Triptans and ergot alkaloids in the acute treatment of migraine: similarities and differences

Up to 20 years ago, ergotamine and dihydroergotamine (DHE) were the only specific antimigraine drugs [1]. Then subcutaneous sumatriptan 6 mg was introduced in 1991 [2,3], and subsequently sumatriptan tablets (50–100 mg) and six other triptans, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan and frovatriptan were introduced [3,4]. This introduction of triptans was a major breakthrough in migraine therapy. The view expressed in 2013 in the vignette on the relative efficacy of triptans and ergot alkaloids (“Ergot alkaloids [ergotamine, dihydroergotamine] are used in patients with frequent, moderate migraine, but are less effective than triptans.” [5]) is probably common among headache experts.

The affinities of ergot alkaloids and triptans indicate, however, that they should have similar efficacy when used in equipotent doses. Thus, both groups of drugs have high affinities at 5-HT_1B and 5-HT_1D receptors [3,6]. In addition, some triptans have affinity for the 5-HT_1F receptor [3], and ergotamine has affinity for the 5-HT_2B receptor, the α₁- and α₂-aderenoceptors, and the dopamine D₂ receptor and DHE have affinity for the same four receptors plus the 5-HT_1A receptor [6]. Triptans were developed as specific drugs for the 5-HT1B/1D receptors [3], and the effect of ergot alkaloids in migraine is also most likely mediated by these receptors [3,6]. Compared with triptans, ergot alkaloids are ‘relatively dirty drugs’ and this lack of specificity probably explain the higher incidence of adverse events (AEs) with ergot alkaloids than with triptans, see below [3,6].

Apparently, the author of the vignette is correct. In three comparative, randomized controlled trials (RCTs), oral triptans were superior to oral ergotamine 2 mg plus caffeine 200 mg for headache relief (HR) (a decrease from moderate or severe headache to none or mild) at 2 h [3]: oral sumatriptan 100 mg (HR: 66%) was superior to oral ergotamine (HR: 48%); oral eletriptan 40 mg (HR: 54%) was superior to oral ergotamine (HR: 33%); and oral rizatriptan 10 mg (HR: 76%) was superior to oral ergotamine (HR: 47%) [3]. The oral doses of triptans and ergotamine used in these three RCTs are the standard therapeutic doses [4,6], but one can seriously question whether equipotent doses were used. Thus, the oral bioavailability of ergotamine is <1% [6]. In contrast, the oral bioavailability for the triptans varies from 14% (sumatriptan) to 40% (rizatriptan) and to 50% (eletriptan) [3]. If equipotent doses were used, one would expect, because of a wider range of possible effects of ergot alkaloids (see above), a higher incidence of AEs in the ergotamine group but this was not the case. Thus, AEs occurred in 45% of patients after sumatriptan and in 39% after ergotamine; and in 35% of patients after both rizatriptan and ergotamine [3].

Two other RCTs [7,8] demonstrated that ergot alkaloids can be equipotent [7] or superior [8] to a triptan. In one RCT, subcutaneous DHE 1 mg was compared with subcutaneous sumatriptan 6 mg [7]. After 2 h, DHE (HR: 73%) was inferior to sumatriptan (HR: 85%), but after 4 h, efficacy was the same (HR: 86% for DHE and 83% for sumatriptan) [7]. Thus, DHE had a slower onset of action than sumatriptan [7]. Rectal ergotamine 2 mg (HR: 73%) was in one RCT superior to rectal sumatriptan 25 mg (HR: 63%) [8]. The most likely explanation for the better results with rectal than with oral ergotamine is the fact that the rectal bioavailability of ergotamine is 1–3% compared with <1% for oral ergotamine [6]. As would be expected with approximately equipotent doses, rectal ergotamine (28% AEs) caused more AEs than rectal sumatriptan (8% AEs) [3].

Thus when given in equipotent doses, triptans and ergot alkaloids have similar efficacy in the treatment of migraine attacks.

When evaluating a drug for acute migraine treatment, it is, however, not only efficacy per se that should be taken into account. In addition, onset of effect (patients want to be pain free quickly [9]), recurrence (the reappearance of the migraine attack hours after an initial successful treatment) and tolerability and safety should all be taken into account.

Onset of effect could be compared in two RCTs [7,8]. As mentioned above, subcutaneous DHE had a slower onset of effect than subcutaneous sumatriptan but the same effect after 3 and 4 h [7]. In one comparative RCT, rectal sumatriptan (HR: 59%) was superior to rectal ergotamine (HR: 52%) after 1 h, whereas ergotamine (HR; 73%) was superior to sumatriptan (63%) at 2 h [8]. For the first hour, ergotamine thus had a slower onset of effect than sumatriptan. The onset of orally inhaled DHE was recently reviewed, and DHE has in this formulation a T_max of 12 min while the effect slowly increases from 30 min to 2 to 4 h [10–12].

Nobody had observed recurrence in migraine treatment before the advent of triptans, most likely because clinicians did not look for it. ‘In the triptan development programmes, recurrence was defined as HR (a decrease in headache from moderate or severe to mild or none) after 2 h and recurrence of moderate or severe headache within 24 h’ [13]. In sumatriptan, RCTs recurrence occurs in 20–40% of primary successfully treated migraine patients [3]. In six comparative RCTs with ergot alkaloids and triptans, recurrence (R) occurs with lower incidences after ergot alkaloids than after triptans: oral ergotamine (R: 30%) versus oral sumatriptan (R: 41%), oral ergotamine (R: 8%) versus oral eletriptan (R: 21%), oral ergotamine (R:15%) versus oral rizatriptan (R: 31%), subcutaneous DHE (R:18%) versus subcutaneous sumatriptan (R: 45%), intranasal DHE (R: 13%) versus intranasal sumatriptan (R: 23%) and rectal ergotamine (11%) versus rectal sumatriptan (22%) [3]. This is most likely due to the longer duration of the pharmacodynamic effect of ergot alkaloids than of triptans. Thus, the vasoconstrictive effect on human leg arteries of oral rizatriptan 10 mg was minor and only present for 0–4 h, whereas the effect of intravenous ergotamine 0.25 mg was much larger and well sustained upto 8 h (the last measurement time point) [14]. That ergot alkaloids, ergotamine and DHE have a slow dissociation from the receptor site, have also been shown in vitro where their effect on isolated coronary arteries cannot be washed out, whereas the effect of sumatriptan can easily be washed out [15].

Concerning tolerability, the oral comparative RCTs are not informative because of the extremely low bioavailability of ergotamine, see above. In the comparative RCT with equipotent doses of the rectal drugs, ergotamine (AEs: 28%) caused more AEs than rectal sumatriptan (AEs: 7%) [3]. For intravenous injections, there are no comparative RCTs, but intravenous sumatriptan 2 mg was associated with mild, short-lived feeling of heaviness and pressure in 60% (15/25) of patients treated in an open study [16], whereas intravenous ergotamine 0.25 caused any AEs in 100% (16/16) of patients in a RCT [14] and caused mild to severe nausea in 88% (14/16) of patients; and two patients actually vomited [14]. With repetitive intravenous DHE, the most common AEs is nausea that occurred in 72% of patients in one open study [17]. The emetic effect of the intravenous ergot alkaloids corresponds to the high affinity of both drugs for the dopamine D2 receptor [6]. It should be noted, however, that orally inhaled DHE 0.5 mg caused nausea in only 5% of patients in a RCT [11]. Whereas rare cases of ergotism do occur with clinical use or overuse of ergotamine [18]; this disorder with spasms of peripheral arteries has not been described with clinical use of triptans.

In conclusion, triptans and ergot alkaloids have, as would be expected from their high affinities for the 5-HT_1B/1D receptors [3,4,6], similar efficacy in migraine when given in equipotent doses. Oral administration of ergotamine is not suitable for migraine treatment because of an extremely low bioavailability, <1% [6]. The kinetics at the 5-HT_1B/1D receptor site is most likely quite different for the two group of drugs [15,19] with ergot alkaloids demonstrating very slow dissociation from the receptor and triptans having a quick dissociation. Consequently, triptans have a relatively quick onset of action and a short duration of action, whereas ergot alkaloids, even with subcutaneous [7] or orally inhaled DHE [11,12], have a delayed onset of action but a long duration of action resulting in fewer recurrences than after triptans, see above. Tolerability is much better for triptans than for ergotamine [3,6], whereas tolerability for orally inhaled DHE [11] apparently is similar to triptans [3], but comparative RCTs are needed.

Generally, the triptans are the specific drug of first choice for treatment of migraine attacks, mainly because they work orally [3,4,20], the route of administration preferred by most patients, and because of better tolerability than ergot alkaloids [3,4,6]. In some patients, recurrence or even multiple recurrences [13] are a major problem and in these patients either rectal ergotamine [21] or orally inhaled DHE [11,12], if available, could be used. Orally inhaled DHE could also be a possible alternative to triptans if oral drugs are usually vomited. Patients should then be informed about a relative slow onset of action of these ergot alkaloids.

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