Triptans are serotonin 5-HT1B/1D receptor agonists, whose significant role in relieving pain and associated symptoms of migraine are demonstrated by a countless number of large controlled trials. They can also limit disability and improve health-related quality of life [18]. The efficacy of all the marketed drugs of this class has been confirmed by the inclusion with level A evidence in the guidelines from the American Academy of Neurology and from the European Federation of Neurological Societies [11, 13, 14] and by the results of published meta-analyses [24, 25].

There are currently seven triptans available in most countries: almotriptan (oral tablet), eletriptan (oral tablet), frovatriptan (oral tablet), naratriptan (oral tablet), rizatriptan (oral tablet, orally dispersible tablet), sumatriptan (subcutaneous injection, oral tablet, fast-disintegrating oral tablet, nasal spray, suppository), and zolmitriptan (oral tablet, orally dispersible tablet, nasal spray).

Some contraindications must be considered before prescribing triptans: coronary heart disease, Raynaud’s disease, untreated arterial hypertension, history of ischaemic stroke, pregnancy, and severe liver or renal problems. The suggested doses of the most widely prescribed triptans are reported in Table 3.1.

Side effects include drowsiness, nausea, dizziness, tightness, or flushing in areas such as the face, the neck, and the chest. Serious adverse events – namely, increased risk of vascular events – were not reported when sumatriptan users were compared with a healthy population. These events have been reported rarely and only when used in patients who had contraindications against triptans or a wrong diagnosis of migraine. According to meta-analyses, each triptan has some specific characteristics, although these are often not confirmed in clinical practice. Subcutaneous sumatriptan has the fastest onset of efficacy.

The effect of rizatriptan, eletriptan, oral sumatriptan, and almotriptan is evident in 30–40 min. Among these drugs, rizatriptan 10 mg and eletriptan 80 are more effective than sumatriptan 100 mg, and almotriptan shows better consistency and tolerability. Naratriptan and frovatriptan may need up to 4 h for the onset of efficacy, but they have a better tolerability profile, and the duration of efficacy is longer as compared with all others.

Clinicians should be aware that an individual patient may respond differently to different triptans, with possible variability as well as the degree of effectiveness and tolerability. Clinicians should be aware that an individual patient may respond differently to different triptans, with an individual variability. Thus, many patients may benefit from switching triptans if they are not satisfied taking into account the degree of effectiveness and tolerability.

Triptans are effective in most patients who do not respond to NSAID, and although they are effective at any time during a migraine attack, there is evidence that their efficacy is better the earlier they are taken. For these reasons, stratified care and early treatment approaches have been proposed (see Sect. 3.4.2).

A list of level A drugs among the most used drugs in this class was included in the European guidelines [11] based on the evidence of efficacy and taking into account also the level of tolerability and consistency. Among NSAIDS are ibuprofen, oral; diclofenac, oral or rectal; and naproxen, oral or rectal. Among analgesics are acetylsalicylic acid (ASA), in both oral and intravenous administration; and paracetamol (or acetaminophen) in oral or rectal administration. For all the above-mentioned drugs, recent Cochrane Database of Systematic Reviews have confirmed the evidence in migraine patients, with significant effects in relieving pain and associated symptoms, with mild side effects, but with pain-free responses in a minority of patients [26–30]. Tolfenamic acid is rated as a level B drug in the same guidelines.

The suggested doses of the most widely prescribed NSAIDS and analgesics are reported in Table 3.1.

The side effects of drugs in these classes are usually gastric irritation/discomfort, nausea, and vomiting. NSAID-related gastrointestinal adverse effects may be more evident in elderly persons, patients with a Helicobacter pylori infection, and concomitant use of oral anticoagulants and corticosteroids.

Before prescribing these drugs, clinicians must be aware of the presence of contraindications, such as previous allergy to ASA or any NSAID, possible defect of coagulation, and peptic ulcer. The use should be monitored in patients with asthma and liver and renal problems.

Drugs of this class are considered as “migraine-specific” compounds, as they can act on a variety of catecholamine receptors, with a consequent widespread use before the introduction of triptans. A few placebo-controlled trials, which are often old with relevant methodological problems, demonstrated the efficacy of the two most commonly used ergot alkaloids, i.e. ergotamine tartrate, oral, and dihydroergotamine, suppositories. Furthermore, in comparative trials, ergot alkaloids generally showed lower efficacy than triptans, although the latter showed a lower recurrence rate [11]. More recent trials with dihydroergotamine nasal spray suggested its efficacy, but without conclusive evidence [13]. The prescription of ergot alkaloids should be discouraged for several reasons: the evidence was relatively inconsistent to support their efficacy; they have a high potential to induce medication overuse headache; they have relevant side effects (nausea, vomiting, and paraesthesia; ergotism may rarely occur with chronic use); they could not be administrated together with triptans; and they are often marketed in association with other substances (caffeine, pentobarbital, butalbital, belladonna alkaloids) which can increase the rate of side effects and the risk of medication overuse. Ergotamine may be considered in the treatment of selected patients with moderate to severe migraine with poor response to triptans, particularly in prolonged attacks, status migrainosus, and menstrually related migraine.

A new orally inhalable formulation in which dihydroergotamine is released by an inhaler that incorporates a breath-triggered mechanism with delivery of a standard amount of the drug into the lung. This novel orally inhalable formulation is under consideration for approval for the acute treatment of migraine in adults. It is a promising, practical formulation which is likely to have minimal side effects [31].

The use of antiemetics is recommended in attacks with prominent nausea and vomiting, particularly if occurring at the onset of attacks. No prospective, controlled trials are available. These drugs may also improve the resorption of analgesics. Oral metoclopramide can be used, but a better effect is obtained by IM or IV administration; domperidone (oral) or prochlorperazine (oral, IM, IV or in suppositories) may be alternative options; chlorpromazine IM may be required in severe, repeated emesis [13]. All these drugs can cause extrapyramidal side effect, i.e. dyskinesia, and are contraindicated in pregnancy.

Generally, opioids are of only a minor efficacy in migraine. Dependence and addiction are prominent issues. Furthermore, the main concern about the use of opioids is the increased risk for medication overuse headache and chronic migraine, which in fact is higher than other drugs used in the symptomatic treatment of migraine [17]. Opioids should be avoided in migraine patients.

Antiemetics and opioids are associated in some anti-migraine combinations, often with caffeine. Fixed combinations of NSAIDS/analgesics and/or caffeine and antiemetics are available in some countries. The combination of ASA, paracetamol, and caffeine was significantly more effective than placebo in controlled study for various endpoints [11]. Also, an indomethacin/prochlorperazine/caffeine combination is available in some countries, in oral and rectal formulations, and it was found effective and well tolerated in migraine patients in randomized, active-comparator controlled studies [32]. These combination products may represent an option in the symptomatic treatment of migraine. Although the risk of medication overuse is greater than NSAIDs alone [17].