Triptans

Acute Migraine Therapy

Ninan T. Mathew, M.D., F.R.C.P.(C)
Director, Houston Headache Clinic

Pathophysiological Basis of Acute Migraine Pharmacotherapy.

It is important to recognize that migraine pain as distinct from other kinds of pain namely, nociceptive and neuropathic. Migraine has a unique pathophysiology and pharmacology; therefore, it is inappropriate to equate migraine pain with other types of pain.

Pain of migraine may be due to activation of the trigeminal vascular system (The trigeminal nerve and the blood vessel it supplies, predominantly intracranial blood vessels, including dural blood vessels and major cerebral arteries.).¹ There are four components of the pathophysiology of migraine pain; (a) vasodilatation, predominantly of the intracranial extracerebral blood vessels; (b) a rapid onset of neurogenic (sterile inflammation) in the perivascular areas; (c) activation of the central trigeminal system – namely, spinal tract of the trigeminal nerve (trigeminal nucleus caudalis) and its connections centrally including functional connections to the nausea vomiting centers of the brain (nucleus tractus solitarius);² (d) sensitization of 1^st, 2^nd and 3^rd order trigeminal neurones.³ Drugs, which are effective for relieving the symptoms of acute migraine, should have effects on these mechanisms. 

Serotonin (5-HT) and Migraine

Serotonin has been implicated in migraine pathophysiology for quite a long time. Intravenous serotonin may relieve a migraine attack; however, it is unpleasant for clinical use. Based on that observation, specific serotonin agonists were developed and sumatriptan was the first to be introduced in 1991.⁴ Many of the drugs used in the acute treatment of migraine as well as prophylactic treatment have some link to serotonin.

Serotonin Receptors

Among the various families of human 5-HT receptors, 5-HT₁, 5-HT₂ and 5-HT₃ are relevant to migraine. The 5-HT₁ family of inhibitor receptors is subdivided into 5-HT_1A, 5-HT_1B, 5-HT_1D, and 5-HT_1F.⁵ Most of the specific agents used in the treatment of acute migraine are 5-HT_{1B, 1D} agonists. Many also have affinity to 5-HT_1F. Specific5-HT_1F agonists are being developed at the present time.

Intracranial blood vessels have a rich supply of 5-HT_1B receptors. 5-HT_1B receptors are also found to a smaller degree in the coronary arteries; hence, 5-HT_1B agonists would cause some degree of vasoconstriction in the coronary arteries. The central trigeminal system also contains 5-HT_1B receptors.

The 5-HT_1D presynaptic receptor, on the other hand, is on trigeminal nerve endings and in the central trigeminal system. Stimulation of this receptor causes reduction in the release of vasoactive polypeptides such as CGRP and substance P, and hence reduction in the degree of neurogenic inflammation.

Mode of Action of  5-HT₁ Agonists

5-HT_{1B, 1D} agonists cause (1) constriction of the dilated intracranial blood vessels, (2) they reduce neurogenic inflammation around the blood vessels by inhibiting the release of neuropeptides such as CGRP and substance P and (3) deactivates the central trigeminal system, thereby, reducing the pain processing as well as nausea and vomiting associated with migraine.⁶ When a triptan (5-HT_1B,1D agonists) is used in migraine patients, it reduces the nausea and vomiting as well as the pain and thereby not requiring additional antinausea medicines in the majority of patients.

5-HT₂ excitatory receptors are important, as many of the preventive medications such as methysergide and propranolol are 5-HT₂ antagonists.

The 5-HT₃ family is also relevant to migraine pharmacotherapy. The nausea and vomiting associated with migraine may be partly due to stimulation of 5-HT₃ receptors, which are found predominantly in the nausea, vomiting centers of the brain stem. 5-HT₃ antagonists such as metoclopramide are useful in treating migraine associated nausea.

Therapeutic Options in the Treatment of Acute Migraine

Three classes of drugs, which have scientific validity in the treatment of migraine, include:

(1) 5-HT₁ agonists,
(2) dopamine antagonists and prokinetic agents, and
(3) prostaglandin inhibitors.

5-HT₁ Agonists

Pharmacology

5-HT₁ agonists can be divided into selective and nonselective (Table 1). All triptans are selective because of their specific affinity to 5-HT_1B/5-HT_1D group of receptors. Another group of drugs, which are specific 5-HT1F receptor agonists (SSOFRA), is under development.
The nonselective 5-HT₁ agonists include ergotamine and dihydroergotamine. They have a wider spectrum of receptor affinities outside the 5-HT₁ system, which include 5-HT₂, 5-HT₃ adrenergic and dopaminergic receptors. Because of their affinity to dopaminergic receptors, ergotamine and dihydroergotamine cause more nausea than the triptans, which on the other hand have been shown to reduce nausea associated with migraine.

Table 1. Acute Migraine-Specific Agents

5-HT₁ Agonists

Pharmacokinetics of Selective 5-HT₁ Agonists (Triptans)

All triptans share a basic indole ring, with side chains being different. Because of the differences in the side chains, the pharmacokinetic properties also differ. Important pharmacokinetic parameters that determine efficacy are T-max, half-life (t ½), bioavailability, lipophilicity and CNS penetration and other receptor affinities.7
Table 2 lists the pharmacokinetic properties of triptans. Table 3 shows various triptan preparations for migraine management. Eletriptan, almotriptan and frovatriptan are expected to be available soon.

Table 2. Pharmacokinetics of Triptans

*Tmax during migraine

Table 3. Triptans

*Not yet available ND – Not Determined

T-max

Sumatriptan has a T-max of two hours outside a migraine attack and 2.5 hours during migraine. Two agents, which have been shown to have lesser T-max, are rizatriptan and eletriptan (1 to 1 ½ hours). The T-max of rizatriptan is not prolonged during migraine, which may be an advantage accounting for the rapid onset of action with oral rizatriptan.

Half-life

Sumatriptan has a half-life of two hours and receptor binding is reversible resulting in relatively short lasting biological effects. On the other hand, naratriptan has the highest half-life among the currently available triptans, nearly six hours. Frovatriptan, soon expected to be available has an even longer half-life, 25 hours. Because of longer half-life, the effect of naratriptan in relieving headache symptoms may persist up to 24 hours and recurrence rate of headache is lower than that with sumatriptan. However, its time of onset of action is longer than other agents.

Oral bioavailability is an important factor and may account for consistency in response with repeated use. Sumatriptan tablets have a low bioavailability (15%); all second generation triptans have better oral availability. Naratriptan and almotriptan have close to 70% bioavailability and the bioavailability of rizatriptan is in the range of 40 to 45%, as is that of zolmitriptan.

Lipophilicity

Lipophilicity determines whether the medications cross the blood brain barrier. All new generation triptans, namely zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan cross blood brain barrier, as does DHE. On the other hand, sumatriptan has not been shown to cross blood brain barrier when the blood brain barrier is intact. It is possible that during a migraine attack, there is disruption of blood brain barrier and hence, sumatriptan may get into the central nervous system. Whether central effects of triptan have any clinical relevance to efficacy is still not determined.

Clinical Use of Triptans

Sumatriptan (Imitrex)
 Sumatriptan, the first to be introduced is available in three forms, tablet (25 mg, 50 mg, and 100 mg), nasal spray (5 mg and 20 mg) and 6 mg subcutaneous injection. Subcutaneous injection is available in two forms, as a pre-filled syringe, which is very convenient for use and as a stat dose auto-injector.

Subcutaneous sumatriptan with 90% bioavailability is the most efficacious of all triptans, with 81% efficacy at two hours.⁸ The onset of action is extremely rapid, within ten minutes, and is most appropriate for patients with rapidly peaking headache conditions, such as cluster headache or severe nocturnal “crash migraine.” Subcutaneous sumatriptan may be associated with more triptan symptoms, which include chest discomfort, heaviness of the chest and throat, paraesthesias involving the head and neck and the extremities, anxious feeling and mild difficulty breathing. Of these symptoms, chest pressure and discomfort are the most worrisome for the patient. There is no evidence that the chest symptoms induced by triptans are due to coronary spasm. Esophageal, pulmonary, musculoskeletal and anxiety/panic mechanisms are implicated to explain chest symptoms. However, it is important to be sure that triptans are not prescribed to patients with known coronary artery disease and to those with multiple uncontrolled risk factors for vascular disease.

Recommended dose of sumatriptan nasal spray is 20 mg for adults and 5 mg for small children. Efficacy of sumatriptan nasal spray is intermediate between tablets and subcutaneous injection. The time of onset of action after sumatriptan nasal spray is about 15 to 20 minutes. If rapidity of onset of action is important, sumatriptan nasal spray is a reasonable option. Sumatriptan nasal spray has recently been shown to be effective in adolescents with migraine and may soon obtain an indication for that section of the headache population. It has been shown to be effective in acute cluster headache recently.⁹ Recurrence rate in children and adolescents is lower. Two-hour efficacy of sumatriptan nasal spray is approximately 64%.¹⁰

Sumatriptan tablets are slower in onset compared to injections and nasal spray. It begins to show its effect around 30 minutes and the maximum two hour efficacy (from severe or moderate headache to mild or none) is 56 to 61 percent.¹¹ Fifty to 100 milligram is the recommended oral starting dose of sumatriptan with a 24 hour maximum of 200 mg.

A number of studies have shown sumatriptan to be effective in special subgroups of migraine patients, such as women with menstrual migraine, migraineurs with asthma, those with early morning migraine, and in children and adolescents. Sumatriptan is generally not associated with central nervous system symptoms, unlike the newer triptans, which may cause such symptoms as somnolence, asthenia, and dizziness. This may be based on the fact that sumatriptan poorly penetrates the central nervous system.

Zolmitriptan (Zomig)
olmitriptan (Zomig) is available in 2.5 and 5 mg tablets and a rapimelt preparation. A nasal spray is under development. Zolmitriptan has been shown to have both a central and peripheral action on the trigeminal vascular system. Five randomized double blind placebo controlled trials found zolmitriptan to be highly effective in acute migraine.^12,13 From an efficacy point of view, 5 mg zolmitriptan may have slightly higher two-hour response rate. However, head to head comparisons with 100 mg sumatriptan did not show any statistically significant difference in efficacy. Average time of onset of action is 45 minutes. Recurrence rate is somewhat similar to that of sumatriptan. It has been shown that the second dose of zolmitriptan is useful for recurrence and for patients who have obtained partial relief after the first dose.  One recent study has shown that zolmitriptan may be effective in oral sumatriptan non-responders but rizatriptan performed better in this study population.¹⁴

Naratriptan (Amerge)
Naratriptan (Amerge) is somewhat distinct from other triptans because of its longer half-life, very good oral bioavailability and excellent tolerability. These features are translated to longer duration of action (up to 24 hours) and lower recurrence of headache.¹⁵ However, two-hour efficacy rate of naratriptan is not as good as sumatriptan, zolmitriptan, rizatriptan, eletriptan, or almotriptan and it is slower in its onset of action. Naratriptan may be most useful in patients with slow onset prolonged migraine such as menstrual migraine and habitually prolonged nonmenstrual migraine episodes. In a comparative study, naratriptan has been shown to be more effective in moderate migraine attacks, where sumatriptan has better efficacy in severe attacks. Recurrence of headache is lowest for naratriptan in comparison with other currently available triptans. Tolerability is excellent with many studies showing that adverse events were similar to that of placebo. Naratriptan may be useful in sumatriptan nonresponders and those with multiple recurrences from sumatriptan.

Miniprophylaxis of menstrual migraine using naratriptan has been studied with 1 mg and 2.5 mg naratriptan twice daily during menstrual time.¹⁶ Naratriptan 1 mg bid effectively reduced menstrually associated migraine compared to placebo.¹⁶

Rizatriptan (Maxalt)
Because of shorter T-max and fairly good bioavailability many studies have shown that oral rizatriptan (Maxalt) results in a larger percentage of patients with relief at two hours than is obtained with other oral triptans currently available.^17,18 Pain-free response at two hours is also higher with rizatriptan. Direct comparative studies of 100 mg of sumatriptan with 5 and 10 mg of rizatriptan showed that statistically significantly higher percentage of patients responded to 10 mg rizatriptan compared to 100mg sumatriptan.¹⁹ At one and a half and two hours, the response to 10 mg rizatriptan was numerically superior to that of 100 mg sumatriptan. In the same direct comparative study, the pain-free state was better with rizatriptan 10 mg compared to 100 mg of sumatriptan at one and a half and two hours.¹⁹

Time to headache relief analysis showed that 10 mg rizatriptan was more rapid in onset compared to 100 mg sumatriptan. This has been analyzed using time to headache relief, a survival curve methodology,²⁰ that demonstrated hazard ratio for loss of headache, which is greater likelihood to have headache relief, of 1.21 (95% CI 1.02 to 1.4 P <.05).²¹ There was similar superiority for the headache-free endpoint of 1.29 (95% CI 1.02 to 1.63), again in form of rizatriptan 10 mg.²¹ Calculation of hazard ratios for two hour headache response and two hour pain-free state also showed superiority of rizatriptan 10 mg over 100 mg of sumatriptan and 2.5 mg of zolmitriptan.²²

Sustained pain-free, (pain-free at 2 hours, no recurrence for 24 hours, no rescue medication for 24 hours) is higher for rizatriptan 10 mg, compared to sumatriptan 100 mg and zolmitriptan 5 mg.²³ Average number of tablets consumed per migraine attack was lowest for rizatriptan (rizatriptan 1.2, sumatriptan 1.7, naratriptan 1.4, zolmitriptan 1.6).²⁴

Oral sumatriptan non-responders responded to rizatriptan better than to zolmitriptan, both in efficacy and time of onset of action.¹⁴

Rizatriptan is available in two forms, tablets and MLT. Maxalt MLT is a

convenient route of administration over the tongue. The medication dissolves quickly in the saliva, which is swallowed without the need for water. It can be taken very discreetly and is a preferred route of administration for many whom may have a headache developing while they are at work such as teachers or office workers. There is no evidence that efficacy of Maxalt MLT is superior to that of Maxalt tablets.²⁵

Central side effects of rizatriptan include somnolence, dizziness and asthenia, which are seen slightly more with 10 mg than with 5 mg. The incidence of chest and other triptan symptoms is relatively low with rizatriptan.

Eletriptan (Relpax)
Eletriptan has good basic characteristics: relatively well absorbed with a short T-max and excellent bioavailability. A slower rate of dissociation from 5-HT_1D/5-HT_1B receptors and longer half-life may suggest longer duration of action and lower recurrence rate, as shown with 80 mg (placebo 40 vs 21% P<0.01).²⁶ Two hour headache response was 62% for 40 mg and 65% for 80 mg compared to 19% with placebo, resulting therapeutic gain of 43% for 40 mg and 46% fro 80 mg Eletriptan.⁷ Headache free were 32% and 36% respectively compared with 3% in the placebo group. Eighty milligram eletriptan caused central side effects in approximately 8 - 9% of patients.

Almotriptan (Axert)
Almotriptan has the highest oral bioavailability among all triptans (80% vs 14% for sumatriptan). T-max of almotriptan is not much better than sumatriptan. Optimal oral dose is 12.5 mg. One comparative study reported that 12.5 mg almotriptan was comparable to 100 mg sumatriptan.²⁷ Statistically significant response has been demonstrated for 12.5 mg at 30 minutes. Recurrence rate was 18 – 30 in three different trials.²⁸ Almotriptan has a very satisfactory tolerability profile, resembling naratriptan, however, almotriptan is faster-acting than naratriptan. Almotriptan, therefore, combines the efficacy of sumatriptan with tolerability of naratriptan.

Frovatriptan (Frovaelan)
Plasma half-life of frovatriptan is 25 hours. T-max of Frovatriptan is not much better than sumatriptan, and is less than that of rizatriptan. Oral bioavailability, though higher than sumatriptan is not as good as other triptans. Median time to headache response with frovatriptan is 3.3 hours,²⁹ much slower than other triptans. Reported recurrence rate in patients respond at 4 hours was significantly lower 8 – 24% compared to 24 – 40% for placebo.²⁹ Frovatriptan has the lowest recurrence rate, however, the slow speed of onset of action and the poor initial efficacy makes it less attractive than agents like rizatriptan.

A study done in patients with high risk of coronary artery disease (CAD) or with known CAD, reported that frovatriptan was well tolerated and was not associated with an increase in cardiovascular abnormalities.³⁰

Comparative Efficacy of Oral Triptans

Since direct comparisons between all triptans are not available, the next best way of assessing a relative efficacy is comparisons of drug performance based on results of different clinical trials. Such comparisons are never fully reliable, because studies are conducted at different times, with different samples of patients, by different investigators using different criteria or different interpretation of the same criteria, and under different conditions (dose regime, etc). Quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study. However, meta-analysis of all the published studies for currently used triptans is available (Table 4).³¹
It is obvious that rizatriptan 10 mg has a better two hour efficacy rate compared to all the other three oral triptans. The therapeutic gain is also higher for rizatriptan in another analysis.³²

Table 4. Headache Response and Therapeutic Gain* for Selected Oral Triptans at 2 hrs.

Meta-analysis of All Published DATA

From meta analysis and comparative trials, it appears that compared to benchmark oral sumatriptan,

- Rizatriptan and eletriptan show better efficacy,
- Naratriptan and frovatriptan are inferior in efficacy, but have better tolerability and low recurrence,
- Rizatriptan has better consistency,
- Almotriptan has equal efficacy, with better tolerability,
- Eletriptan has higher initial response and low recurrence rate,
- Sustained relief is best for rizatriptan and eletriptan.

Table 5 compares the statistical time of onset of action of various triptan preparations. Among the oral triptans, rizatriptan appears to have the fastest onset of action followed by sumatriptan tablets. Zolmitriptan has an average 45 minutes of time of onset of action whereas naratriptan takes approximately an hour.

Table 5. Time of Onset of Action of Triptan Preparations

Statistical Onset of Action

Contraindications for Triptan Therapy

Table 6A lists the contraindications for triptans.

Table 6A. Contraindications for Triptan Therapy

· Uncontrolled Hypertension
· Ischemic Heart Disease
· Prinz-Metal Angina
· Cardiac Arrhythmias
· Multiple Risk Factors for Atherosclerotic Vascular Disease
· Primary Vasculopathies
· Basilar and Hemiplegic Migraine

Practical Considerations in Triptan Therapy

Table 6B lists the aspects of triptan therapy, which the clinician should be familiar with.

Table 6B. Practical Considerations in Triptan Therapy

“ Triptan Symptoms
– Adverse Events
· Recurrence
· Partial Response and Headache Persistence
· Non-response
· Inconsistency
· Tachyphylaxis
· Multiple Recurrences and Rebound
· Safety

Triptan Symptoms

Some patients who use triptans may develop a group of symptoms, which is referred to as, “triptan symptoms.” A list of common triptan symptoms is listed on Table 7. These symptoms are more often seen with injectable sumatriptan and less often with oral triptans. There is no evidence that these symptoms are due to coronary spasm. (See the section on safety.). These symptoms have to be explained to the patient in order for them not to panic if it happens. The newer triptans namely, naratriptan, rizatriptan, zolmitriptan, eletriptan, almotriptan and frovatriptan appear to have less of those symptoms than injectable sumatriptan. The incidence of chest symptoms are lower with almotriptan. However, the newer triptans may have more central side effects such as somnolence, dizziness and fatigue. In therapeutic doses, none of these central symptoms are severe enough to discontinue the medication. Patients generally get used to some of these mild adverse events.

Table 7. Triptan Symptoms

· Tingling sensation involving the head or any other part of the body
· Numbness
· Strange feeling
· Sensation of warmth, heat, burning, cold
· Pressure sensations – throat, chest, feeling of heaviness, feeling of tightness
· Anxiety
· Agitation

Recurrence

Recurrence occurs with the use of all triptans. The average recurrence rate is around 30%. Naratriptan, eletriptan and frovatriptan have been reported to have less recurrence compared to others. The patients who have recurrence are not different from those who do not show recurrence. In general, the most likely candidates for recurrence are those with prolonged migraine, those with severe attacks and those who continue to have an ongoing feeling of low-grade headache even after the first dose has relieved the more severe part of their headache.

A second dose of the same triptan is useful for treating recurrence in the majority of patients. This has particularly been shown with rizatriptan. Treatment of recurrent headaches with a second dose resulted in two-hour headache response of 82% and pain-free response in 49% in one study using rizatriptan.

In those who have habitual recurrence with one triptan may be switched to another triptan as the recurrence rate may vary in individual patients when they use different triptans. Recurrence may be less with early treatment while the pain is still mild. Combination of a triptan with NSAIDs or COX₂ inhibitor may also reduce recurrence rate. In a recent study, a combination of rizatriptan 10 mg and rofecoxib 25 mg resulted in higher sustained pain-free response, than with either medication alone.³³

Partial Response and Headache Persistence

Some patients may get a partial response to triptan tablets. In that case, a second dose is useful in the majority. This has been shown to be true in case of zolmitriptan.

Nonresponse

Some patients do not respond to triptans well. If a patient does not respond to a particular triptan, it is prudent to try another triptan. It has been shown that sumatriptan nonresponders do respond to zolmitriptan 5 mg and rizatriptan 10 mg in an open crossover study.¹⁴ One hundred and twenty attacks each were studied with zolmitriptan 5 mg and rizatriptan 10 mg. The overall response to rizatriptan was better than that of zolmitriptan and the patient’s satisfaction was better with rizatriptan. Nineteen percent of those patients who did not respond to sumatriptan also did not respond to zolmitriptan and rizatriptan.

Lack of response to one triptan does not necessarily mean that those patients will not respond to another triptan. 

Inconsistency

Low bioavailability and inadequate absorption may be one of the reasons of inconsistency when sumatriptan tablets are used. Only 64% of patients on sumatriptan tablets respond consistently (two out of three attacks). The consistency rates for other triptans are better particularly for zolmitriptan, rizatriptan and eletriptan. With continued treatment of 12 months or longer (long-term consistency), 93% of attacks were relieved by rizatriptan in those patients who responded initially.³⁴ A better objective measure of consistency is a double-blind study and for rizatriptan, a three-way, placebo controlled, crossover study demonstrated an 86% headache response in two out of three attacks.¹⁷ These are the best published consistency data.

Tachyphylaxis

Tachyphylaxis or falling off of the response after repeated use may be seen in some patients. If that happens, one may switch them to a different triptan.

Multiple Recurrences and Rebound

Multiple recurrences and rebound with triptan use has been reported.^35,36,37 The agents, which have been cited, are sumatriptan, zolmitriptan and naratriptan. The larger and longer experience with sumatriptan may account for more reports with rebound from sumatriptan.

If rebound occurs, patients should be switched to a longer acting triptan such as naratriptan with low occurrence and prophylactic medications added. One should also evaluate the comorbidities associated with migraine in these patients, as anxious and depressed patients tend to take more medications than those with stable psychological profile.

Safety of Triptans

In the human coronary artery, 5-HT₂ receptors are more important, but 20 to 35% of the response is mediated by 5-HT₁ receptors. Accordingly, triptans moderately constricts human coronary arteries, both in vivo and in vitro. Available data indicate that all triptans have more or less the same effect on coronary arteries. Studies by Maassen Van Den Brink,³⁸ et al has showed that triptans are expected to cause only little coronary constriction on therapeutic doses in migraine patients without coronary artery disease and there are no major differences between them. However, in patients with coronary artery disease (stenosis or hyperreactivity), all triptans may still cause myocardial ischemia.

In clinical practice, between 20% (tablets) and 40% (subcutaneous injection) of patients are reported to experience tightness, heaviness, or pressure in the chest, neck or throat in association with sumatriptan treatment. ³⁹ After reports of coronary spasm, myocardial infarction, cardiac arrest after sumatriptan the main concern has been cardiovascular safety of triptans. In one report from Netherlands Center for monitoring adverse reactions to drugs, there were 29 reports of chest pain and 4 reports of myocardial infarction attributed to the use of sumatriptan.⁴⁰ In a recent review, however, it was remarked that fatal cardiovascular events are remarkably rare. ³⁹ Between 1991, the year sumatriptan was introduced, and December 1996, 39 deaths due to cardiovascular causes were spontaneously reported worldwide within 24 hours of administration of sumatriptan tablets or injection for more than a 100 million treated migraine attacks. Such reports usually do not clearly indicate the drug as the cause of the adverse event.

In vivo, it has been shown that 6 mg subcutaneous sumatriptan caused 14% reduction in the coronary artery diameters in patients undergoing coronary angiography without any clinical symptoms.⁴¹ In contrast, 1.5 mg subcutaneous naratriptan failed to induce coronary constriction in 10 patients with known or suspected coronary disease in a placebo controlled study.⁴² Although triptans have the potential of coronary constriction, the vast majority of frequent chest symptoms that occasionally mimic angina are, however, most likely not due to coronary constriction.  ECGs recorded in 119 patients complaining of chest symptoms after sumatriptan did not show any significant changes and in 23 migraine patients with these symptoms after an oral dose of 150 mg avitriptan. ECG Holter monitoring and echocardiographic monitoring did not show signs of myocardial ischemia.⁴³ Alternatively, it has been suggested that these chest symptoms after triptans could be due to esophageal spasm, intercostal muscle spasm, skeletal muscle mitochondrial impairment, or facilitation of nociceptive neurotransmission. Other rare adverse events reported after sumatriptan administration include cerebrovascular disorders and ischemic colitis, in both cases most likely due to vasospasm. A few cases of serotonin syndrome have also been reported with injectable triptan and DHE in patients on combinations of SSRIs or MAO inhibitors or lithium.⁴⁴

More Effective Ways of Using Triptans

Early Treatment
With more experience in using triptans, most clinicians and researchers would agree that early treatment with a triptan leads to better efficacy, early pain-free state and less recurrence.^45,46 Diagnosed migraine patients should be instructed to take their medications early.

Combination of Triptans With Other Agents
Combining triptans with nonsteroidal antiinflammatory agents, NSAIDs, or COX₂ inhibitors or prokinetic agent like metoclopramide may result in better efficacy and reduced recurrence, and better sustained pain-free.³³

Sequential Use of Triptans
Even though it is not recommended by the manufacturers, in clinical practice, one may combine a rapid acting triptan preparation such as sumatriptan injection or nasal spray followed by a longer acting oral tablet such as naratriptan. These kind of combinations have reduced the length of headache, reduced recurrence and also helped to cut down the total number of triptan doses taken by the patients.⁴⁷

Recognizing the Spectrum of Headaches in Migraine Patients
A recent study has shown that migraineurs may suffer from different kinds of headache namely IHS migraine (Migraine diagnosable by the International Headache Society classification criteria.)(IHS 1.1 and 1.2), migrainous headaches (1.7 of IHS classification) and tension-type headache (2.1 of IHS classification). There is some indication that triptans may be effective in all this wide spectrum of headaches suffered by patients with migraine.⁴⁸

Clinical Use of Nonselective 5-HT₁ Agonists.

Ergotamine. The oral and rectal absorption of ergotamine is erratic, displaying great interindividual variation. Bioavailability is less than 5% for the oral dosage form but is considerably higher after rectal dosing.⁴⁹ Peak plasma concentrations are reached about 1 hour after oral or rectal dosing, but plasma levels after rectal administration are as much as 20 times higher.^50,51 The biologic effects of the drug last much longer than the drug’s short elimination half-life of 2 to 3 hours would suggest. This is probably explained by the actions of one or more of its metabolites. The elimination half-life of its metabolites (20 hours) conforms closely to the duration of peripheral vasoconstriction after ergotamine administration.

Powerful and selective constriction of the external carotid artery and its branches is produced by ergotamine. Only slight alpha-adrenergic blockage occurs at doses used clinically, and the vasoconstrictor effect is mediated by a direct effect on arterial serotonin receptors.⁵² Ergot alkaloids have been found to depress the firing rate of serotonergic neurons of the brain stem raphe,⁵³ so that stabilization of serotonergic neurotransmission may be the major action of ergotamine, as appears to be the case for the preventive antimigraine drugs.

An adequate dose should be taken as soon as possible and should not be divided into half-hourly or hourly supplements; if the initial dose fails, subsequent doses usually fail also. A subnauseating dose, if possible, should be determined. A dose that provokes nausea – probably a centrally mediated side effect – is too high and may even intensify a migraine attack. The appropriate dosage of ergotamine is best arrived at by titrating the patient’s capacity to tolerate ergotamine during a headache-free period. The average dose of the suppository is one-half (1 mg), so that if encountering a patient for the first time during a headache attack, it is common to give 1 mg immediately and, if there is no improvement within 45 minutes, another 1 mg. Rectal administration is more effective. Nausea and vomiting are limiting side effects. Ergotamine is also contraindicated in coronary and peripheral artery disease.

Dihydroergotamine (DHE). About 10 years after the introduction to clinical medicine or ergotamine, DHE was studied for its effectiveness in aborting attacks of migraine and was found to be as good as ergotamine, if not better.⁵⁵ It was further noted in early studies that despite the close similarities in chemical structure, unlike ergotamine, DHE had minimal to no effects on peripheral arterial constriction. Modern studies have affirmed that DHE has only modest arterial effects⁵⁶ but is a potent venoconstrictor, allowing for its usefulness in the treatment of orthostatic hypotension. Like ergotamine, idiosyncratic hypersensitivity to the drug occasionally occurs, and rare instances of severe peripheral arterial spasm and coronary spasm have been reported.

DHE is presently available as a parenteral preparation and as a nasal spray. A major advantage of DHE over ergotamine is that the former can be given intravenously with far less nausea, and thus can terminate an acute attack quickly even when the attack is at its peak and attended by profuse vomiting and prostration.⁵⁷ A further advantage is that it does not result in physical dependence.⁵⁸

DHE for Acute Migraine. Following parenteral administration, peak plasma levels of DHE are rapidly achieved: 15 to 45 minutes after its administration, and 2 to 11 minutes following intravenous dosing, minutes after nasal administration. Plasma levels obtained after subcutaneous dosing are 40% lower than those after intramuscular administration of 1 mg. Therefore intramuscular administration of 1 mg is preferable to subcutaneous administration. Patients can be taught to self-administer intramuscular injection. After DHE nasal spray administration, plasma levels are achieved in 30 to 60 minutes.

For attacks that have already climaxed, the accepted protocol includes prochlorperazine, 5 mg intravenously, followed immediately by 0.75 mg DHE given slowly, over 2 to 3 minutes. If the attack has not begun to subside in 30 minutes, another 0.5 mg DHE is given intravenously (without perchlorperazine). Using this protocol in a prospective controlled study with patients entering a hospital emergency department because of headache, 85% were treated successfully, without the need for narcotic analgesics.⁵⁷

DHE in Intractable Migraine. Mathew et al. have documented that episodic migraine may become incessant and refractory to standard therapy.⁵⁹ For many of these patients, drug dependence cycles have become established; for others, disabling headaches continue unabated, seemingly indefinitely. The use of DHE ½ ml given intravenously every 8 hours has revolutionized the therapeutic approach to this segment of the patient population, 90% of whom become headache-free within 2 days of treatment.⁵⁸ Metoclopramide 5 mg is used adjunctly with DHE.

Dopamine Antagonist and Prokinetic Agents

There is some evidence to suggest that dopaminergic system may be activated during the initial phases of migraine, such as the prodrome of migraine.⁶⁰ The nausea and vomiting associated with migraine may also be due to activation of the dopaminergic system. In addition, there is a relative gastroparesis during acute migraine attacks, resulting in poor absorption of medications. Prokinetic agents such as metoclopramide increase gastric motility and enhance absorption, in addition to being effective antinausea drugs.

Antidopaminergic agents used in acute migraine are intravenous (IV) chlorpromazine, IV prochlorperazine, metoclopramide, IV droperidol, and domperidone. In an emergency room setting, these medications are effective alternatives to 5-HT_1D/1B agonists and opioids.

Other Agents For Acute Migraine

Recent open trial reports indicate the IV diphenhydramine (Benadryl) 50 mg is a useful agent in the emergency room.

IV valproate sodium (Depacon) given slowly has been shown to have very rapid effect in resolving a migraine attack.⁶¹ IV valproate sodium is tolerated very well and the efficacy is comparable to that of DHE.

Magnesium sulphate 1 gm given intravenously diluted in 100 ml of 5% dextrose has also been reported to be effective in relieving the symptoms of acute migraine.

Prostaglandin Inhibitors

Prostaglandin inhibitors, such as nonsteroidal antiinflammatory agents, are effective in mild to moderate migraine. Nonsteroidal antiinflammatory agents like indomethacin reduce the neurogenic inflammation in the trigeminal vascular system in experimental animals. NSAIDs like Difenac potassium is as effective as oral ergotamine. One report indicated that aspirin/metoclopramide combination is only slightly less effective than oral sumatriptan.⁶² Naproxen sodium 550 to 750 mg is a fairly effective agent in mild to moderate headache. Intramuscular ketorolac (60 mg) is useful in many acute attacks.

The COX₂ inhibitors may give us a better option, as they lack gastrointestinal side effects. Oral rofecoxib alone has been shown to be effective in producing pain-free status in 2 hours in 35% of patients with early intervention.³³ Combinations of triptans with COX₂ inhibitors may enhance efficacy of both.

Opioids in Migraine Treatment

Opioids have no place in the routine management of acute migraines. However, opioid may be used in a controlled fashion when specific 5-HT_1D/1B agonists are totally ineffective or when they are contraindicated, as in cases with ischemic heart disease. Mixing opioids with DHE and triptans may nullify the effect of the later agents.

Current Concepts in Acute Migraine Treatment

Doctors treating migraine face important decisions on how to optimize treatment for individual patients. Migraine patients would receive faster resolution of their pain and disability if physicians were more often able to identify successful therapies at the first consultation. This might be achieved by using assessment of the level of disability caused by migraine to assign patients to treatment groups rather than using the same sequence of treatment options for all patients. The development of strategies for optimizing therapy may also increase motivation to focus on, and communicate more widely about, headache-related disability.

The typical traditional algorithm for treatment of migraine might be as follows:

1.  Exclude secondary headache.
2.  Diagnose migraine.
3.  Choose a treatment.

This simple algorithm is suboptimal for a number of reasons. First, migraine is heterogeneous, and the nature, severity, and associated disability of attacks and the need for treatment vary among individuals.^63,64 Many people are able to control mild to moderate migraine with over-the-counter medications and do not require prescription drugs.⁶⁵ At the other end of the spectrum are those with frequent, severe, disabling attacks whose lives are completely disrupted. It is obvious that these two kinds of individuals differ in their treatment needs. The second reason that diagnosis does not give us enough information to optimize therapy is the enormous and expanding range of therapeutic options for migraine. Third, there are no systematic strategies for identifying individual patients for particular treatments or programs of care. Clinical trials are conducted by randomizing migraineurs diagnosed by the International Headache Society criteria, and the results inform us that particular drugs are useful for migraine in general but they do not tell us which patients require which kinds of drugs.

Step Care

The traditional approach to acute treatment of migraine might be termed step care. Patients are started at the bottom of the therapeutic pyramid, and if the treatments fail, the therapy is escalated. This is the approach recommended in some of the published treatment guidelines. The patient consults, migraine is diagnosed, and the patient starts at the bottom of the therapeutic pyramid. If patients are satisfied with the first-line treatment (usually simple analgesics), they continue it. If not, they may have a follow-up consultation and be prescribed treatment a second time (usually combination analgesics), or all too often they conclude that the doctor has nothing to offer and they lapse from care. If second-line treatment works, the patient is satisfied and continues on that treatment; if it does not work, either the patient lapses from care or, if the patient is highly motivated and the doctor allows it, the patient may receive a third-line treatment (specific antimigraine drugs). If this also fails, further options may be explored, such as an injectable rather than an oral triptan, or a different triptans therapy. Another option might be a complicated program to identify and avoid headache triggers. At some stage in this sequence of step-wise care there may be a referral from primary care to specialist tertiary care.

The fundamental assumption of step care is that all patients have the same

treatment needs. This is a useful cost-effective methodology if the patient responds favorably to first-line therapy. The disadvantages of step-wise care are that successful treatment may be delayed, resources may be wasted on follow-up visits and failed prescriptions, patients and physicians may become discouraged, and patients may lapse from care.

Stratified Care

Stratified care, on the other hand, stratifies attacks and patients according to their

therapeutic need.⁶⁶ Those with severe episodes, which are disabling, would then be assigned specific medications that have proven efficacy, and patients with mild or low disability, whose therapeutic needs are less, may be treated with simple analgesics. Patients and physicians should be flexible in using medications according to need. Patients and their attacks must be stratified. Patient education is highly essential in this respect. Stratified care results in less disability, better patient satisfaction, less need for multiple doses and multiple medications. Stratified care has been shown to be cost effective.⁶⁷

Examples of Stratified Care

Tables 8, 9, 10, 11 give treatment options according to the severity of migraine attack.

Table 8. Stratification According to Severity of Migraine – Options

Mild:

Simple analgesics
NSAIDs
Isometheptene
(Metoclopramide may be added to reduce nausea and enhance absorption.)

Table 9. Stratification According to Severity of Migraine – Options

Moderate:

NSAIDs
Isometheptene
Ergotamine – oral, nasal
Sumatriptan – oral, nasal
Zolmitriptan – oral, Rapimelt
Naratriptan – oral
Rizatriptan – oral, MLT
DHE – nasal
(Metoclopramide may be added with oral agents.)

Table 10. Stratification According to Severity of Migraine – Options

Severe:

Ergotamine – rectal
Antiemetic – rectal
Sumatriptan – subcutaneous, nasal, oral
Zolmitriptan – oral
Naratriptan – oral
Rizatriptan – oral, MLT
DHE – I.V., intramuscularly, nasal

Table 11. Stratification According to Severity of Migraine – Options

Extremely Severe: Rescue Medications

Ketoralac-intramuscularly (60 mg)
DHE IV
+
Metoclopramide
Dopamine antagonists IV
Opioids

Mild migraine can very well be treated by simple analgesics, nonsteroidal antiinflammatory agents with or without metoclopramide, and isometheptene. Moderate to severe headaches respond better to 5-HT_1D/1B agonists, which will include ergotamine, dihydroergotamine (DHE), and triptans.

The choice of drugs will depend on a number of factors, which will include the time to peak, associated symptoms (eg, nausea and vomiting), and severity of the headache pain and habitual duration of the migraine attack. For rapidly peaking headache, such as in cluster headache, crash migraine, and severe nocturnal migraine, subcutaneous sumatriptan is the drug of choice. Nasal sumatriptan is also very rapid in onset of action; therefore it may be considered under those circumstances. Oral medications in general take longer to work: however, oral sumatriptan, rizatriptan, zolmitriptan and almotriptan have been shown to have a significant effect within an hour.

Clinical experience indicates that rizatriptan is faster in its onset of action, than zolmitriptan.

Some patients may need to have more than one drug available so that they can choose the one most suitable for the migraine attack in question.

Extremely severe headache, particularly in an emergency room, may be treated with intravenous dihydroergotamine with intravenous prochlorperazine or metoclopramide. The response to intravenous DHE is almost 80%. Those who cannot tolerate DHE or who have contraindications may be tried on a dopamine antagonist, such as intravenous chlorpromazine or perchlorperazine, droperidol, or intravenous diphenhydramine (Benadryl). An excellent alternative is IV valproate sodium.⁶¹

Triptans and Prophylactic Medications

Use of Abortive Medications Along With Prophylactic Treatment

Even though preventative agents reduce the frequency and severity of migraine attacks, many patients still have breakthrough migraine or tension-type headache while on prophylactics. Menstrual migraine is a good example of the breakthrough headache. In general, preventative medications make acute agents more effective. While using the prophylactic medication, one should make sure that abortive medications are not overused. Limiting use to twice a week is recommended in order to prevent secondary failure of prophylactic treatment. Table 12 shows the potential drug interactions between abortive and preventive agents.

Table 12. Caution and Contraindications for Combining Abortive and Prophylactic Migraine Therapy

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17. Kramer MS, Matzura-Wolfe D, Polis A, et al. A placebo-controlled crossover study of rizatriptan in the treatment of multiple migraine attacks. Neurology 1998; 51:773-781.

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19. Protocol No. 030: MK-0462 [Clinical Study report]. A randomized, placebo-controlled, parallel groups, outpatient study to examine the safety, tolerability, and efficacy of single oral doses of MK-0462 10-mg, and sumatriptan 100-mg for acute treatment of migraine. West Point, Pa: Merck Research Laboratories; 1997.

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21. Tfelt-Hansen P, Teall J, Rodriquez F, et al. Oral rizatriptan versus oral sumatriptan: A direct comparative study in the acute treatment migraine. Study in the acute treatment migraine. Headache 1998; 38:748-755.

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26. Jackson NC. For the Eletriptan Steering Committee: A comparison of oral eletriptan (U.K. 116, 044) 20-50 mg and oral sumatriptan (100mg) in the acute treatment of migraine. Cephalalgia 1996; 16:368.

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28. Martinez E, Cabarrocas X, Peris F, Ferrer P, Luria X. Meta-analysis on efficacy and safety of almotriptan in the treatment of migraine. Cephalalgia 1999:19-362.

29. McDaris HL, Hutchison J. On behalf of the frovatriptan phase III investigators. Frovatriptan: A review of overall clinical efficacy. Cephalalgia 1999; 19: II-G1-29.

30. Elkind A, McDaris HL, Satin L, Eywood C. The cardiovascular safety of frovatriptan in patients at high risk of or with known coronary artery disease during a migraine attack. Cephalalgia 1999; 19:II G1-35.

31. Ferrari MD. “The triptan war. Anno 1998.” Presented at the annual meeting of the American Academy of Neurology April 1998.

32. Ferrari M. How to assess and compare drugs in the management of migraine:  success rate in terms of response and recurrence. Cephalalgia 1999; 19[Suppl 23]:2-8.

33. Mathew NT, Kailasam J, Fischer A. Early intervention using rofecoxib alone,  rizatriptan alone and combination of rizatriptan and rofecoxib in acute migraine. To be presented at the 2001 International Headache Congress, New York.

34. Block GA, Goldstein J, Polis A, et al. Efficacy and safety of rizatriptan verses  standard care during long-term treatment for migraine. Headache 1998; 38:764-771.

35. Kaube H, May A, Diener HC, Pfaffenrath V. Sumatriptan. BMJ 1994; 308:1573-1574.

36. Catarci T, Lenzi GL, Cerbo R, Fieschi C. Sumatriptan and daily headache. J Neurol Neurosurg Psychiatry 1995; 58:508.

37. Limmroth V, Kazarawa Z, Fritsche G, Diener HC. Headache after frequent use of serotonin agonists zolmitriptan and naratriptan [letter][see comments]. Lancet 1999; 353(9150):378.

38. Maassen Van Den Brink A, Reekers M, Bax W, et al. Coronary side effect potential of current and prospective antimigraine drugs. Circulation 1998; 98:25-30.

39. Dahlöf CGH, Mathew N. Cardiovascular safety of 5-HT_1B/1D agonists – is there a cause for concern? Cephalalgia 1998; 18:539-545.

40. Ottervanger JP, Wilson JHP, Stricker BHC. Drug-induced chest pain and myocardial infarction. Reports to a national centre and review of the literature. Eur J Clin Pharmacol 1997; 53:105-110.

41. MacIntyre P, Gemmill J, Hogg K, Bhargava B. The effect of subcutaneous

sumatriptan on central haemodynamics and the coronary circulation. Clin Pharmacol Ther 1992; 51:152.

42. Swan L, Birnie DH, Hood S, et al. The effect of subcutaneous naratriptan 1.5 mg on the systemic, pulmonary, and coronary circulation in patients with suspected coronary disease. Cephalalgia 1988; 17:428.

43. Dahlöf CGH, Falk L. Risenfors M, Lewis CP. Safety trial with the 5-HT_1B/1D agonist avitriptan (BMS-180048) in patients with migraine who has experienced pressure, tightness, and/or pain in the chest, neck and/or throat following sumatriptan. Cephalalgia 1998; 18:546-551.

44. Mathew NT, Tietjen GE, Lucker C. Serotonin syndrome complicating migraine pharmacotherapy. Cephalalgia 1996; 16:323-327.

45. Cady RK, Lipton RB, Hall C, et al. Treatment of mild headache in disabled migraine sufferers. Results of the spectrum study. Headache 2000; 40:792-797.

46. Cady RK, Sheftell F, Lipton R, et al. Effect of early intervention with sumatriptan on migraine pain. Retrospective analysis of data from three clinical trials. Clinical Therapeutics 2000; 22:1035-1048.

47. Mathew NT, Kailasam J, Meadors L, Gentry P, Chernyshev O. Sequential use of rapidly acting sumatriptan preparations and naratriptan in rapid onset, habitually prolonged migraine. Headache 1999; 39:367-368.

48. Lipton RB, Stewart WF, Hall C, et al. Sumatriptan for the range of headaches in migraine sufferers: Results of spectrum study. Headache 2000; 40:783-791.

49. Perrin VL. Clinical pharmacokinetics of ergotamine in migraine and cluster headache. Clin Pharmacokinet 1985; 10:334-352.

50. Ibraheem JJ, Paalzow L, Tfelt-Hansen P. Low bioavailability of ergotamine tartrate after oral and rectal administration in migraine sufferers. Br J Clin Pharmacol 1983; 16:695-699.

51. Sanders SW, Haering N, Mosberg H, et al. Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing. Eur J Clin Pharmacol 1986; 30:331-334.

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Individualised Therapy for Migraine Possible as the Triptan Family Expands

Introduction

The available triptans can be distinguished by formulation - sumatriptan is the most versatile, available in several different dosage forms. With regard to clinical efficacy, headache response at 2 hours seems somewhat higher for sumatriptan, zolmitriptan and rizatriptan and lower for naratriptan (see Differential features table), although data from direct clinical comparisons are limited and naratriptan has a tendency towards less recurrence. Common adverse events, 'triptan sensations', are similar for oral sumatriptan, zolmitriptan and rizatriptan. There are significantly fewer adverse events for naratriptan.

Clinical use will yield familiarity with the various triptans, and it should be possible to match individual patient needs with the specific characteristics of the individual triptans to optimise therapeutic benefit.

Cause of Migraine Becoming Clearer

5-HT_1B receptors, located on the meningeal vessels, constrict these vessels when activated by 5-HT₁ agonists. 5-HT_1D receptors are presynaptic inhibitory autoreceptors on trigeminal sensory neurons. Activation of these receptors turns off the neurogenic inflammation by inhibiting the release of neuropeptides such as calcitonin gene-related peptide.^[1]

5-HT_1D receptors are also located centrally in the trigeminal nucleus caudalis.^[4] Activation of these receptors appears to interfere with central transmission of pain signals.^[1]

Guidelines Assist in Efficacy Assessment

Sumatriptan: the Original Triptan

Different Dosage Forms Provide Flexibility

The injection has a very fast onset of action and is packaged as a self-administration unit, which improves patient acceptance.^[6] Sumatriptan injection provides very fast relief and high 1- and 2-hour efficacy. A disadvantage with sumatriptan, however, is the relatively high recurrence rate after use.^[1]

Although not as rapidly acting as the injection, sumatriptan nasal spray provides a faster onset of effect than the tablets.^[1] The spray comes in a single-use device. The patient sprays once into a single nostril without sniffing and discards the device.

A sumatriptan suppository is available in some European and Asian countries. Its efficacy is similar to that of the other dosage forms.^[1]

Adverse Effects Not Usually Serious

Sumatriptan nasal spray has an additional adverse effect of an unpleasant bitter taste. The taste can be minimised and the absorption, efficacy and consistency of response maximised by having the patient spray upward and forward with the head in a neutral position without sniffing or swallowing.^[1]

Potential for Vascular Events...

Even patients with cardiovascular risk factors, but without established cardiovascular disease, are not considered to be at increased risk.

...But Only in Those With Known Disease

Avoid Concurrent Use With Some Antidepressants...

...and Ergotamine

Newer Triptans Offer Advantages

Zolmitriptan Rapidly Absorbed

The efficacy of zolmitriptan has been demonstrated in a number of randomised placebo-controlled double-blind trials in adults with moderate to severe attacks.^[8] The drug is effective across a wide range of migraine subtypes.^[8]

Because zolmitriptan is, in part, metabolised by monoamine oxidase type A, the dosage of zolmitriptan should be reduced in patients treated with MAOIs, such as moclobemide.^[1,2]

Dosage reduction is also appropriate in patients receiving cimetidine, fluvoxamine or quinolones as these drugs inhibit the metabolism of the triptan.^[2] As with sumatriptan, zolmitriptan should not be used concurrently with ergotamine.^[2]

The most commonly reported adverse events in patients receiving zolmitriptan are the typical triptan sensations.^[1]

Naratriptan: The 'Gentle Triptan'

The incidence of triptan sensations, and all adverse effects, with naratriptan is very low. In fact, in some cases the incidence of adverse events was lower with naratriptan than with placebo. Therefore, naratriptan has been referred to as 'the gentle triptan'. Furthermore, because naratriptan is metabolised by a variety of cytochrome P450 enzymes and not the MAO system, it is not associated with significant drug interactions.^[1,2]

Rizatriptan Available as a 'Melt'

Propranolol may increase the plasma concentration of rizatriptan, most probably because of a first-pass metabolic interaction since MAO type A plays a role in the metabolism of both drugs.^[2,11] Therefore, rizatriptan should be administered at half the usual dose (i.e. 5mg) in patients receiving propranolol.^[1,2] Rizatriptan should be avoided in patients receiving MAOIs and should not be administered concurrently with ergotamine.^[1,2]

Can Future Triptans Offer More?

Eletriptan 80mg orally has very high efficacy and has consistently been significantly superior to sumatriptan 100, 50 and 25mg for headache response at 2 hours.^[1] However, adverse events (classic triptan sensations) occur with a higher frequency at this dose compared with lower doses. Lower doses of eletriptan show efficacy similar to that of sumatriptan (see table 2). Recurrence rates are low.

Frovatriptan has a very long half-life compared with other triptans and has an onset of action and efficacy similar to those of naratriptan, although direct comparative efficacy data are lacking. The drug has recurrence rates which are among the lowest for any triptan.^[1]

Almotriptan has the highest oral bioavailability of all the triptans. Headache response with almotriptan is similar to that with oral sumatriptan but the newer drug is associated with a lower rate of headache recurrence.^[1]

Table 1. International Headache Society clinical end-points used to assess efficacy of medication in patients with migraine^[5]

Parameter	Definition
Headache response	Reduction of migraine intensity from moderate or severe to none or mild at a point in time
Therapeutic gain	Percentage of patients who respond to active drug therapy minus percentage of patients who respond to placebo (30% suggests good drug response, 40% excellent, 50% superb)
Pain-free state	Decrease in migraine severity from moderate or severe to no pain at a given time after medication administrationa
Relief of associated symptoms	Effect of medication on symptoms such as nausea, phono- and photophobia a
Time of pain relief	Chance of obtaining headache relief over time. Calculated using a sliding scale or survivor curve
Time to headache relief	Survival of the headache
Recurrence	The return of moderate to severe headache within 24 hours of treatment following initial headache response at 2 hours
Complete or sustained pain-free response	Patient is pain-free at 2 hours with no recurrence or use of rescue medications within 24 hours

 

a	Preferably measured at 2 hours post-administration.

 

Table 2. Selected features of various triptans which are still undergoing development^[1,12-15]

Feature	Almotriptan	Eletriptan	Frovatriptan
Usual dose (mg)	12.5	40	2.5
Pharmacokinetic parameters
tmax (h)	1.4-3.8	1-2	2-4
t1/2 (h)	3.2-3.7	3.6-5.5	25
Lipophilicity	?
Bioavailability (%)	70-80	50	24-30
Efficacy
Headache response at 2h (%)	57-65	65	36-46
Therapeutic gain (%)a	15	41	13-19
Recurrence rate (%)	18	19-23	7-25

 

a	Percentage of patients who respond to active drug therapy minus percentage of patients who respond to placebo.
Abbreviations and symbols: h = hours; tmax = time to achieve maximum plasma concentration; t1/2 = elimination half-life; = low; = high; ? = unknown.

 

Differential features

Comparison of various features of selected triptans for the treatment of acute migraine^[1-3]

Feature	Naratriptan	Rizatriptan†	Sumatriptan				Zolmitriptan
	Tablet	Tablet and water (melt)	Tablet	SC injection	Nasal spray	Suppository†	Tablet
Dosage information
Usual dose (mg)a	2.5	10b	50	6	20c	25	2.5
Time when repeat dose can be given (h)	4	2	2	1	2	NS	2
Maximum dose in 24h (mg)	5	30 (US) 20 (EU)	200 (US) 300 (EU)	12	40	50	10-15
Pharmacokinetic parameters
tmax (h)	2-3	1.3d	2.5	0.2	1 (range 0.08-4)	-	2
t1/2 (h)	5-6.3	2-3	2			-	2.5-3
Lipophilicity
Bioavailability (%)	63 (men) 74 (women)	45	14	97	17	-	40-48
Efficacy
Headache response at 2h (%)	48	67-77	61	77e	64	68	62-65
Therapeutic gain (%)f	18	27-40	33	48	34	43	28-29
Recurrence rate (%)f	17-28	30-47	32	34-38	32-34	44	30
Consistency (mean % of attacks aborted over 1 year)	70 at 4h	80 at 2h	84 at 2 (100mg dose)	70 at 1h	77 at 2h	-	95 with 1-2 doses of 2.5-5mg
Tolerability
Common adverse effects	Paraesthesia, heaviness, tightness in any part of the body (especially throat and chest)g , flushing, heat sensations, dizziness, feeling of weakness, fatigue, nausea and vomiting
Drug interactions:
avoid concurrent    use	§	Ergotamine, MAOIs	Ergotamine, MAOIs, SSRIs				Ergotamine
dosage adjustment    required	§	Propranolol	-				Cimetidine, fluvoxamine, MAOIs, quinolones
Acquisition costh
In the UK (£)	4.00	4.46	4.70	19.57	6.00	†	4.00
In the US ($)	16.74	11.93	16.00	48.61	20.81	†	14.17

 

†	Rizatriptan is not available in Australia and France; sumatriptan suppositories are not available in Australia, Canada, France, Spain, the UK and the US.
a	Oral dosage listed, unless otherwise specified.
b	Also available in a 'melt' formulation, a wafer which dissolves rapidly when placed on the tongue and is then swallowed for gastrointestinal absorption.
c	Use 1 spray in 1 nostril only.
d	tmax for tablet is 1.3h; water (melt) has similar pharmacokinetic properties.
e	Response at 1h.
f	See table 1 for definition.
g	Discontinue drug if sensation intense as it may be due to coronary vasoconstriction or anaphylaxis.
h	For a single dose at the usual dosage.
Abbreviations and symbols: EU = European Union; h = hour(s); MAOIs= monoamine oxidase inhibitors; NS = not specified; SC = subcutaneous; SSRIs = selective serotonin (5-hydroxytriptamine, 5-HT) reuptake inhibitors; tmax = time to achieve maximum plasma concentration; t1/2 = elimination half-life; = low; = moderate; = high; § = there are currently no recognised drug interactions with naratriptan.

References

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