Migraine

What are the Symptoms?

Migraine is the second commonest form of headache after tension-type headache.  It is more common in women than men, with around 5% to 15% of women having the condition and up to around 5% of men. Although it can come on at any age, it most commonly comes on in either teenage or young adult years but can also come on in childhood. It is possible to get migraine for the first time in middle age onwards, but under such circumstances one might look for underlying conditions.

This headache is clearly one of the key symptoms of migraine but as I will come to later, there are occasional patients who have migraine without headache. One specific feature of migraine headache is that it is typically one-sided and the word “migraine” comes from the Greek meaning “half a head”. Individual attacks tend to be on one side, but many patients have attacks sometimes on one side of the head and others on the other side. It may even swap sides during an attack. Sometimes, patients notice that, for example, left-sided headaches have one particular pattern of symptoms in them and right-sided headaches have a different pattern. It is still possible, however, for migraine headache to be on both sides.

The headache is typically pulsatile or banging. That means that there is a beat type increase in the intensity of pain often in time to the patient’s heartbeat. The pain is usually worse with movement and hence patients prefer to lie still. The typical duration of headache is around 4 to 72 hours but patients can get shorter or longer attacks.

It is usual for other symptoms to accompany the headache.

Before the headache, some patients get characteristic symptoms indicating that parts of the brain are working differently from usual. The commonest is a disturbance of vision and, rather than the loss of vision, patients often get lined patterns and colours or shapes that often start at the edge of vision and slowly grow and move towards the centre. Other patterns include tunnel vision and bright lights. Other symptoms suggestive of altered brain function include difficulty with speech, tingling or numbness in an arm or leg. Paralysis can occur but is very rare. These “brain symptoms” are referred to as “aura” and only around one third to one quarter of migraine patients experience these types of symptoms. The typical duration of aura is less than 20 min. The very first time that patients get such symptoms they may feel that they are having a stroke and often go to hospital. Even though there is a wide range of symptoms that can be part of aura, individual patients often get fairly similar episodes and they get to know the symptoms.

Nausea is quite common during migraine and some patients vomit. Clearly this is a problem with taking oral medication. However, it is also known that even in a patient who is not vomiting, in migraine the stomach stops emptying, so even if you do manage to swallow medication and keep it down, it may stay in the stomach and not get absorbed as it does not reach the intestine where drugs are absorbed. This has been particularly shown for paracetamol and may be one reason why the drug may not work as well in migraine patients.

Patients may experience unusual sensitivity to light, sound, or even smells. This is why typically, migraine patients prefer to lie quietly in a darkened room.

There are other symptoms that can be associated with migraine. Even though the aura lasts about 20 minutes before the attack, some patients may get up to a half a day or so of characteristic disturbance; often of mood which tells them a migraine is on the way. This can be transient inappropriate depression, or even improved mood. Patients may be hungry or thirsty and have learned to recognize that this tells them that a migraine is on the way. These types of symptoms are called prodromes.

What Causes it?

What all these symptoms tell us is that migraine is a disturbance of the brain. There is a strong genetic influence in migraine and so it is likely that patients with migraine have blood relatives who also have the condition.

The current evidence suggests that migraine occurs because people have a largely inherited increased sensitivity in parts of the brain. In our brain there are billions of nerve cells with complex connections which communicate by either stimulating or inhibiting the connected cells. In migraine, it appears that there is a relative deficiency in the inhibitory circuits, especially in parts of the brain involved in vision. This leaves the brain sensitive to stimulation.

What happens during an attack is that the brain spontaneously goes into a pattern as if it had been injured. If you had been hit on the head by a baseball bat you would not be surprised to get headache and nausea and sensitivity to light. The same changes appear to be happening spontaneously in migraine, probably due to this increased sensitivity. This is why many of the preventative treatments are directed at reducing brain sensitivity.

What are the Treatments?

Treatment for the Attack

1) GENERAL PAIN RELIEVING DRUGS

PARACETAMOL
Paracetamol is a widely available pain relieving drug which is available without prescription and also outside pharmacies in shops and supermarkets. It has been shown to be effective, although in migraine it is known that it is slowly absorbed because of the slowing in stomach emptying. Its speed of effect can be increased by adding an anti nausea / stomach emptying drugs such as metoclopramide (eg a combination of paracetamol and metoclopramide “Paramax”).

Paracetamol has very good safety provided patients do not exceed the recommended maximum daily dose of 4000 mg (8 standard strength 500 mg tablets).  At higher doses within a given 24-hour period there is a risk of damage to the liver which can be fatal. Do not exceed the recommended dose.

ASPIRIN
Aspirin is another widely used general pain relieving drug. It can be rapidly absorbed in migraine, especially when given as a soluble formulation as a drink (e.g., “Aspro Clear”). A high dose of 900 mg (equivalent to 3 standard tablets) is more effective than lower doses. Aspirin should not be used in patients who have aspirin-sensitive asthma, or who have swallowing or stomach problems such as reflux or peptic ulcer disease. Aspirin should not be given to children.

ANTI-INFLAMMATORY DRUGS
This is a large family of drugs which have similar actions to aspirin that have largely replaced aspirin for chronic treatment as they cause less irritation to the stomach but still all have the potential to do so. Members of this family include:

• ibuprofen
• diclofenac
• indomethacin
• mefenamic
• acidnaproxen

Many of these drugs can be bought over the counter without prescription and outside pharmacies as well. They are effective, but all have the potential to cause irritation to the stomach, and with continued use can cause fluid retention, high blood pressure and kidney damage. Chronic use should only be done under the supervision of your doctor.

COMBINATIONS
Other ingredients may be added to the above painkillers with the intention of improving the response. Caffeine, the active ingredient of tea and coffee which gives us a buzz, is included in some painkillers. There is weak evidence that it may slightly increase the effectiveness. However in headache, there is good evidence that chronic intake of caffeine may make you more sensitive to getting headaches especially in the morning as the caffeine comes out of the bloodstream. I would recommend avoiding using caffeine-containing medicines for headache.

Sedatives and muscle relaxants such as doxylamine are included in some well-known brand name products with little evidence that they improve the outcome.

MORPHINE LIKE DRUGS INCLUDING CODEINE - CAUTION!!
The use of these drugs is very controversial. Codeine is available without prescription at pharmacies at low strength (up to about 12 mg  per tablet) in combination with paracetamol or ibuprofen. Codeine itself is not a painkiller but in most people about 10% is converted to morphine, a narcotic with strong pain relieving properties. About 1 in 16 people in the Caucasian population cannot convert codeine to morphine and hence the drug is ineffective. A much smaller proportion, about a 10th of 1%, convert codeine to morphine more efficiently and can get severe stomach pain when given standard doses of codeine. Codeine frequently causes constipation, and may cause drowsiness and impairment of ability to drive or function at work. However of much more concern is frequent use of codeine making headache worse.

Many headache clinics see patients who have a history of relatively infrequent migraine sometime previously, but over time the headaches have become much more frequent and the patients are taking medication on most days. Initially it was thought that the high frequency of medication was simply related to the high frequency of pain but a number of doctors became suspicious that it may be the medications were making the headache more frequent. Although all acute medications have been alleged to cause this problem, the evidence is much strongest for codeine. The alert level is generally if a patient is taking the drug about 50% of the time, i.e. 15 days per month, there is concern about medication overuse headache. Unfortunately, this is quite difficult to treat. The standard advice is to tell patients not to use their codeine-containing medication, but in the short-term they are often worse and find this difficult to do. Sometimes patients even have been admitted to hospital to achieve this. Although the mechanism is not certain, my colleagues and I at the University of Adelaide believe we have discovered a mechanism by which this happens. We think that the morphine-like drugs activate immune cells in the brain which are there to protect the brain from injury. This causes them to put out a “danger signal” which makes the brain more sensitive to pain. We are currently trialling a drug which we think may block this process yet allow the pain killing benefits to continue. If you think you may be in this category please see our information under ‘Participate’.

Sometimes patients have been given full strength morphine-like drugs including morphine, oxycodone and pethidine. The last drug, pethidine (known as meperidine in the United States), is sometimes preferred by patients but there is evidence that this is associated with higher potential for addiction and so availability of this drug is highly restricted in South Australia.  Although morphine-like drugs, especially given by injection, are effective painkillers and are the usual treatment of choice for severe pain such as following injuries or post-operativela, their use in headache is strongly discouraged because a number of patients have ended up with addiction problems as a result. There are many disadvantages to taking these medications. Patients should not be driving when taking such medications. Urine testing would be positive for narcotics. It can be very difficult to travel with such drugs. Only one doctor should be prescribing the medication and this should be through a register held by the Drugs of Dependence Unit. As a result, my belief is that patients should only be offered such medication after a very thorough specialist review and trial of other treatments.  It should be quite rare that such drugs are necessary.

The above paragraphs referred to morphine like-drugs given as short acting formulations being given intermittently and acutely for attacks. Occasionally I have come across patients with high headache frequency who have been given chronic oral long-acting morphine-like drugs. In my view this is completely inappropriate and I always attempt to completely withdraw such drugs if possible. This is for two reasons. The first is that there is strong evidence that such drugs make headache worse. The second is that since migraine pain comes in attacks, a steady trickle of drug is insufficient for the peaks and too much for the gaps and all it does is cause problems.

2) SPECIFIC MIGRAINE DRUGS

TRIPTANS
This is a group of drugs available only on prescription. Four are available in Australia, although another two (frovatriptan, eletriptan) are available overseas. They are the most recent new class of treatments for migraine to become available, having been developed in the 1980s to 1990s.  The 4 drugs available in Australia are:

• Sumatriptan: available as tablets, nasal spray and self-administered injection
• Zolmitriptan: available as tablets
• Naratriptan: available as tablets
• Rizatriptan: available as tablets

These drugs work on specific pathways in the brain and on the blood vessels in the brain to calm down the migraine process. They can be very effective with up to around half the patients becoming pain-free or nearly pain-free within 2 hours of taking the medication. Unfortunately they are not very well or rapidly absorbed as tablets, which is why other ways of getting them into the bloodstream can be useful. The nasal spray approach sounds good in that it doesn’t rely on the stomach for absorption. Unfortunately, the sumatriptan nasal spray has a very bad taste and most patients find it puts them off so much they don’t wish to use it. The self-administered injection can be very effective within minutes but unfortunately it is not subsidized on the PBS in Australia and so cost can be prohibitive. The non-injection formulations are subsidized on the PBS but only in very small quantities (i.e. four doses her prescription). The absorption is fairly consistent within an individual patient and so patients learn how quickly the drugs work for them.

The drugs overall seem to have similar effectiveness and side-effect profiles and there is no one clear “best”. In general, naratriptan is marketed at the lowest effective dose compared to the others and tends to have a lower side-effect profile, although this is not guaranteed. Rizatriptan may have a slightly higher tendency to cause patients to feel dizzy. The best approach to work out which one is best for you is a “wine tasting” approach:  if you get a very good result with the first one your doctor has prescribed you, stick with that. However if you don’t get a good result, especially if that is because it doesn’t work rather than because it causes side-effects, you should try another one.

Some of these medicines are available as a “melt-type“ tablet or as a wafer.  It is generally assumed by patients that these formulations are more rapidly absorbed than the standard tablets but this is not the case. There are simply more convenient to take when a glass of water for example is not available.

Typical side effects of these drugs include feelings of heaviness or tightness in the chest or neck. These symptoms can superficially be confused with the symptoms of heart disease. Since most migraine patients are quite young, generally it is fairly easy to reassure people that there is no problem. Many millions of doses have been used and generally there is no concern about these drugs causing heart problems. However, as they do narrow blood vessels to a minor degree, they are not suitable for patients who have known coronary artery disease. Other side effects can include feelings of being drained or washed out which may last for some days.

It is also been recognized that if people use these medications too frequently, they may cause the headaches to become more frequent (i.e. a vicious cycle). Is recommended that no more than 8 doses per month should be taken to avoid this problem.

ERGOTS
Two older drugs, ergotamine and dihydroergotamine, have also been proved to be beneficial in migraine.

Ergotamine is the principal ingredient in Cafergot, but this is much harder to access now as the manufacturer has withdrawn this from the market in Australia. This is not because of safety reasons but simply because they were not making enough profits. Cafergot can be given by tablets but it is very poorly absorbed and not reliably effective. The most effective way of giving this was by a suppository (inserted into the back passage).

Dihydroergotamine is available in Australia as an injection. It is often used for prolonged or severe attacks in which the drug may be given intravenously by a doctor. It can also be used at home by patients as a self-administered injection into the skin. There is a nasal spray available overseas which can be quite effective and avoids the need for an injection but has to be individually imported.

Treatment to Reduce the Frequency of the Attacks

For patients who only have relatively infrequent attacks, treatment just at the time of the attack may be sufficient. However, this will not be suitable as the only method of treatment for:

• patients with very high frequency of attacks
• patients who have not found any suitable treatment that is effective
• or if the attacks are very prolonged

Under such circumstances, giving drugs on a daily basis to try and prevent migraine may be worthwhile. There is no exact frequency at which we consider preventative therapy as it depends on the individual patient preferences, but a rule of thumb is that when attacks occur more than 4 times per month, preventative therapy should be considered.

There is a wide range of treatments that have been shown to be effective in reducing the frequency of attacks. As an overall rule of thumb, when a drug has been shown to be effective, that generally means about half the patients get a 50% or more reduction in the frequency of attacks. A number of patients have not been explained this, and are disappointed when taking their so-called “preventative therapy”  they continue to have attacks, even though it may be at a lower frequency. It is important to have realistic expectations.

1) "BETA-BLOCKERS"
These drugs were initially developed for high blood pressure and heart disease. However, it was noticed that patients being treated for these conditions who had migraine noticed an improvement in their migraine. This benefit was proven in many clinical trials. They are generally our first line preventative treatment as they are moderately effective and generally quite well tolerated. The best studied and most frequently used is propranolol “Inderal”. In my experience, most patients in Australia who don’t get a good result with this had been given doses that are too low or of the wrong formulation. The standard tablet only stays in the body for a few hours and in general need to be given 3 or 4 times a day to be effective. To get around that, there is a sustained-release formulation (“Inderal LA”) which only needs to be given twice daily. It is usual to start at relatively small doses of around 40 to 80 mg per day, but can be increased up to 640 mg per day if lower doses are well tolerated but not effective.

Another widely used beta-blocker in migraine is atenolol and the effective dose is between 25 and 100 mg per day. This only needs to be given once per day. I prefer to avoid metoprolol, as it is known that approximately 1 in 16 people are very sensitive to this drug and effectively is getting overdosed on standard doses.

Beta-blockers are not suitable for patients who have asthma, even if very mild, as they will block the effects of standard asthma sprays and may even cause life-threatening asthma attacks. They also impair performance in competitive sport and hence are not suitable for athletes. Otherwise, they are generally well tolerated.

2) TRICYCLICS - AMITRIPTYLINE
Amitriptyline has proven efficacy in migraine prevention and is used in similar doses and patterns as tension-type headache above. It is not a requirement to be depressed to be treated and get benefit with this medication. If it is effective but rather sedative, other drugs of this class can be used.

3) TOPIRAMATE
This is a drug initially developed for epilepsy which has proven benefit in migraine. One of its positive features and which is unusual in the migraine preventative drugs is that most patients lose weight on this drug as they feel less hungry. There have even been attempts to develop this in combination with other drugs as a weight-loss treatment but I don’t think it’s suitable for that purpose. In clinical practice, what is remarkable about this drug is the very wide range of variation in the way patients respond. In clinical trials, patients were generally started on between 100 and 200 mg daily but quite a few dropped out due to side effects. I, and most other headache specialists, generally start at a very low dose of 25 mg daily and increases by 25 mg increments every couple of weeks or so. This means it may take a month or more to get to what might be a therapeutic dose for you. However, I have found that some patients develop quite marked side-effects at doses even as low as 75 mg daily. There are others, however, who get benefit with the drug, tolerate it well and may continue to get further benefit at doses up to 1000 mg daily. Hence the principle is to start low, go slow, and keep going.

A side-effect of particular concern with topiramate is that it may cause slowness of thinking. This is not quite the same as sedation which is an awareness of being sleepy. Sometimes people just seem to think more slowly. This might make it unsuitable for people whose jobs are intellectually very demanding but I do have some patients who cope very well with this drug even in very high-performance jobs. It is simply a matter of taking it gradually and seeing whether it works for you and whether you tolerate it well. Other side-effects include dizziness, numbness and tingling and sleepiness. It is important to have a good fluid intake on high doses in the summer weather to avoid kidney stones.

It has recently been confirmed topiramte may causes birth defects (cleft palate) and hence should not be used in women who may become pregnant.

4) VALPROATE
Valproate is another drug initially for epilepsy which has been proven to be of benefit in patients with migraine. It is not specifically licensed in Australia for the treatment of migraine, although it is registered for this purpose in other countries such as the United States. In my experience the effective dose range is from 400 to 800 mg per day. There may be more effectiveness at higher doses but sedation tends to be a problem. It also causes weight gain.

5) GABAPENTIN /  PREGABALIN (“LYRICA”)
These related drugs are also antiepileptic drugs. They are not licensed in Australia for the treatment of migraine and are only on the PBS for epilepsy. They can be effective in migraine but should be used after the drugs discussed above. The tolerability is generally good although sedation and weight gain can occur.

6) PIZOTIFEN (“SANOMIGRAN”)
This is an old drug which has been used for migraine prevention for a long time. In clinical trials it is frequently found to be no different to inactive treatment (placebo) and in others it does appear to work. My clinical impression is that overall its effect is rather weak and doesn’t help many patients. Side-effects of particular concern are that it is a powerful appetite stimulant and many patients put on large amounts of weight.
It is also sedative. Hence I rarely use this drug but it does seem to be helpful particularly in children and teenagers.

7) METHYSERGIDE (“DESERIL”)
This is an old drug related to ergotamine and is one of the most effective migraine preventers. However, because of safety concerns we generally use it only after other drugs have failed: patient’s quality-of-life is significantly affected by their disease, and patients are aware of the risks.

Chronic use of methysergide is associated with scarring (thickening) of some important issues in the body including heart valves and the tissue around the kidneys. This can lead to heart problems requiring heart valve replacement or kidney failure. It is estimated that the risk of this is approximately 1 in 2000 patients treated long-term with the drug. It is suspected, but not proven, that this risk is lower if we use the drug in courses no longer than 6 months at a time and this is what is currently recommended. After 6 months treatment we recommend a one-month break before restarting the drug. It is my practice to do a cardiac ultrasound and abdominal ultrasound (these tests are quick and painless) every 6 months to detect for problems early. This is because the scarring is probably not reversible and the only management is to stop the drug before it becomes too much of a problem.

Other non-serious side-effects associated with methysergide include leg cramps. The manufacturers of most of the triptans recommend that they should not be used in patients taking mesthysergide.

8) BOTULINUM TOXIN (“BOTOX”)
I continue to be amazed about the number of requests I have for information about this treatment. This toxin paralyses muscles and this is why as a medicine it is used to treat spasticity following conditions such as stroke. It is also why it smooths out wrinkles. It was initially tried in tension-type headache because of the possibility that increased tension in the muscles was causing the pain. However it did not work in this condition. It was then tried in regular migraine and also did not work. However, it has been confirmed to have a modest effect in patients who have so-called “chronic migraine” (i.e. patients who have at least 15 days per month of migraine like headache). Although the decrease in headache days was quite impressive in the clinical trials (being about 50%), there was also quite a marked reduction in the group that received placebo. This is probably because the treatment requires 31 injections into the head and neck produces quite a strong placebo response.

9) OTHERS
Two drugs for high blood pressure, candesartan and lisinopril, have been shown to have modest anti-migraine actions. For lisinopril, the action was initially discovered by a Norwegian neurology professor who had migraine and high blood pressure and noticed that his migraine was better when his blood pressure was treated with that drug. That on its own is not enough to conclude effectiveness, but he then did a placebo-controlled trial to confirm the benefit of the drug. If patients have migraine and high blood pressure, one of these, or a beta-blocker, would be the treatment of choice.

Another antihypertensive drug, clonidine, was marketed at low-dose (“Dixarit”) for the treatment of migraine. However, a review of the literature suggests that it is probably not effective. It causes dry mouth and sleepiness.

Another group of antihypertensive drugs, “calcium antagonists”, has been studied in migraine. One, flunarizine, has some evidence of effectiveness but it is not available in Australia. Verapamil, nifedipine and nimodipine are overall not effective although verapamil is the treatment of choice in cluster headache.

The garden herb feverfew has been suggested to have effect in migraine in small clinical trials. However, overview of all the trials suggested that it was probably ineffective. However, there appears to be no safety concern. Another herbal treatment, butterbur, may have some effectiveness.

Magnesium salts may have some effectiveness but diarrhea can be limiting.

10) DRUGS FOR SYMPTOMS OTHER THAN PAIN
Nausea and vomiting are particularly distressing symptoms commonly seen in migraine. They also interfere with people being able to take treatment by mouth. One of the most widely used anti-nausea / vomiting drugs is metoclopramide (“Maxolon”).  It can be given orally, in combination with paracetamol (Paramax) or by injection. It is moderately effective and has fairly good safety, although occasionally can cause strange movements in some people. Other drugs related to the action of metoclopramide include domperidone.

One drug class which in general is often spectacularly effective in treating the nausea and vomiting of migraine is a group of drugs called 5-HT3 antagonists which were initially developed for the nausea and vomiting of cancer drug treatment. Drug names include ondansetron and tropisetron (i.e. they all end in “- setron” ). They are also used to treat the nausea and vomiting that may occur following surgery. Although clinical trials that have been shown to be very effective in migraine and their safety record is good, they are not licensed in Australia for this purpose and hence the use is “off-label”. Also, their safety is only been demonstrated when given in courses up to 5 days at a time because that is how they are used for cancer treatment. I use these drugs in patients who have severe nausea and vomiting and are not responding to metoclopramide and only give small quantities of 5 to 10 at a time.

11) NON-DRUG TREATMENTS
Most patients would prefer a nondrug treatment and many such treatments have been tried.

One very interesting approach has been to look for and close a hole in the heart in patients with migraine with aura. All of us have a hole between the left and right small chambers of the heart (“foramen ovale”) when we are in the womb. Normally that closes over soon after birth. However, in some patients it persists. It was noted by some patients and doctors that in patients who also had migraine with aura, there was a marked decrease in attack frequency after surgical closure of the hole.  There was a plausible explanation for this in that small clumps of cells in the blood called platelets would be able to go through the hole and into the brain and trigger migraine. As a result, the trial of searching for such a hole and randomising patients to either having it closed or not was performed. The procedure is done via a tube without needing to cut open the chest. It appeared that there was a very small benefit following the procedure and hence it is not routine practice to look for such a cardiac finding in order to arrange to have it closed.

In migraine and headache and in other painful conditions, there is increasing interest in using electrical stimulation techniques to reduce pain. We don’t really know how this works. There is a range of treatments varying from stimulation of the nerves at the back of the neck, magnetic stimulation of the brain, electrical stimulation of the brain from the scalp, and even direct electrical stimulation of the brain through wires placed into it.

One procedure that seems to have some merit is occipital nerve stimulation. In this procedure a small electrode is placed under the skin at the back of the neck underwire tunneled out to a stimulator, which can be temporary or permanent (embedded under the skin). A tingling sensation is often produced.  Apart from the risk of infection, the procedure seems safe. Although individual patients may report marked improvement, the overall effect is modest. Sometimes when patients are being assessed for the procedure and temporary block of the nerves is done using local anaesthetic to see whether this helps the patient. Unfortunately, it doesn’t appear that such a test predicts whether people will get a good rresult from the simulator. The simulators are very expensive and there is very limited access to these through the public health system. We would tend to use them only when all other drug treatments have failed.

Magnetic stimulation of the brain formed by a wand-like device applied to the scalp is being investigated as an acute treatment for migraine.