CGRP mAbs is sometimes required owing to adverse effects. Most of the reported adverse effects for the anti-CGRPs include upper respiratory tract infection, nausea, constipation, injection site reactions and fatigue^​138​. However, while the SmPC for erenumab lists an incidence rate of 3.2% for constipation as an adverse effect, real-world evidence has shown the actual incidence rate to be as high as 65%^{​139,140​}. As a result, there should be a risk versus benefit discussion prior to initiating erenumab in patients with a history of constipation or other gastrointestinal motility issue.

Both erenumab devices contain natural rubber latex, which may cause severe allergic reactions, so should be avoided in patients with a latex allergy^​126​. Neither the fremanezumab, galcanezumab or eptinezumab products contain latex^{​127–129​}.

Gepants

As with the anti-CGRPs above, patients will normally need to have tried and failed several prophylactic agents before being able to try a gepant. Two gepants are currently licensed in England — rimegepant and atogepant — both of which are administered orally.

Rimegepant

Alongside its acute usage, rimegepant is also licensed for prophylaxis in episodic migraine. As per NICE TA906, rimegepant is recommended for preventing episodic migraine in adults who have 4–15 migraine attacks per month, only if at least three preventative treatments have failed^​73​. Patients must be reviewed after 12 weeks of treatment and treatment stopped if the number of migraine attacks has not reduced by ≥50%. The recommended dose is 75mg on alternate days^​101​.

Atogepant

As per NICE TA973, atogepant has been recommended for the prophylaxis of migraine in adults who have at least four migraine days per month and only if at least three preventative treatments have not worked. This means it can be prescribed for patients with both episodic and chronic migraine. Patients should be reviewed after 12 weeks of treatment and atogepant discontinued if the frequency of migraine attacks does not reduce by at least 50% for episodic migraine, or at least 30% for chronic migraine^​130​.

Atogepant is a tablet that reaches maximum concentration within one to two hours after administration. The side-effect profile is minimal, with only nausea, constipation, decreased appetite and weight, and fatigue commonly reported. Increases in aspartate transaminase and alanine transaminase were uncommon^​133​. 

The recommended dose of atogepant is 60mg once daily. Atogepant is metabolised by the liver, primarily by CYP3A4, and it is also a substrate of several transporters, including P-gp, BCRP, OATP1B1, OATP1B3 and OAT1. As a result, the dose should be reduced to 10mg once daily with concurrent use of strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin), strong OATP inhibitors (e.g. rifampicin, ciclosporin, telmisartan), or in poor renal function (creatinine clearance <30mL/minute). Atogepant should be avoided in severe hepatic impairment^{​133,141​}.

In a similar fashion to rimegepant, both pivotal studies that investigated the effectiveness of atogepant in preventing migraine attacks excluded patients who had a myocardial infarction, stroke or transient ischemic attack within the previous six months^{​142,143​}.

OnabotulinumtoxinA (Botox)

Originally derived from the bacterium Clostridium botulinum, OnabotulinumtoxinA is a neurotoxin complex that causes localised paralysis by blocking the release of acetylcholine at the neuromuscular junction^​144​. It is thought to work in chronic migraine by blocking the release of vesicles that contain pro-inflammatory and excitatory neuropeptides and neurotransmitters that are involved in migraine, such as substance P, CGRP, PACAP (pituitary adenylate cyclase-activating polypeptide), glutamate and amylin^​145​.

Several brands of OnabotulinumtoxinA are available; however, only Botox is licensed to treat chronic migraine. Botulinum toxin units are not interchangeable from one product to another^{​144,146–152​}. Botox has undergone a NICE technology appraisal and is recommended as an option for the prophylaxis of chronic migraine when patients have not responded to at least three prophylactic agents and medication overuse headache has been effectively managed. Treatment should be stopped if patients do not demonstrate a ≥30% reduction in headache days after two cycles, or if they revert to episodic migraine for three consecutive months^​74​.

Botox is not licensed for episodic migraine as the initial trials showed no statistically significant improvement in the number of migraine days between treated and placebo groups^{​153,154​}.

To treat chronic migraine, a total dose of 155–195 units of Botox is administered intramuscularly across 31–39 sites around the head and back of the neck, with a recommended re-treatment schedule of every 12 weeks^{​144,155​}. The Botox injections are reasonably well tolerated. Side effects are minimal and include temporary neck pain, headache, muscle weakness and ptosis (eyelid droop)^​156​. The ptosis is reversible and normally wears off over time.

Several studies have reported that using a combination of Botox, alongside an anti-CGRP, enhances the overall efficacy and results in a further reduction in the number of headache days, compared with using either as a single agent^​157​. However, in both 2019 and 2022, the European Headache Federation could not recommend this practice owing to a lack of data^{​158,159​}. 

Peripheral nerve blocks

Other injectable treatments that may be offered by a specialist clinic include a variety of peripheral nerve blocks. These involve injecting a local anaesthetic, with or without steroid, to specific nerves around the head^​156​. If a steroid-containing formulation is used, there is the risk of scarring and hair loss at the injection site, although this is rare^​160​.

Conclusion

Migraine is a source of significant morbidity for patients, and there is a need for an individualised and holistic approach to management of the condition. Pharmacists across sectors can support this patient group by recognising the symptoms of migraine, understanding how it can be distinguished from other headaches types and being aware of the approved treatment options, including the latest developments.