J Headache Pain (2001) 2:120–146 © Springer-Verlag 2001 Symptomatic treatment of migraine Two recent, prospective studies demonstrated that early 5-HT agonists 1B/1D oral administration of a triptan gives a better headache response [114, 115]. One study showed the possibility of Efficacy data preventing migraine attack when naratriptan was taken dur- ing prodromic symptoms [116]. Controlled studies have demonstrated the efficacy of 5- HT1B/1D agonists, not only on headache but also on accompa- nying symptoms (e.g. photophobia and phonophobia, nausea and vomiting) and on functional disability [1–64]. The con- Observations sistency of efficacy in the treatment of multiple attacks and the long-term efficacy have also been demonstrated, especial- If headache only slightly improves after the administration ly for sumatriptan administered subcutaneously or in tablets, of a triptan, one should wait at least two hours before taking zolmitriptan, rizatriptan, naratriptan, eletriptan, and almotrip- a second dose [117]. If no response is observed within two tan [55–77]. Slightly higher percentages of headache hours, an additional dose is not useful. response were found for subcutaneously administered suma- Rapid-dissolving oral formulations of rizatriptan and triptan compared with the other formulations of sumatriptan zolmitriptan are now available. They have an efficacy simi- [78, 79]. Although studies comparing the oral formulations of lar to the tablet formulations, and pharmacokinetic data do triptans are available, it is not possibile at the moment to iden- not suggest that the highest plasma levels are reached more tify a parameter of overall efficacy which establishes the rapidly [118, 119]. The formulations could, however, be greater efficacy of one triptan compared to the others [80–90]. useful because they are easier to take. As far as the speed of onset is concerned, a statistically sig- Approximately 25%–35% of patients do not respond to nificant headache response compared with placebo was found triptans. These percentages may be influenced by incorrect at 15–30 minutes for sumatriptan subcutaneously administered diagnoses. In fact, even in specialized headache centers and at 30–60 min for every other triptan formulation [91, 92]. diagnoses not in agreement with IHS criteria are in fact for- The administration of sumatriptan during aura appeared mulated in about 28% of the cases [120]. When the diagno- to neither shorten the aura duration nor prevent the subse- sis of migraine is confirmed, in the case of no response to quent headache [93]. The administration of zolmitriptan one of the triptans, the use of another triptan may be con- during aura has been shown to be effective on head pain but sidered. Recent open studies have demonstrated the possi- not on aura symptoms and was not accompanied by signifi- bility of using another triptan with success, when one trip- cant adverse events [94]. No data in this regard are available tan fails [121, 122]. In the case of no response to one trip- for the other triptans. The percentages of headache recur- tan, however, it is mandatory to reconsider the diagnosis. rence, emerging from the various efficacy studies, vary from Cases of daily use or abuse of triptans have been record- 20% to 40%, with slightly greater values for subcutaneous- ed, and this may cause migraine to become a chronic ly given sumatriptan [95–97]. For all triptans, in any formu- headache [123–128]. It is advisable not to exceed the rec- lation, the efficacy of a second dose on recurrent headache ommended doses. has been demonstrated [98–102]. The efficacy of the differ- Although use of oral triptan formulations is not recom- ent triptans has also been confirmed on migraine attacks mended below 18 years of age, recent studies suggest their related to the menstrual cycle [103–113]. efficacy and safety in this age group [129–136]. 121 Studies on the effects of different triptans in the treatment patients treated with other formulations. It can mimic an of migraine crises during pregnancy are not available, with the angina crisis and alarm a patient who is not adequately exception of results of international prospective studies informed. The mechanism underlying these chest symptoms [137–139] relative to the monitoring of migrainous pregnant is unknown: a spasm of esophageal muscles has been sug- women who used sumatriptan. These studies did not show a gested [172–176]. ECG modifications have rarely been greater incidence of malformations in the newborns of women recorded [177]. In a recent study carried out on healthy vol- who treated their migraine attacks with sumatriptan during unteers with positron emission tomography (PET), no sig- pregnancy compared to those in the general population, but in nificant variations in myocardial perfusion were shown after one of these studies a higher percentage of low birth-weight subcutaneous administration of sumatriptan [178]. newborns was associated with the use of sumatriptan as well The most significant pharmacological interactions, from as a greater incidence of preterm deliveries [137–139]. The a clinical point of view, are with ergot derivatives, selective results available at the moment do not lead to definitive con- serotonin-reuptake inhibitors (SSRIs), monoamine oxidase clusions. The use of triptans during pregnancy or by women (MAO) inhibitors, propranolol and drugs which are sub- who intend to become pregnant is not recommended. strates of CYP450. Insufficient data are available to evaluate the safety of After taking a triptan, it is necessary to wait at least six triptan use after 65 years of age. In this case, their use is not hours before taking an ergot derivative. Conversely, after recommended. taking an ergot derivative it is recommended to wait at least 24 hours before taking a triptan [139]. Likewise for coad- ministration of the different triptans, it is advisable to wait at least 24 hours between doses. Contraindications, adverse events and pharmacological In the case of the coadministration of one triptan with interactions antidepressants of the SSRI class, the occurrence of a sero- tonergic syndrome is possibile. It is characterized by motor The use of triptans is contraindicated in the case of positive incoordination, marked asthenia and hypereflexia [179–182]. history or suspicion of ischemic cardiopathy, coronary MAO-A inhibitors should be suspended at least two vasospasm, peripheral vascular disease, uncontrolled hyper- weeks before initiating treatment with a triptan [183–187]. tension, or basilar or hemiplegic migraine [140]. Recent The contemporary administration of propranolol increas- studies showed that an adjustment of the zolmitriptan dose es the plasma concentration of rizatriptan [188]. In the case is unnecessary in the case of mild hypertension or renal of the contemporary use of propranolol, the administration insufficiency [141–143]. If coronary disease or risk factors of the 5-mg dose of rizatriptan for the attack and the maxi- for cardiovascular diseases are suspected, an electrocardio- mum daily dose of 10 mg are recommended. Rizatriptan gram (ECG) should be carried out before beginning treat- should be taken at least two hours after taking propranolol. ment with a triptan [144, 145]. Theoretically, rizatriptan and zolmitriptan interact with The percentages of adverse events are variable in clini- drugs which are metabolized by CYP450 [189, 190]. The cal trials and in post-marketing studies. They are frequent clinical relevance of this observation should be clarified. for the subcutaneous formulation of sumatriptan and occa- sionally for the other triptan formulations. In the majority of cases, they are not clinically relevant, and of short duration (generally 10–15 min) [146–165]. The most frequent Administration and dosages adverse events are: local reactions in relationship with the route of administration (e.g. subcutaneous, rectal, nasal The following paragraphs summarize the mode of adminis- spray), sensation of chest tightness, constriction or pain, tration and the dosages of common triptans. Readers are flushing of the face and chest, asthenia, myalgia, somno- cautioned to consult the packaging for specific governmen- lence, warm or cold sensation of the head or arms, paresthe- tal regulations (e.g. rules, warnings, norms). sias, postural instability, dizziness and, sometimes, neck Sumatriptan is administered as follows: pain or sensation of neck stiffness. Among the severe – Subcutaneous route: 6-mg ampoule; maximum daily adverse events, which occur rarely, unstable angina, dose, 12 mg. myocardial infarction, cardiac arrest and ischemic stroke – Oral route: 50–100 mg tablets; maximum daily dose, 200 should be mentioned [166–171]. Other rare adverse events mg. are akathisia, dystonic crises and euphoria. – Rectal route: 25-mg suppository; maximum daily dose, In particular, the sensation of chest tightness or pain is 50 mg. referred by 4%–5% of patients treated with sumatriptan, – Nasal spray: 1 single-dose spray (20 mg); maximum subcutaneously administered, and by a lower percentage of daily dose, 40 mg. 122 Zolmitriptan is administrated orally as a: The efficacy of ASA and other NSAIDs on migraine – 2.5-mg tablet; maximum daily dose, 5 mg; or aura has not been investigated. – 2.5-mg rapimelt formulation; maximum daily dose, In migraine crises associated with the menstrual cycle, 5 mg. only the efficacy of mefenamic acid has been assessed. The Rizatriptan is given orally as a: drug appeared to be significantly more effective