Dr Dowson is director of the King’s Headache Service, London
The first of a new series on the various types of headache and their management looks at migraine. This severe form of headache can have a considerable impact on the daily life of sufferers
Credit for learning
This article forms the basis of questions under the PJ/College of Pharmacy
Practice Credit for Learning scheme
Migraine is a common condition, which is believed to affect between 15 and
18 per cent of women and 6 per cent of men, although estimates vary.1-6
Accurate diagnosis of the different presentations of migraine is the foundation
of effective prescribing. The introduction of the 5-HT1 agonists (triptans)
has increased the treatment options for migraine and provided an opportunity,
not only to reappraise management strategies, but also to deliver care that
is more effective. This article considers both the diagnosis and management
of migraine.
| Panel 1: Diagnostic pointers for migraine7 | |
|
Diagnosis
In any medical condition it is of paramount importance for the diagnosis to
be accurate. Unless this is the case, it is unlikely that a good management
plan will be established. In the late 1980s, the International Headache Society
(IHS) formulated a classification for migraine, which has helped us to determine
the correct patient groupings for migraine clinical trials. This classification
is described in Panel 1. It was never intended to be used for individual attacks,
but merely to identify people with migraine. Therefore, if five attacks meet
the criteria, the patient is given the diagnostic label of “migraineur”.
It is important to realise that the main four symptoms do not all have to be
present. So, it is quite possible for the patient to have a mild headache which
is bilateral, but still have migraine.
Over recent years, clinicians have realised that it is helpful to ask questions
of patients with acute or intermittent headaches. Information about their quality
of life and ability, or otherwise, to perform normal activities is very important.
High impact, acute headache would, therefore, tend to have a default diagnosis
of migraine and the IHS classification is used to confirm this.
The main part of the classification is concerned with the headache phase of
the attack. However, approximately 10 per cent of patients will have reversible
sensory symptoms in the hour preceding the headache. These symptoms are known
as aura and will often include visual changes, such as zigzag lines or scotoma
(holes in the vision), but a variety of other symptoms may also occur.
Other symptoms include “word salading” (words being mixed up), dizziness
and numbness. About 40 per cent of patients describe more vague symptoms of
aura that can last substantially longer. In the day or two before an attack,
prodromal symptoms, such as cravings and lethargy, can be observed. From within
these two groups of symptoms, useful warnings can be identified and patients
taking simple treatments during such a warning may have success in heading off
a migraine before it has started. The other phase of migraine, which is often
ignored, is the postdrome. This occurs once the headache has subsided and usually
involves the patient feeling quite washed out or hung-over. Occasionally, a
patient may feel entirely the opposite, almost as if they are super-human. Even
though relatively little can be done to alleviate these prodromal symptoms,
the cost in terms of disruption to work, chores and social activities, which
can result from this phase of the attack should not be underestimated.
By paying attention to the impact on the patient of the various phases of a
migraine attack, different management strategies may be developed. Headache
specialists often draw “impact curves” to illustrate to the patient
the shape of their attacks.
Differential diagnosis
| Panel 2: Trigger factors for migraine | ||
|
Sinister symptoms are outside the scope of this article but, in reality, patients, pharmacists and general practitioners all worry about misdiagnosing presenting symptoms of serious underlying disease. However, they should be reassured that such presentations are extremely rare. It is important to remember that those patients whose management is unsuccessful may have been misdiagnosed and, therefore, be taking inappropriate treatment. The majority of headache sufferers who seek advice will have the common, acute, high impact headache of migraine or, alternatively, chronic daily headache, with or without analgesic dependence.
Chronic daily headache
Chronic daily headache (CDH) will be discussed in a later article within this
series. In short, CDH is defined as headache which is present on most days,
typically occurring over a six-month period or longer. In some patients, an
episode of chronic headache resolves in a much shorter time.
CDH is characterised by a combination of background, low-grade muscle contraction-type
symptoms, often with stiffness in the neck, and superimposed migrainous symptoms.
Patients might have had migraine in the past and experienced a difficult patch
of high frequency headache, prompting them to increase their analgesic intake.
These analgesics can then lead to a worsening of the chronic headache pattern
resulting in analgesic dependence.
In the United Kingdom, the most commonly implicated drugs are those containing
codeine but all simple analgesics and ergotamine compounds have been implicated.
In recent times, the triptan class of drugs has also been reported to cause
chronic headache, although it is my opinion that this situation is uncommon.
However, the medication probably does not actually cause the condition. It is
more likely that patients achieve transient relief from this class of drug,
leading them to repeat dosing. Risk factors appear to include not only a past
history of migraine and high analgesic intake, but also injuries to the head
and neck, such as a whiplash injury. The aim of management in CDH is to return
patients to their original acute headache pattern, which requires a combination
of treatments including:
l Physical measures in the neck and shoulder areas (eg, exercises or formal
physiotherapy, acupuncture or osteopathy)
l Avoidance of analgesics and ergotamine
l Use of effective, regular prescription medicines, usually drawn from the antidepressant
or antiepileptic groups
This package of care is clearly different from that required for straightforward migraine and it is, therefore, critical that CDH is not misdiagnosed and subsequently mistreated. It should be borne in mind that approximately 2 per cent of the population might have CDH at any time and 4 per cent at some time in their lives. This is not a small problem.
Management of migraine
It may be useful to draw a picture of the average migraineur.8 Most migraine
sufferers will:
The most commonly used aid to diagnosis is the IHS classification. However,
a more modern approach might include questions relating to the disruption of
normal activity and quality of life (see Figure 1).
It should be remembered that, untreated, an average attack would last approximately
one day. It must be stressed that it is extremely important to include the patient
in all decisions regarding migraine management. It is the patient who needs
to develop the strategy that works specifically for them. This strategy usually
includes:
Patients with less frequent but more prolonged attacks may warrant prophylactic treatment if their migraine is unresponsive to the full range of acute therapies.
Avoiding trigger factors
It is believed that a patient is born with a susceptibility to migraine attacks
and that various trigger factors will come together on a particular day to tip
the patient into the acute symptoms described above. Some of these trigger factors
are outlined in Panel 2. Once identified, many risk factors, especially foods,
are easily avoided. Others, such as weather changes or menstrual cycles, are
more difficult or impossible to avoid. Nevertheless, appreciation of their importance
can be put to good use.
Acute treatment
Assessment of the acute response to drug interventions has become more confused
because of the diversity of end points now used in clinical trials.10,11 I do
not propose to dwell on these analyses but would merely say that treatments
fall into two broad categories: first, analgesics and analgesic combinations
and, secondly, migraine-specific therapies, such as the triptans, ergotamine
and dihydroergotamine. Many of these are available only on prescription but
there is a variety of therapeutic options available over the counter and pharmacists
can advise patients about these.
Analgesics and analgesic combinations Most patients will have
tried taking analgesics before consulting a health care professional. However,
they may not have used the appropriate dosage of the drugs or used them at the
correct time. Because of the worries about gastric stasis, to achieve reasonable
blood levels, higher doses of analgesics than are usually recommended are suggested.
I advise 900mg of aspirin, 1.5g of paracetamol or 600mg of ibuprofen to be taken
at the beginning of an attack. These doses should be taken even before the headache
develops, if possible. The timing of the dose is paramount in achieving the
best possible outcome.
There is little evidence from clinical trials across large populations that
combination drugs with caffeine and codeine are more effective than simple analgesics.
However, individual patients can experiment with different analgesics. As long
as the patient achieves the goal of being back to normal within a couple of
hours with OTC therapy and frequency of headaches does not increase (as in analgesic
dependent CDH), I have no major objection to this approach. However, the pharmacist
should be aware that patients using large amounts of analgesics, particularly
those containing codeine, may be developing, or indeed have, CDH. These patients
would be best referred to their general practitioner.
The addition of a gastric motility agent, such as metoclopramide or domperidone,
not only helps increase oesophageal motility and gastric emptying but is of
particular benefit to those patients in whom vomiting is a major part of their
migraine. Increasing gastric motility also allows better absorption and efficacy
of analgesics. In clinical trials, soluble aspirin 900mg with metoclopramide
10mg tended to give headache relief in about one-third to one-half of patients
at two hours.
A recently released migraine-specific combination, Migramax, contains both metoclopramide
and lysine acetylsalicylate. The lysine makes the drug more soluble resulting
in rapid absorption of the aspirin. Aspirin is, therefore, in contact with the
gastric mucosa for a shorter length of time, potentially giving fewer gastric
side effects and enhanced efficacy.
Another drug with a specific migraine indication is tolfenamic acid (Clotam
Rapid) which is a non-steroidal anti-inflammatory drug.11 A placebo-controlled,
randomised trial has shown tolfenamic acid to be equivalent to sumatriptan.
However, in the trial, the success rates were above those normally expected
from sumatriptan 100mg at a two-hour interval. It would, therefore, be useful
to have other studies to confirm these results.
The triptans Triptans appear to work by stimulation of 5-HT1B
and 5-HT1D receptors. During a migraine attack, the trigemino-vascular system
is activated, particularly peripheral blood vessels and the trigeminal nerve.
This nerve communicates peripherally with these blood vessels and centrally
with the trigeminal nuclei. The important receptors are serotonergic, as the
blood vessel is driven by the 5-HT1B and the trigeminal nerve by the 5-HT1D
subtypes at both ends.
In the UK, there are four licensed triptans — sumatriptan (Imigran), zolmitriptan
(Zomig), naratriptan (Naramig) and rizatriptan (Maxalt). All these drugs are
used in clinical practice but the mainstay is still sumatriptan. Three further
drugs from this family are expected to be launched during the next 12 months
— eletriptan, frovatriptan and almotriptan.
Sumatriptan was launched about a decade ago and there is now substantial clinical
experience of this agent. For patients who do not gain control with more general
approaches, the triptans have proved to be a life-changing therapeutic option,
although only a minority of those who could possibly benefit from them have
been exposed to them. Sumatriptan is available in a subcutaneous and intranasal
formulation to avoid the upper GI tract. This drug is, therefore, attractive
for patients who have early vomiting as a major feature of their migraine. These
formulations also have a quicker action than tablets. Sumatriptan is available
in both 50mg and 100mg tablets.
Zolmitriptan was the second agent to be launched in the triptan family. It was
originally thought that it had activity at all three of the 5-HT1 sites and
was, therefore, expected to penetrate the trigeminal nucleus better than sumatriptan.
However, it remains unclear whether this actually confers additional benefits.
Zolmitriptan is currently only available in tablet form but other formulations
are soon to be released.
Naratriptan is given at a dose of 2.5mg to minimise side effects. The drug’s
summary of product characteristics says that side effect rates are similar to
those of placebo. In studies, a disadvantage was that, at two hours, some patients
found it less effective than other drugs in the family. In those who find the
drug effective, an advantage is a reduction in recurrence rate (recurrence being
defined as headache successfully relieved but returning with 24 hours). Recurrence
occurs about one-fifth of the time with naratriptan compared with one-third
achieved with the other triptans. In summary, it would appear that naratriptan
has advantages for those patients who have recurrence or adverse events and
this leads some practitioners to favour using the drug first-line, then moving
to the other triptans if it is ineffective.
Rizatriptan was launched in 1998 and was designed as a very small molecule,
allowing rapid absorption and quick access to the target areas. It was also
designed to have little stimulation of other 5-HT receptors, particularly 5-HT1A.
This may be of some benefit in the early phase of treatment, as there may be
less nausea caused by 5-HT1A stimulation. Tablets are available in 5mg and 10mg
and there is a 10mg melt-on-the-tongue wafer version (Maxalt Melt). With the
wafers, the patient merely places the wafer on the tongue and it dissolves in
the saliva within a few seconds. The solution is then swallowed and absorbed
from the stomach. It appears to be well tolerated and rarely causes any taste
disturbance. The most commonly reported advantage of Maxalt Melt is that the
drug is convenient to take; the patient can take the treatment earlier in the
attack because no glass of water is required. This gives the wafer formulation
a better chance of success because the hurdle, in terms of severity, is lower
early in the attack.
All the drugs in this class have a similar range of unwanted effects. The most
common are tiredness, dizziness, nausea, neck and shoulder stiffness and a sensation
of heaviness or pressure in various parts of the body, including the chest and
throat. All drugs in the class have been extensively investigated and evidence,
including ECG monitoring, suggests that the chest and throat symptoms are not
necessarily of cardiac origin. Although the mechanism has yet to be determined,
causes such as oesophageal spasm have been postulated. In practical terms, it
is usually best to warn the patient that these side effects may occur but also
to reassure them that true cardiac symptoms are extremely rare. All the triptans
are contraindicated in patients with known ischaemic heart disease or uncontrolled
hypertension and they are not recommended in patients over the age of 65 years.
Ergotamine The use of ergotamine has been almost completely superseded by the triptans because of its potential to cause acute side effects, such as nausea, abdominal pains and cramps, and also because of its relatively low efficacy, particularly in the oral formulation. Patients who are currently using ergotamine on an infrequent basis and who find it efficacious without side effects would appear to be using the drug optimally and do not necessarily require a change in therapy. The most worrying aspect would be the possibility of increasing use of ergotamine leading to ergotism, a form of chronic daily headache. In this circumstance, the patient should be referred for further GP assessment.
Dihydroergotamine Dihydroergotamine (Migranal) is superior to ergotamine but is inferior to the triptans in terms of efficacy two hours post dose. Its side effect profile is reduced in comparison with ergotamine. Currently, the drug is available as a nasal spray and is used by specialists in cases of triptan failure. It is not widely used in the UK.
Prophylactic therapies
Drugs that reduce the frequency of migraine have been used for decades and not
always with good reason. The mode of action of these drugs is poorly understood
but it is thought that antagonism at the 5-HT2 receptor may be important. In
general, drugs are thought to be successful if there is a 50 per cent reduction
in the rate of attacks in 50 per cent of patients.
The most commonly used licensed drugs in the UK are beta-blockers and
5-HT2 antagonists.The general rule in prophylaxis is that, because prescription
agents have relatively low efficacy and a reasonable risk of causing side effects,
compliance becomes a major issue. Because of this, it is my opinion that it
is best to start with modest doses and gradually titrate up, if necessary.
Beta-blockers This class of drug is the most commonly used world-wide for migraine prophylaxis. Beta-blockers are contraindicated in patients with conditions such as asthma and peripheral vascular disease. Propranolol, atenolol, metoprolol and timolol are all used, although propranolol is the most commonly prescribed in the UK. My own approach is to start with a low dose (10mg bd), building up gradually. Inderal LA 160mg or Half-Inderal LA 80mg is commonly used, but the larger daily dose does confer the problem of additional side effects. One analysis of propranolol reported that, on average, there was a 44 per cent reduction in the frequency, duration and intensity of attacks.
Pizotifen Pizotifen (Sanomigran) has antihistamine and 5-HT2 receptor blocking activity and, in adults, the reduction in frequency of attacks is less than that of beta-blockers. This effect is at the expense of side effects, such as weight gain and sedation.
Methysergide Methysergide (Deseril) is an effective prophylactic agent but it carries the serious side effect of fibrotic conditions, such as retroperitoneal fibrosis (fibrous material that can affect the ureters and, therefore, urinary flow). Because of this adverse effect, the drug is usually reserved for those patients who require prophylaxis but who have failed to respond to alternatives.
Other prescribed prophylactic agents Tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and sodium valproate have all been shown to have some efficacy in migraine prophylaxis.
Non-prescription prophylactic agents OTC medicines, such as vitamin B2 (riboflavin) 400mg daily, magnesium 200mg daily, feverfew and even aspirin 75mg daily are all options for prophylaxis. When using prophylactic agents, it is always useful to explain to patients that they should only change one treatment at a time. In this way, they can reduce the possibility of confusion over which drugs are effective.
Conclusion
The management of migraine initially requires an accurate diagnosis, especially
to exclude chronic daily headache. Once the migraineur is correctly identified,
an appropriate strategy needs to be developed with the patient, which includes
the avoidance of trigger factors, the use of an effective intervention and,
in the case of high frequency sufferers, the use of a prophylactic agent.
It should be remembered that, during patients’ lives, the expression of
their migraine may vary and the intervention required may need to be reassessed
and adjusted from time to time. Patients may have a variety of migraine types
in the short term and can require a range of treatments to achieve optimal control.
In the general population, soluble oral preparations, such as aspirin or paracetamol,
with or without an anti-emetic, may be all that is required. More specific migraine
therapies, such as the triptans, are available for those in whom this approach
fails.
Prophylaxis is also available and there are forms that can be bought over the
counter, as well as those on prescription. Because of the relatively low efficacy
and high tolerability of prescribed treatments, patients often prefer to try
OTC options first. During the past decade, with the advent of the high efficacy
triptans, there has been a change, with less emphasis now being placed on prescription
prophylactic agents. The aim of a good management strategy should be to enable
patients to be in control of their migraine rather than have it control them.
Figure 2 outlines a migraine management strategy.