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-HT1B and 5-HT1D receptors [3,6]. In addition, some triptans have affinity for the 5-HT1F receptor [3], and ergotamine has affinity for the 5-HT2B receptor, the a1and a2aderenoceptors, and the dopamine D2 receptor and DHE have affinity for the same four receptors plus the 5-HT1A 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 THEMED ARTICLE y Migraine + Headache Editorial