everything you wanted to know about triptans


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Posted by DougW on November 15, 2001 at 15:48:10:

A rather long article from medscape (uses the "M" word too much!), but reviews all the current triptans and the new ones.

The tables are hard to read, if you subscribe to medscape (it's free)go to:
www.medscape.com/adis/DTP/2001/v17.n02/dtp1702.02/dtp1702.02-01.html


Individualised Therapy for Migraine Possible as the Triptan Family Expands
[Drug & Ther Perspect 17(2):4-10, 2001. 2001 Adis International Limited]

Introduction
With the advent of the triptans, the approach to the treatment of migraine is changing. These migraine-specific medications are selective 5-HT1B/1D agonists which are believed to reverse the mechanisms of migraine, stopping pain and associated symptoms. The hydrophilic agent sumatriptan works peripherally, reducing vasodilation and neurogenic inflammation. The more recently introduced triptans (zolmitriptan, naratriptan, rizatriptan) may in addition interfere with central transmission. A number of new triptans (eletriptan, frovatriptan, almotriptan) are undergoing clinical development.
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
The exact pathophysiology of migraine remains unknown. However, events thought to contribute to migraine may include changes in dural vessel calibre, neurogenic inflammation and central trigeminal neuronal activation. These changes are believed to be reversed by agonists at certain serotonin (5-hydroxytriptamine, 5-HT) receptors.[1]
5-HT1B receptors, located on the meningeal vessels, constrict these vessels when activated by 5-HT1 agonists. 5-HT1D 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-HT1D 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
As alleviation of headache pain is a subjective parameter, measuring response to drug treatment in patients with migraine is not always straightforward. The International Headache Society (IHS) has published guidelines which can be used to assess the efficacy of medications for headache (see table 1).[5]

Sumatriptan: the Original Triptan
Sumatriptan, the first designer 5-HT1B/1D agonist, has now been available for almost 10 years. It is estimated to have been used in over 200 million migraine attacks by close to 10 million patients.[1]

Different Dosage Forms Provide Flexibility
Sumatriptan is available in several different dosage forms - an oral tablet, a subcutaneous injection, a nasal spray and a suppository (see Differential features table) - allowing the patient and physician to match the form of administration to the intensity and speed of onset of the pain as well as to the degree of disability produced.
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
There is a spectrum of adverse events with sumatriptan, now referred to as 'triptan sensations' as they are common to all of the drugs in this class (see Differential features table).[1] Although these events are generally not serious, drug withdrawal is recommended if the patient experiences a particularly intense sensation of tightness in the throat or chest because it may be caused by coronary vasoconstriction or anaphylaxis.[1,2]
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...
A major concern with the triptans has been their potential to cause vasoconstrictive effects. In fact, all of the triptans cause similar mild coronary artery contraction.[1] However, it is thought unlikely that the drugs would cause myocardial ischaemia at therapeutic plasma concentrations in healthy patients.
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
Triptans are not recommended, however, for use in patients with known cardiovascular or cerebrovascular disease.[1]

Avoid Concurrent Use With Some Antidepressants...
Because of a risk of CNS toxicity, sumatriptan should not be used in patients receiving treatment with mono-amine oxidase inhibitors (MAOIs) or selective serotonin reuptake inhibitors (SSRIs).[1,2] Furthermore, if these drugs are discontinued, a suitable 'wash-out' period (e.g. 2 weeks) should elapse before sumatriptan can be used.

...and Ergotamine
Sumatriptan and ergotamine should not be use concurrently because of an increased risk of vasospasm.[2] If required, ergotamine could be used 6 hours after the last dose of sumatriptan or, conversely, sumatriptan could be administered 24 hours after the last dose of ergotamine.

Newer Triptans Offer Advantages
Zolmitriptan, naratriptan and rizatriptan have been launched after sumatriptan and each has some distinct clinical advantages. All of the newer triptans are more lipophilic and have higher oral bioavailability than sumatriptan.[1,7]

Zolmitriptan Rapidly Absorbed
The second triptan to be marketed, zolmitriptan, was developed with the goal of creating a centrally acting drug which is more lipophilic and more rapidly orally absorbed than sumatriptan.[1] In addition to the oral tablet, a fast melt preparation and a nasal spray are being developed.
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'
Naratriptan has a relatively slow onset of action and appears to have a somewhat lower headache response at 2 hours than some other triptans. However, it is associated with the lowest headache recurrence rate of the currently available triptans (see Differential features table).[1] The low recurrence rate may be enhanced in those patients who use naratriptan early in a migraine attack, treat less severe attacks and obtain complete pain relief.[9]
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'
Rizatriptan is a very fast acting oral triptan, with a recurrence rate similar to that of oral sumatriptan. Like zolmitriptan, it was synthesised in the hope of creating a faster acting, more lipophilic, tablet and its efficacy has also been demonstrated in a number of large randomised trials.[10] The drug is available as both a tablet and an orally dissolving melt, which is placed on the tongue and dissolves rapidly. The melt is used for convenience where liquid is not available or when the patient wants to use the medication discretely. The melt is not absorbed from the tongue or mucous membranes but rather dissolves in, and is subsequently swallowed with, saliva for gastrointestinal absorption.[1]
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?
The development of triptans is still ongoing with more drugs in this class being synthesised and studied. Some of the features of the emerging triptans are outlined in table 2.
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
Tepper SJ, Rapoport AM. The triptans: a summary. CNS Drugs 1999 Nov; 12 (5): 403-17
British National Formulary. No. 39. London: The Pharmaceutical Press, 2000 Mar: 219-20, 596-7
Drug Topics Red Book. Montvale (NJ): Medical Economics Company, 2000
Edvinsson L, Goadsby PJ. Neuropeptides in headache. Eur J Neurol 1998; 5: 329-41
International Headache Society Committee on Clinical Trials in Migraine. Guidelines for controlled trials of drugs in migraine. 1st ed. Cephalalgia 1991; 11: 1-12
Gobel H, Baar H, Beikufner HD, et al. Practicability and acceptance of subcutaneous self-administration of the selective serotonin agonist sumatriptan. Headache 1998; 38: 267-9
Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs 2000 Dec; 60 (6): 1259-87
Spencer CM, Gunasekara NS, Hills C. Zolmitriptan: a review of its use in migraine. Drugs 1999 Aug; 58 (2): 347-74
Sheftell F, O'Quinn S, Watson C, et al. Low headache recurrence with naratriptan: clinical parameters related to recurrence. Headache 2000 Feb; 40 (2): 103-10
Dooley M, Faulds D. Rizatriptan: a review of its efficacy in the management of migraine. Drugs 1999 Oct; 58 (4): 699-723
New Ethicals Compendium. 7th edition. Auckland: Adis International Limited, 2000: 1110-2
Goadsby PJ, Ferrari MD, Eletriptan Steering Committee. Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Neurology 2000 Jan 11; 54 (1): 156-63
Holm KJ, Spencer CM. Almotriptan. CNS Drugs 1999 Feb; 11 (2): 159-64
Easthope S, Goa KL. Frovatriptan. CNS Drugs. In press
Bardsley-Eliot A, Noble S. Eletriptan. CNS Drugs 1999 Oct; 12 (4): 325-33







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