The treatment – migraine
Neurology specialist Dr Giles Elrington takes you through the treatment options for migraine.
Most disabling headache is migraine, and attacks can occur without head pain. Typically seen as an episodic disorder, it is better understood as attacks with abnormalities present in between, which can become chronic. People with migraine are relatively light and noise intolerant between attacks, and are more than normally subject to non-migraine pain. Migraine is a neural disorder, reflecting abnormal gain of brainstem pathways (perception of head, vision, hearing, smell, balance, gut) and, in migraine aura, spreading depression of the cerebral cortical activity towards the back of the brain.
Migraine is diagnosed on clinical grounds, from history, with normal neurological examination between attacks.
The definition of migraine headache requires attacks lasting four to 72 hours, with nausea or vomiting, or light and noise sensitivity, plus two of the following:1
- Moderate or severe pain.
- Pulsing or thumping pain.
- Lateralised pain.
- Pain worse with activity.
Migraine does not require an aura, and associated features may need probing.
Attacks may begin with a prodrome – typically mood change, confectionery craving or yawning – hours before the full attack. Up to one third of patients experience aura, typically but not exclusively visual, usually lasting 15-60 minutes, often before head pain. Aura can occur without headache, when the differential from transient ischaemic attack (TIA) is achieved by migraine aura taking seconds or minutes to evolve (TIA is maximal at onset). Aura brings positive visual symptoms, TIA causes loss of vision.
Current therapeutic advances have shown that frequent acute treatment paradoxically worsens migraine, triptans are very effective for migraine headache, and botulinum toxin is effective for chronic migraine.
Standard current treatment
A triptan is taken soon after pain onset, with seven triptan drugs available. The goal is to be pain free two hours post-dose, with no recurrence thereafter, in 90% of attacks. Each triptan dose and route of administration should be tried in three separate attacks, because as triptan response is stereotypic during an attack, not all attacks respond the same. A separate attack is one preceded by two pain-free days.
- Sumatriptan – familiar, available at 50mg or 100mg doses, 10% respond better to 100mg.
- Naratriptan – 2.5mg. Few side-effects, less potent.
- Zolmitriptan – 2.5mg or 5mg. Largely similar to sumatriptan but some patients find it better.
- Rizatriptan – 10mg.
- Eletriptan – 20mg, 40mg and 80mg doses. The top dose is most potent oral triptan, but higher risk of triptan side-effects such as nausea, chest and throat tingling, rarely dysphoria.
- Almotriptan – 12.5mg. Highly-effective, notably well-tolerated.
- Frovatiptan – 2.5mg. Long half-life, just over a day (the others have maximum half-life of six hours). Can take up to four hours to work.
Which triptan preparation?
All triptans are available as tablets to be swallowed with water.
Orodispersible preparations – sumatriptan, zolmitriptan and rizatriptan. These are swallowed with saliva and as such have no absorption speed advantage but are convenient to take.
Nasal sprays – sumatriptan and zolmitriptan. Sumatriptan 10mg nasal spray is the only licensed triptan for children. The taste is unpleasant to many patients. There is an opinion that nasal zolmitriptan may be better absorbed through the nose, whereas nasal sumatriptan is absorbed through the gut, so nasal zolmitriptan may have a speed of benefit advantage in some patients.
Sumatriptan is the only injectable triptan at a 6mg dose, which provides the most rapidly-effective rescue and is suitable for patients who vomit early in their attack.
Generic or branded triptan?
Sumatriptan, zolmitriptan, naratriptan and rizatriptan are available as generics. Some patients report reduced benefit with generics, although there is no evidence to support that viewpoint. Generic injectable sumatriptan is not a lot cheaper than branded.
Alternatives to triptans
Alternatives include aspirin 900 to 1200mg, or NSAIDs such as ibuprofen 600mg or naproxen 250 to 500mg. A soluble preparation can augment rapid absorption. Paracetamol is typically disappointing in migraine.
A pro-kinetic anti-emetic such as domperidone, with a maximum dosage of 30mg daily, palliates gastric stasis nausea and can speed the absorption of oral medication. Rectal domperidone is potentially useful but has been hard to obtain recently.
Steroids can abort acute migraine, perhaps prednisolone 60mg or dexamethasone 4 to 8mg. However, this is unlicensed opinion, not evidence-based.
Timing of rescue treatment
There is a ‘sweet spot’ for optimal response. Triptans should be reserved until the onset of head pain, as if they are taken in anticipation of head pain, they can often be ineffective. At that early phase of migraine, aspirin or NSAIDs plus domperidone 10-20mg can be helpful. Concurrent triptan, plus aspirin or NSAID, possibly also domperidone, can benefit greater than the sum of the parts. Treat early, hit the migraine hard at the start, if possible with one dose, perhaps with two to three drugs.
Recurrence of migraine following initial response
This affects up to one third of patients and normally responds to a repeat dose of whatever worked initially, subject to maximal daily dose limits. It is futile to repeat a treatment that has been ineffective earlier in the same attack.
When attacks recur frequently over a few or more days, for example, when migraine is triggered by menstruation, a short course of regular naproxen 250mg or 375mg to cover the anticipated duration of the bout can be effective and reduce the risk of medication overuse.
Suboptimal therapy with acute treatment alone should consider a daily treatment to diminish migraine impact. The target is a 50% reduction of attack frequency. It is helpful to keep a diary to note the attack frequency for sufficiently long to avoid sampling errors before starting prophylaxis. No absolute attack frequency indicates prophylaxis, as monthly disabling rescue-unresponsive attacks may need prophylaxis while once or twice weekly responsive attacks may not.
This is a ‘slow burn’ therapy. Three months is normally the minimum treatment, as any less can mean the risks of treatment may overlook any benefits. Responders often choose six to 12 months of treatment, exceptionally a few years. It is not life-long. Dose titration is slow and comes in two phases, the first for tolerability, the second for benefit. Insufficient duration, over-rapid or sub-maximal dose titration are common causes of failure.
Anti-epilepsy drugs, particularly topiramate, are probably the most effective among the commonly-used prophylactics. This drug is described in detail as an example. Side-effects can be troublesome (dysphoria, psychiatric change, tingling digits, weight loss, less commonly kidney stones and, exceptionally, acute glaucoma). It may perhaps be best to start the patient with topiramate 25mg, and increase the dosage weekly to 50mg twice daily. I prefer a fortnightly increase and can begin with half a 25mg tablet or a part of the 15mg sprinkle capsule. So, a typical regime might be six weeks dose escalation, followed by six weeks at 50mg twice daily.
If the patient is seeing insufficient benefits and is showing an adequate tolerance, it is acceptable to step up the dosage by 25mg fortnightly to 100mg twice daily for a further six weeks, before possibly moving similarly to 150mg and eventually 200mg twice daily. This can be abandoned after six weeks if disappointing, perhaps reducing the dosage in 50mg weekly decrements to zero, with many months of treatment at the minimum effective dose if there is a good outcome.
Beta blockers are widely used in primary care. Propranolol is licensed and commonly used, but as metabolism is variable it is hard to find the right dose. Atenolol is unlicensed but seems to work well, is easy to titrate (25mg – 50mg – 100mg) and has no interaction with rizatriptan. Other blood pressure drugs such as candesartan and amlodipine may be finding a place as unlicensed migraine prophylactics.
Antidepressants such as tricyclics or SNRIs – though unlicensed – are widely used. SSRIs are of little or no benefit – data sheet caution for SSRI and triptans potentially causing a serotoninergic syndrome is being overcautious. Migraine and mood disorder are comorbid, but mood disorder is not required for antidepressant efficacy in migraine.
Counselling is also important. Low serotonin at the back of the brain causes migraine, while the same chemical change at the front of the brain causes mood disorder. A tolerance of tricyclic side-effects is achieved through slow titration, for example, starting amitriptyline at 10mg and adding 10mg every week, up to 50mg or whatever lower dose proves beneficial. Consider a tablet cutter to start and step in 5mg increments, or even a liquid preparation to start and step at least initially in 1mg increments. Take amitriptyline 10 to 12 hours before planning to get up, to reduce sedation.
The evidence base is for one prophylactic drug at a time. Combinations may be considered where there is partial response to individual prophylactics. It is important, however, to avoid polypharmacy which brings increased risk of side-effects.
Nutraceuticals are popular with patients. Vitamin B2 at the very large daily dose of 400mg after breakfast is evidence-based and NICE-endorsed, while co-enzyme Q10, magnesium, feverfew and butterbur are not.
What’s newly available?
Botulinum toxin has revolutionised treatment of chronic migraine,3 that is, three or more months of head pain on at least 15 days a month, of which eight days have migrainous symptoms. The other seven or more days can be a featureless, non-disabling-tension-type headache. The key question is the number of crystal clear pain-free days the patient enjoys. In the pivotal trial, the magnitude of benefit on headache days was modest. However, the improvement in quality-of-life was impressive, resulting in NICE approval.
The NHS restricts botulinum toxin to people aged 18 to 65 suffering from chronic migraine, who have failed three prophylactics and addressed medication overuse. After two cycles of treatment, three months apart, treatment is stopped if pain is reduced to less than 15 days a month, or there is a less-than 30% reduction in the monthly number of pain days. An accurate and complete diary of all headaches is needed. Stop criteria mean that a person with 15- to 21-monthly pain days pre-treatment cannot stay on NHS botulinum toxin beyond two cycles of treatment. The product licence is less restrictive than NICE guidance, so self-funding chronic migraine patients have greater flexibility then NHS patients.
Medication overuse headache (MOH)
Assume that chronic headache is MOH, until proved otherwise. Usually, combination analgesics should be taken at least 10 days per month, with the threshold being the same for triptans, opiates and combinations. The NICE recommendation for MOH is simply to abandon the overused medications, preferably abruptly, but phased out over time if necessary. This is usually achieved as an outpatient, planned alongside family support and with a couple of week’s sick leave. It is unclear whether the addition of a prophylactic or bridging with regular naproxen offers additional benefit to plain simple medication cessation. Relapse is common and needs to be watched for.
There is a range of opinion on whether analgesics used for non-headache indication can trigger MOH, and the International Headache Society’s guidance is that they do so. MOH appears to be a specific complication of migraine, and not of other types of head pain. Two months following the last dose of formerly overused medication, recovery attributable to the overuse of medication is complete, with other treatments considered at this time.
Persistent dizziness and vertigo is often migrainous, often requiring both vestibular rehabilitation (not vestibular sedatives) and migraine prophylaxis.
What has fallen out of fashion and why
Migraine is not a disorder of the mind, the cerebral blood vessels, the neck and spine, the immune system, or the heart.
Elimination diets have no place in the management of migraine, as they are not caused by either food allergy or food intolerance. People with migraine may consume chocolate, cheese, citrus fruits, dairy products and processed meats, all in moderation. Regular high caffeine intake may worsen migraines, so many experts would limit sufferers to two cups of normal strength coffee or cola a day.
The ‘analgesic ladder’, such as paracetamol – NSAID – opiate, is not appropriate for migraine, as it tends to lead to MOH. Do not use opiates as they are of little benefit, worsen nausea and gastric stasis, and lead to tolerance dependence and MOH.
Some prophylactics have fallen out of favour, with clonidine and cyproheptadine being ineffective. Pizotifen is widely used despite an unconvincing evidence base, with most UK experts regarding it as useful in children and teenagers – if sedation and weight gain are tolerated – but of little value in adults. Methysergide has been withdrawn because of adverse side-effects, frustrating many migraine experts and patients.
Patent foramen ovale (PFO) is more common in people with migraine aura, and anecdote suggested PFO closure is useful but a clinical trial was negative. PFO detection and closure has no part in the management of migraine.
Special/atypical cases and their treatment/tailored treatment
‘Atypical migraine’ is not an evidence-based diagnosis.
There is no evidence base for treating migraine aura other than it is known to not respond to triptans. Aspirin or NSAIDs may abort aura, and migraine headache prophylaxis may be used for frequent aura without headache.
The oestrogen drop at menstruation is a common trigger of migraine without aura. This can be addressed by suppressing the menstrual cycle with daily desogestrel, tricycling the contraceptive pill (which is contraindicated by migraine aura), or possibly with a hormonal IUD. Perimenstrual bridging with regular naproxen can help menstrual migraine. Hysterectomy is never the right treatment for migraine. The menopause has no specific migraine impact, other than to terminate pure menstrual migraine. Women with migraine may safely use HRT, and this includes women with migraine aura, as HRT – unlike the contraceptive pill – does not induce fibrinogen and bring thrombotic risk. High oestrogen levels can worsen aura. A smooth, unchanging oestrogen level may be better achieved with a patch rather than with a tablet.
Non-drug options and their evidence base
Physical treatments are of speculative value only, probably addressing the musculoskeletal consequence of migraine pain and tending to offer only transient relief from muscle spasm in the scalp, face, and neck.
Acupuncture is better than ‘sham’ acupuncture and needs to be given once or twice a week for several weeks, so is more expensive in patient and therapist time.
Lifestyle hygiene is important in migraine management and moves focus of control from the external to the internal. The goal is a regular and unchanging biorhythm. Time of going to bed, and getting up, should be relatively constant. Meals should be little and often, certainly consisting of breakfast, lunch, and an evening meal, with breakfast taken before commuting or school run, or within an hour of arising if not leaving the house. It should be fibre-based to maintain a smooth blood sugar profile through the day, with those out of the breakfast habit starting with a small dose. Adequate hydration seems important, and the goal is to drink two litres of water a day.
Many believe stress triggers migraine. Certainly the letdown from stress like at weekends can trigger migraine, although the body clock is also relevant here. There is no evidence that stress management helps migraine. Migraine prodrome includes mood change, which can be mistaken for stress causing migraine.
Vigorous unaccustomed exercise can appear to trigger migraine, and the solution is to gradually build tolerance. It is better for migraineurs to jog a mile a day, the same time every day, than to jog seven miles once a week.
Finally, there are a number of medical devices available that allegedly treat migraine. Marketing a medical device requires less evidence than marketing a drug. All that is required is a CE mark, which means the device is medically safe and ‘does what it says on the tin’. These migraine relief devices typically deliver an electrical or magnetic stimulus to the brain, cranial or cervical nerves. The majority with a stimulus or effect that the patient can perceive are difficult to test in a blinded trial. These devices are, however, safe. Three are now available for patient purchase or hire. At a highly specialist level, surgically-implanted devices, typically nerve stimulators – which actually partially block neural activity – are increasingly used at substantial expense in very carefully selected and monitored patients. The evidence base is imperfect, but this is probably because patients in clinical trials are treated so late in the disease that chronicity is established. Expect to see a growth in migraine device use, both internal and external, over the next few years.
Dr Giles Elrington is a consultant neurologist at Barts Health NHS Trust
1. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia, 2013;33;9;629–808
2. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet, 2001;358(9294);1668-75
Dodick DW, Turkel CC, DeGryse RE, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache, 2010;50;921-936