Cluster headache

Medication-overuse headache

Migraine

Post-dural puncture headache

Tension-type headache

This post reviews the management of headache, in particular migraine and cluster headache, and the drugs used mainly for their treatment. The mechanisms of head pain or headache are not fully understood but may involve neurovascular changes (as in migraine and cluster headache), muscle contraction (tension headache), nerve lesions (neuralgias), direct head injury, infection (meningitis), or referred pain (sinusitis, toothache, eye disorders). Headache is also an adverse effect of many drugs including, paradoxically, those used to treat it. The International Headache Society has published guidelines to aid the diagnosis of the various headache types. Patients may have more than one headache disorder simultaneously and require separate treatment for each.

Cluster headache

Cluster headache (migrainous neuralgia, histaminic cephalalgia, Horton’s syndrome) is of unknown aetiology but may be neurovascular in origin. Patients experience one or more short-lived attacks of intense unilateral head pain, usually at me same time of day (often at night). These are associated with autonomic symptoms such as conjunctival injection or lachrymation, miosis or ptosis, nasal congestion or rhinorrhoea, forehead or facial sweating, and eyelid oedema. Restlessness during the attacks is characteristic. The period during which attacks occur is called a cluster period; it may last several weeks or months. In the typical episodic form of cluster headache, cluster periods are followed by periods of remission lasting for months or years but in the more rare chronic form, patients may have cluster periods lasting for more man a year, or with short periods of remission in between. Substances such as alcohol, histamine, or glyceryl trinitrate can precipitate headache attacks during cluster periods, but not during periods of remission. There is speculation mat sleep-disordered breathing and increased body heat may also trigger cluster headaches.

The treatment of individual acute attacks during a cluster period is difficult because the headache is short-lived and oral analgesics are unlikely to be absorbed fast enough to produce much benefit. Inhalation of 100% oxygen is rapid and effective in aborting attacks, but has practical difficulties; inhaled ergotamine has also been used. Some consider subcutaneous sumatriptan to be the acute therapy of choice in cluster attacks. Dihydroergotamine is also effective but generally has to be given by injection and is usually reserved for use in emergency settings. Intranasal dihydroergotamine and intranasal sumatriptan have also been used. Oral zolmitriptan may be considered for patients who cannot tolerate subcutaneous or intranasal sumatriptan and oxygen, or who prefer oral medication. Intranasal instillation of lidocaine has been reported to be of some benefit but most patients do not obtain complete pain relief.

Since individual attacks are difficult to treat it is probably more effective to manage cluster headache by prophylaxis once a cluster period has started. Ergotamine may be used for prevention in episodic cluster headache; it is given by mourn or rectally for limited periods of up to 2 weeks. It is often given for only 5 to 6 days in each week, which allows the patient to assess whether the cluster period has ended. Other drugs that have been used, either alone or with ergotamine, include verapamil, lithium carbonate, and prednisolone. Some consider verapamil to be the preventive therapy of choice particularly in patients with chronic long-lasting cluster periods. Lithium may also be useful for the chronic form of the disorder. Methysergide and corticosteroids are considered by some to be the drugs of choice in those with short-lasting cluster periods (less than 2 months). Pizotifen and valproate have also been tried; other drugs under investigation include gabapen-tin, melatonin, and topiramate.

Paroxysmal hemicrania is a rare variant of cluster headache and differs mainly in the high frequency and shorter duration of individual attacks. One of its features, which may be diagnostic, is its invariable response to indometacin.

Medication-overuse headache

Overuse of tings such as ergotamine, triptans, and analgesics (including opioids and combination preparations containing caffeine or butalbital) to treat headache or migraine can lead to dependence and paradoxical chronic daily headache in headache-prone patients. Such headaches do not appear to occur with regular use of analgesics to treat other disorders except occasionally in patients with a history of migraine. Medication-overuse headaches, also referred to as rebound, analgesic abuse, or analgesic-induced headaches, can be difficult to treat and are relieved by withdrawal of the offending drug, but the primary headache may still persist and revert to its previous pattern of occurrence. Furthermore, stopping abruptly can exacerbate headache and produce other symptoms of withdrawal. This may men lead the patient to resume treatment to relieve the headache thereby setting up a vicious circle. Options for outpatient treatment include either abrupt or gradual withdrawal of the overused drug. Substitution with long-acting NSAID or intramuscular dihydroergotamine has been tried in withdrawal from ergotamine or analgesics; prednisolone has also been used. However, withdrawal symptoms may persist for up to 2 weeks and detoxification from ergotamine or analgesics may require hospitalisation; intravenous metoclopramide and repetitive intravenous dihydroergotamine may be required to control nausea and vomiting and intractable headache, respectively. Although withdrawal from triptans has been reported to be of shorter duration with no intensive withdrawal symptoms, triptan overuse produces headaches at a faster rate and at lower dosages compared with ergotamine and analgesics, and is associated with an increase in migraine attack frequency. General advice on the prevention of medication-overuse headache has included limiting the frequency of use of such drugs, and starting prophylactic therapy in migraine patients having more than 2 headache days a week.

Migraine

Migraine is characterised by recurrent attacks of headache which typically last 4 to 72 hours. Attacks persisting for longer man 72 hours are referred to as status migrainosus.

The headache is usually a unilateral pulsating pain mat is aggravated by movement and is usually of sufficient severity to disturb or prevent daily activities. It is frequently accompanied by nausea, vomiting, or other gastrointestinal disturbances and mere may be photophobia and phonophobia. Migraine with aura (classic migraine) is characterised by an aura consisting of visual or sensory symptoms that lasts less man an hour. The headache usually follows the aura directly, or within 1 hour, but may begin simultaneously with the aura. In addition, aura can occur without headache. Migraine without aura (common migraine) is the more common form occurring in about 75% of patients with migraine. Premonitory symptoms may occur before a migraine attack (with or without aura). Familial hemiplegic migraine is a rare syndrome in which migraine with aura may be preceded or accompanied by dysphasia, confusion, and hemiparesis. Basilar-type migraine is another rare form of migraine with aura in which mere may be disturbances of the brain stem or occipital lobes accompanied by symptoms such as decreased level of consciousness, vertigo, ataxia, dysarmria, and diplopia. Migraine is described as a neurovascular headache. Traditionally, intracranial vasoconstriction was considered responsible for the aura and extracranial vasodilatation for the headache. However, it appears that vascular events may be secondary to neuropathic changes and the liberation of vasoactive substances including serotonin (5-HT), catecholamines, histamine, kinins, neuropeptides such as calcitonin gene-related peptide (CGRP), and prostaglandins.

There are several factors mat may precipitate migraine attacks. These include anxiety, physical and emotional stress, a change in sleep pattern, bright lights, fasting, some foods, and menstruation. Menstrual migraine has no specific definition, but it is believed to occur around the time of menstruation and to be characterised by attacks without aura. Migraine may also be precipitated by drugs including combined oral contraceptives and oestrogens, and glyceryl trinitrate. The frequency of migraine attacks can be reduced if such precipitating factors can be identified and avoided. Quiet, darkness, and sleep can ease an attack, with sleep heralding recovery.

Treatment. There is evidence mat therapy tailored to the severity of individual disease from the outset (stratified care) is preferable to beginning with simple analgesics and adjusting treatment subsequently according to response (step strategy).

Simple analgesics (paracetamol or aspirin and other NSADDs) are effective if taken at the earliest signs of an attack. Weak opioid analgesics such as codeine are sometimes included in oral compound analgesic preparations. However, many consider that opioids are best avoided, especially in patients who experience frequent headaches, to decrease the risk of medication-overuse headaches. Other drugs used with analgesics in antimigraine preparations have included caffeine and the sympathomimetic vasoconstrictor isomemeptene.

If the initial treatment of migraine is delayed, absorption of oral tings may be compromised by development of gastric stasis and nausea and vomiting; antiemetics such as bu-clizine and cyclizine, and the prokinetic drugs metoclopramide and domperidone are often included in compound antimigraine preparations. Prokinetic tings also have the advantage of promoting gastric emptying and normal peristalsis. Dispersible and effervescent analgesic preparations are preferable because of their more rapid absorption. If nausea and vomiting are prominent rectal administration may be necessary.

Attacks not responding to simple analgesics or NSADDs may be treated with specific antimigraine tings such as the selective serotonin (5-HT1) agonists (e.g. sumatriptan) or the ergot derivatives ergotamine and dihydroergotamine; poor absorption and adverse effects limit the use of ergot derivatives and selective serotonin (5-HT1) agonists are generally preferred.

Serotonin (5-HT1) agonists are highly effective in relieving the pain and nausea of a migraine attack. There are a number of triptans available; patient characteristics and preferences vary in response to use and can sometimes be unpredictable. Some patients experience recurrence of the headache within 24 to 48 hours and often respond to a second dose. Finding the best triptan to suit the individual patient may involve trial and error. Triptans should not be used in patients wim major risk factors for, or suffering from, cardiovascular disease. The main concern wim all triptans is their potential for coronary vasoconstriction and no triptan appears to be safer man the others.

If ergotamine is used it should be given at the first warning of an attack; the earlier it is given, the more effective the treatment. Since its oral bioavailability is poor and may be reduced further during a migraine attack, ergotamine has sometimes been given in sublingual or rectal preparations. Ergotamine can also exacerbate nausea and vomiting; metoclopramide or domperidone, or in severe cases the phenothiazines chlorpromazine or prochlorperazine, may be given. Dihydroergotamine may be of use if parenteral treatment is required; it can also be given intra-nasally but mere is less experience with mis route.

Patients who rapidly develop severe migraine may be given parenteral dihydroergotamine or sumatriptan. Some consider parenteral metoclopramide to be suitable first-line treatment. If there is no response to these drugs, dopamine antagonists such as chlorpromazine or prochlorperazine given parenterally may be effective in relieving the pain of acute migraine attacks. Prolonged attacks (status migrainosus) may require intravenous administration of dihydroergotamine with metoclopramide.

Other drugs that may be given alone or in combination include corticosteroids or pethidine. Lidocaine has been given intravenously for the emergency treatment of migraine; intranasal lidocaine has also been hied. The opioid agonist-antagonist butorphanol, given by nasal spray, has been advocated, but its place in therapy, if any, remains to be established. Other drugs under investigation include botulinum A toxin and CGRP antagonists; intravenous valproic acid has also shown promise in aborting acute attacks.

Guidelines have been issued for the treatment of migraine in children and adolescents. For acute treatment, ibuprofen and paracetamol were found to be effective in children aged 6 years and over; sumatriptan nasal spray should be considered in those aged 12 years and over.

Prophylactic treatment should be considered for patients in whom abortive measures are ineffective or migraine attacks occur frequently, or for those with less frequent but severe or prolonged attacks. Some recommend prophylaxis if attacks occur more often than once or twice a month. Prophylaxis can reduce the severity and/or frequency of attacks but does not eliminate mem completely and patients still need additional abortive or symptomatic treatment. Drugs suggested for prophylaxis have a range of actions which reflects uncertainty over the pathogenesis of migraine. It is important to give prophylactic tings for an adequate period before assessing their efficacy. Once an optimum effect has been achieved the need for continuing prophylaxis should be reviewed at intervals of about 3 to 6 months.

The main prophylactic drugs are beta blockers, tricyclic antidepressants, and the antiepileptics, topiramate and valproate. Propranolol is considered by many to be the prophylactic drug of choice. Lethargy appears to be the most common adverse effect. Other beta blockers reported to be effective are those that, like propranolol, possess no intrinsic sympathomimetic activity, which include atenolol, metoprolol, nadolol, and timolol. The potential for beta blockers to interact wim some serotonin (5-HT1) agonists and ergotamine should be borne in mind. Tricyclic antidepressants, particularly amitriptyline, given in gradually increasing doses at night are useful for preventing migraine, especially in patients who also have depression or tension-type headache, although antimuscarinic adverse effects may occur. Valproate is also used for preventing migraine. Nausea appears to be the most common adverse effect. Topiramate is the main alternative to valproate. Weight loss and paraesmesia are commonly reported adverse effects. Topiramate and valproate are particularly useful in patients who also have epilepsy or bipolar disorder.

Other drugs have been used for the prophylaxis of migraine: pizotifen, an antihistamine and serotonin antagonist, has been widely used but evidence for its efficacy is limited; it may be tried in children. Of the tings with calcium-channel blocking activity, flunarizine appears to be effective, and has been suggested for use in children, and verapamil may be useful, but evidence for the efficacy of other calcium-channel blockers such as diltiazem, nifedipine, or nimodipine is less convincing; NSADDs may be worm trying. The use of memysergide, a potent serotonin antagonist, has declined because of serious adverse effects, in particular retroperitoneal fibrosis. MAOIs such as phenelzine have been used occasionally but are best reserved for severe cases refractory to other forms of prophylactic treatment. Cyproheptadine, an antihistamine and serotonin antagonist, has been used for migraine prophylaxis, particularly in children. Other drugs used for the prophylaxis of migraine have included butterbur, clonidine, cyclandelate, indoramin, feverfew, and the ergot derivative metergoline. Positive results have been seen wim magnesium and riboflavin. Other drugs still under investigation, which have shown potential for prevention of migraine attacks are: baclofen, botulinum A toxin, candesartan, gabapentin, lisinopril, andvenlafaxine.

Post-dural puncture headache

For the management of headache associated wim lumbar puncture or spinal anaesthesia, see Post-dural Puncture Headache under Local Anaesthetics.

Tension-type headache

Tension-type headaches, also referred to as muscle-contraction headaches, are probably the commonest form of headache. They are characterised by bilateral pain, which unlike migraine is continuous and non-pulsatile. The pain is often described by the patient as feeling like a tight band pressed around the head. Headaches of this type may be precipitated by many factors including psychosocial stress or muscular stress. Many patients also have associated symptoms of anxiety or depression. Tension-type headaches and migraine often co-exist and may men be referred to as combination or mixed headaches. Some patients only experience isolated acute attacks of tension-type headache (episodic tension-type headache), but others may develop chronic tension-type headache which is difficult to treat.

Treatment is aimed at removing the underlying causes where these can be identified. Simple massage may help if muscle contraction is a prominent component of the pain. Non-opioid analgesics, such as aspirin or other NSAIDs and paracetamol, may be tried for individual acute attacks of headache, but analgesic overuse must be avoided as this can lead to chronic headache resistant to other measures (see Medication-overuse Headache, above). Opioids alone or in combination preparations with other analgesics should also be avoided. Hypnotics or sedatives have sometimes been used in combination preparations wim analgesics in the management of tension-type headache mat disrupts sleep but, because of the potential for abuse, they should be avoided in chronic headaches. Muscle relaxants appear to have little place in the management of tension-type headache; although some patients may respond, results are generally disappointing. Other drugs that have been tried include valproate and botulinum A toxin.

Prophylaxis is preferable to regular short-term use of analgesics in controlling chronic tension-type headache. Tricyclic antidepressants, particularly amitriptyline, are generally considered as first choice, although benefit is rarely complete. The mode of action is unclear and appears to be independent of any antidepressant action. In most cases, improvement is seen wim low doses, but full antidepressant doses are necessary in the presence of underlying depression. Addition of a beta blocker such as propranolol may sometimes be of benefit for patients wim some migraine features.

Axert: Introduction

During a migraine headache attack, changes in brain activity induce inflammation of blood vessels and nerves in the head. Attacks may be triggered by alcohol, certain foods, too much or too little sleep, menstruation, emotional stress, or environmental factors. The “triptan” family of drugs, which bind to serotonin receptors in the brain, is currently the most effective class of agents for treating migraine headache. Sumatriptan (Imitrex, manufactured by Glaxo Wellcome) was the first serotonin agonist to be approved for treating migraine, but the search continues for even more effective agents with fewer side effects.

Axert (almotriptan malate) is one such drug, marketed by Pharmacia & Upjohn and developed by Almirall Prodesfarma, S.A., Spain, where the drug is currently available. Pharmacia & Upjohn filed an New Drug Application for Axert with the FDA on December 17, 1999, for the treatment of acute migraines in adults, and the FDA is currently evaluating data on the drug’s safety and effectiveness. Data presented at the annual meeting of the American Academy of Neurology (AAN) in May 2000 indicate that Axert is as effective as sumatriptan, but with fewer adverse side effects.

Axert: Clinical Study Results

In one reported at the AAN meeting, 1,173 adult patients took a single dose of either Axert 12.5 mg (591 patients) or Imitrex 50 mg (582 patients) at the onset of a migraine attack. Both treatments relieved pain within two hours after taking the drug (58% for Axert vs. 57% for Imitrex). Similar pain relief was also observed between the treatment groups at 30 minutes and one hour.

Fifteen percent of patients treated with Axert experienced side effects compared with 19% of Imitrex patients. A significant difference was reported in the number of patients reporting chest pain: 0.3% of the group treated with Axert and 2.2% of the Imitrex group. The most frequently reported side effects, each of which was reported by less than 3.5% of patients in either group, were nausea, dizziness, and sleepiness. Patients receiving Axert reported that they were less bothered by side effects than those receiving Imitrex.

In another study reported at the meeting — a six-month trial to study long-term safety — 582 adult patients took Axert to relieve the pain from a total of 10,605 migraine attacks. Two hours after administration, patients experienced pain relief in 76% of the attacks. Patients reported being pain-free at two hours in 49% of attacks. In 1,718 migraine relapses that occurred within 24 hours, taking a second dose of Axert relieved pain in 86% and abolished pain in 59% at two hours.

Axert: What You Should Know

The most frequent side effects associated with Axert are nausea, dizziness, and drowsiness. Patients who are also taking propranolol may do so in conjunction with Axert without any interaction.

A family history of migraines also increases your risk for both ischemic and hemorrhagic strokes even if you do not have them yourself. Hemorrhagic stroke occurs when a vessel breaks, allowing blood to bleed into the brain. This deprives cells upstream of an oxygen supply and they die. If enough blood escapes and puts pressure on other vessels, circulation and oxygen will be cut off to other areas of the brain

High blood pressure, use of birth control pills, and/or smoking increase this risk significantly because they cause blood vessels to constrict and limit blood flow to the brain. Changes in frequency or type of migraines were not found to be a predictor of stroke in study participants who use birth control pills. However, if taking birth control pills you should tell the physician prescribing them about your migraines or any other type of headache you experience.

Up to 40 percent of strokes occurring in women with migraines may develop directly from this type of headache.

The findings, which were presented at the Diamond Headache Clinic’s Headache Update `99, analyze the compiled data of three different studies. Each study compared groups of participants that took either zolmitriptan (Zomig) or a placebo, though no one knew which pill they were taking.

The studies show that migraines most often occur between six and seven in the morning when people are getting ready for work and school. Taking the medication between 6 and 9 a.m. provided headache relief for an average of 23 hours for those who responded to the medication. Participants who responded to the placebo had an average relief time lasting only eight hours.

Approximately 60 percent of those taking a single dose (2.5 mg) of zolmitriptan had a positive response within two hours of taking the drug, whereas only 22 to 39 percent of the people taking the placebo responded positively in that amount of time.

The researchers concluded that zolmitriptan (Zomig) does provide long-acting, reliable relief for migraine, despite the time of day the headache occurs.

The manufacturer suggests that the medication is appropriate to treat acute migraines in adults, either with or without an aura. It’s not recommended if you have hypertension, ischemic heart disease, or another significant type of heart condition.

Side effects include feelings of pain, pressure, and heaviness or tightness in various parts of the body, including the chest. Adverse effects that appeared during clinical trials ranged from mild to moderate, with the most prevalent being asthenia (weakness), dizziness, and nausea.

The team found that inflammatory agents released during a migraine seem to signal certain nerve cells (neurons) in your brain to increase production of a neuropeptide, calcitonin gene-related peptide, or CGRP. One result of CGRP’s presence is to stimulate your brain tissue to release more inflammatory agents. The new inflammatory agents send more signals to the neurons to release more CGRP, the cycle continues, and so does your migraine.

At present, the most effective migraine medication on the market is sumatriptan, which provides relief for 50 to 75 percent of the people who use it. Even though scientists know it works, they don’t understand why or how.

While studying the drug, the Iowa researchers discovered that sumatriptan keeps calcium levels high in the neurons. In most cases, a high-calcium level also means a high level of neuropeptides in the affected neurons. However, when the participants took sumatriptan, CGRP didn’t increase, which may be one reason why this drug works so well against migraines. If the CGRP doesn’t increase, then the inflammatory agent-CGRP cycle described earlier is broken.

Interestingly, the same signal (calcium release) can give two different reactions depending on the strength and duration of the signal. A short, fast burst of calcium causes an increase in the CGRP, which continues the cycle and your headache. However, if the calcium increase is a slow, steady rise, it actually lessens the amount of CGRP that is released. Researchers believe it is this second type of calcium increase that sumatriptan brings about.

As a follow-up to this study, researchers will look for the exact mechanism for the initial release of CGRP, with the hope that blocking this action would divert the migraine.

Four patients in the study described various symptoms that preceded the onset of cluster headaches. The first patient’s symptoms were described as “eye discomfort,” a heightened state of anxiety, and a feeling of having “something inside my head.”

The second patient complained of eye discomfort that was aggravated by reading or noise. The third patient reported feeling numbness in the left temple about a week before the onset of the headaches. And the last patient described discomfort on the right side of the head.

Cluster headaches are similar to migraines and occur as often as two or three times a day over a period of weeks. They come on suddenly, and sufferers experience throbbing pain behind the nostril and one eye. The attacks rarely last longer than two hours, and it may be weeks or months in between attacks.

This study is important, said researchers, because it demonstrates that “changes occur in the nervous system that anticipate the autonomic (self-controlling) and painful manifestations.” Also, recognizing that warning symptoms can occur before the severe pain strikes is the first step in developing preventive treatment and a better understanding” of the cause of cluster headaches.

Headaches not directly due to injury or disease are called primary headaches. Included in this category are tension, migraine, and cluster headaches. Magnetic resonance imaging (MRI) or computed tomography (CT) scans have consistently shown no structural abnormality in these people—until now.

With a new type of imaging called voxel-based morphometry, British researchers have conducted a study that shows that people with cluster headaches have an abnormality in the part of the brain called the hypothalamus. The hypothalamus lies deep in the brain and is responsible for maintaining a constant internal environment, including temperature and wakefulness, and carrying out certain behavior patterns—sexual behavior, physical expression of emotions, and pain and pleasure. It affects the nervous system directly and through hormones.

Researchers compared the brain images of 25 people with cluster headaches to the brain images of 29 people in the control group. Fourteen of the headache sufferers had a headache during the test.

The tests showed that all the people with cluster headaches had a greater density of grey matter in their hypothalamus. Researchers then compared the two groups using positron emission tomography (PET). The PET scans showed both structural and functional abnormalities in this same area of the hypothalamus.

Now that an exact area of the brain has been identified with cluster headaches, researchers are hoping to develop more effective treatments for these and other types of primary headaches.

However, they can’t say that the extra grey matter actually causes the headache, just that all the participants with cluster headaches had this hypothalamic density. Perhaps the increased density is the result of the headaches, not the cause. Further testing will be needed to explore the exact association between primary headaches and hypothalamic abnormality.