Almotriptan: a review of 20 years’ clinical experience

ABSTRACT

Introduction: Almotriptan (ALT), a serotonin 5-HT_1B/1D agonist has been used in the acute treatment of migraine with or without aura for 20 years, accumulating data on more than 15,000 patients in studies and from an estimated >150 million treated migraine attacks in daily clinical practice. The last major review of ALT was written almost 10 years ago. The current narrative review provides an overview of the experience gained with almotriptan over that time, and highlights data published in the last decade.

Areas covered: Randomized clinical trials, observational studies, postmarketing studies and meta-analyses involving ALT for the treatment of acute migraine identified through a systematic literature search.

Expert opinion: Triptans are a mainstay of anti-migraine treatment. Findings with ALT over the last 10 years have reinforced the positive efficacy and tolerability results that were reported during the first 10 years following its introduction. In particular, more recent clinical results have confirmed its efficacy in women with menstrual migraine, the usefulness of early intervention, long-term benefit in adults, and also its efficacy and safety in adolescents. Overall, ALT can be considered an optimal choice for managing acute migraine resistant to first-line drugs.

KEYWORDS:

• Acute treatment
• almotriptan
• efficacy
• migraine
• tolerability
• triptans

1. Introduction

Migraine is a disabling, recurrent, headache disorder which can occur with or without transient focal neurological symptoms (aura), with attacks lasting 4–72 hours [1]. Headaches are typically unilateral and are often associated with nausea and/or photophobia and phonophobia [1]. According to the extensive Global Burden of Disease Study, migraine affects more than 1000 million people worldwide, and in 2016 it was ranked as the second leading cause of disability [2,3]. It clearly has a negative impact on the quality of life of the individual [4] and imposes an economic burden on society, with the cost of migraine in the European Union estimated at more than 100,000€ million per year [5].

Migraine involves activation of trigeminovascular pathways and multiple brainstem cortical and subcortical regions, with dysregulation of sensory processing, creating a state of altered excitability in the brain [6,7]. There is evidence of a genetic susceptibility; however, the precise cause of these neuronal alterations is not fully understood [6].

The treatment of acute migraine involves non-specific therapies such as analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and antiemetics, and when the non-specific medications do not provide sufficient relief, new attacks are better managed with specific migraine therapies such as triptans (5-HT_1B/1D receptor agonists) or, less commonly, ergot derivatives [8,9]. Triptans have a long history demonstrating that they are efficacious for relieving migraine [10,11] and thus are recommended by current clinical guidelines for the treatment of acute migraine, especially for patients with an inadequate response to NSAIDs [9,12,13].

Almotriptan (ALT) has been available for approximately 20 years for the acute treatment of migraine with or without aura since it was first approved in Spain in 1999. It was approved in the US and across EU in the early 2000s, and clinical data has accumulated for more than 15,000 patients in studies and from an estimated >150 million treated migraine attacks in daily clinical practice (based upon data for the number of original patented tablets dispensed across 20 countries). The last major review of ALT was written almost 10 years ago [14]. The current narrative review considers the extensive body of evidence accumulated on ALT, including data published in the last decade. A systematic literature search of PubMed (all entries since January 2010) identified randomized clinical trials, observational studies and postmarketing studies of almotriptan for the treatment of migraine. Meta-analyses of triptan data that included ALT were also identified.

2. Almotriptan

Almotriptan (3-2[dimethylaminoethyl]-5-[1-pyrrolidinyl-sulfonylmethyl]-1H-indole D, L hydrogen malate; C₁₇H₂₅N₃O₂S–C₄H₆O₅) is a potent and selective 5-HT_1B/1D receptor agonist [15]. Triptans, including ALT, have several antimigraine modes of action, including vasoconstriction of the craniovasculature, inhibition of nociceptive neurotransmission within the trigeminocervical complex, and inhibition of vasoactive peptide release from trigeminal nerve endings [6,16].

The pharmacokinetic properties of ALT are summarized in Table 1. It is absorbed fairly rapidly after oral administration and this is not affected by food [15,17]. The oral bioavailability of ALT is about 70% [18]. It is not highly protein bound and it is extensively distributed throughout the body tissues [18]. It has a low lipophilicity coefficient and is not expected to cross the blood-brain barrier to a significant extent, although this has not been fully confirmed in specific studies [19]. It is cleared rapidly from the body, with an elimination half-life of around 3.5 hours [18,20]. Approximately 50% of a dose of ALT is excreted unchanged in the urine which is the predominant route of elimination [18,21]. Most of the remainder of a dose of ALT is metabolized to inactive metabolites via monoamine oxidase-A, and cytochrome P450 (CYP) mediated oxidation (via CYP3A4 and CYP2D6) [20–22].

Table 1. Pharmacokinetic properties of almotriptan.

Parameter	Value/Description
Oral bioavailability	70%
Cmax	45 ng/mL for a single oral dose of 12.5 mg ≥75% of Cmax is achieved within 1 hour
Tmax	1.5–4.0 hours
AUC0∞	250–300 ng/mL∙hour (12.5 mg single oral dose)
Volume of distribution	195 L
Protein binding	<40%
Lipophilicity	logD(pH)7.4: −2.1
t1/2	3.0–3.6 hours
Elimination	45–50% excreted unchanged in urine within 24 hours (partly via active tubular secretion) <5% excreted unchanged in feces Remainder metabolized into inactive metabolites (by monoamine oxidase, cytochrome P450 isozymes 3A4 and 2D6, and flavin mono-oxygenase)
Pharmacokinetic drug interactions	No clinically relevant interactions with verapamil, propranolol, ketoconazole, fluoxetine, moclobemide or alcohol

AUC_0∞ = area under the plasma concentration–time curve from time zero to infinity; C_max = peak plasma concentration; T_max = time to C_max; t_1/2: elimination half-life.

Data taken from [15,18–22].

ALT shows little potential for clinically relevant pharmacokinetic drug interactions [23–28]. No dose adjustments are required based on age or gender [15,29]. The clearance of ALT is reduced in severe renal impairment and consequently the dosage should not exceed 12.5 mg/day in such patients [15]. Similar dose recommendations are made for patients with liver disease [21].

3. Clinical efficacy

3.1. Treatment of moderate or severe migraine

As covered in detail in the previous (10-year) review of ALT, initial clinical trials of ALT demonstrated its efficacy at treating migraine pain of moderate/severe intensity in adults (with or without aura) [14].

3.1.1. Placebo-controlled trials

Randomized, double-blind, dose-ranging trials in patients with moderate/severe migraine showed that doses of ALT 6.25 mg and above relieved pain at 2 h after administration compared with placebo, and established that the most favorable balance between efficacy and tolerability was achieved with a dose of 12.5 mg (Table 2) [30–35].

Table 2. Randomized, double-blind, controlled trials of almotriptan for the treatment of patients with moderate/severe migraine with or without aura: 2-h pain relief and 2-h pain free rates.

Trial	N	Treatment^a	2-h pain relief	2-h pain free	Tolerability
Pascual et al. (2000) [30]	722	A 6.25 or 12.5 mg or placebo	A 6.25: 60%* A 12.5: 70%* P: 38%	A 6.25: 29.9%* A 12.5: 38.8%* P: 15.5%	Well-tolerated, similar rate of AEs vs placebo
Dahlöf et al. (2001) [31]	742	A 2, 6.25, 12.5, or 25 mg or placebo	A 2: 30% A 6.25: 56.3%* A 12.5: 58.5%* A 25: 66.5%* P: 32.5%		Well-tolerated; doses of 2, 6.25 and 12.5 mg similar rate of AEs vs placebo
Dowson et al. (2002) [32]	668	A 12.5 or 25 mg or sumatriptan 100 mg or placebo	Overall: A 12.5: 56.8%* A 25: 56.5%* S 100: 63.7%* P: 42.4% Moderate baseline pain: A 12.5: 72.0%* A 25: 66.7%* S 100: 73.9%* P: 46.3% Severe baseline pain: A 12.5: 41.1%* A 25: 44.2%* S 100: 50.0%* P: 34.4%	Moderate baseline pain: A 12.5: 38.7%* A 25: 46.7%* S 100: 36.9%* P: 16.4% Severe baseline pain: A 12.5: 16.7%* A 25: 19.8%* S 100: 29.3%* P: 12.5%	A well-tolerated and associated with significantly fewer AEs vs sumatriptan (8.7% vs 22.2%, p < 0.001)
Spierings et al. (2001) [33]	1173	A 12.5 mg or sumatriptan 50 mg	A 12.5: 58.0% S 50: 57.3% (NS)	17.9 versus 24.6% (p = 0.005)	Treatment-emergent AEs in 9.1% vs 15.5% (p = 0.001)
Goadsby et al. (2007) [34]	1061	A 12.5 mg or zolmitriptan 2.5 mg	A 12.5: 65.4% Z 2.5: 70.2% (NS)	A 12.5: 43.5% Z 2.5: 48.3% (NS)	Similar rate of treatment-emergent AEs vs zolmitriptan
Láinez et al. (2007) [35]		A 12.5 mg or ergotamine 2 mg/caffeine 200 mg	A 12.5: 57.7% E/C: 44.5% (p < 0.01)	A 12.5: 20.9% E/C: 13.7% (p < 0.05)	AEs reported by 16 almotriptan recipients vs 27 ergotamine/caffeine recipients

a Single oral doses unless indicated otherwise.

* p < 0.05 vs placebo.

A = almotriptan; AE = adverse event; P = placebo; N = number of patients; NS = not significant; S = sumatriptan; Z = zolmitriptan.

A pooled analysis of four randomized, double-blind, placebo-controlled trials confirmed that ALT 12.5 mg (n = 1908) was significantly more effective than placebo (n = 386) at relieving pain at 2 h after administration (63.7% vs 35%, p < 0.05; defined as reduction in pain intensity from moderate/severe to mild/none) and also at achieving 2-h pain-free status (36.4% vs 13.9%, p < 0.05) [36]. ALT demonstrated a prompt onset of action, providing significant benefit compared with placebo as early as 30 minutes after administration (pain relief 14.9% vs 8.2%; pain-free 2.5% vs 0.7%; both p < 0.05) [36]. In addition, ALT significantly increased the number of patients who achieved sustained pain-free status (25.8% vs 11.1% with placebo, p < 0.0001; defined as pain free at 2 h with no return of pain within 24 h and no rescue medication) and sustained pain-free with no adverse events (22.2% vs 10.4%, p < 0.0001) [36]. The rate of migraine recurrence (defined as increase of pain within 24 h of migraine onset after a reduction of pain to mild/none on ALT with no use of rescue medication) ranged from 18% to 27% with ALT [37].

ALT 12.5 mg was also effective at reducing other migraine-related symptoms at 2 h after administration. As confirmed by the pooled analysis of four placebo-controlled trials, this included reductions on nausea (30.4% vs 45.4% with placebo), vomiting (5.0% vs 15.8%), photophobia (27.0% vs 45.8%) and phonophobia (21.2% vs 38.9%) (all p ≤ 0.05 for ALT vs. placebo) [36].

3.1.2. Comparisons with other migraine medications

Randomized, double-blind trials showed that, overall, ALT was as efficacious as sumatriptan 50 or 100 mg [32,33] and zolmitriptan 2.5 mg [34] and more efficacious than ergotamine plus caffeine [35] for the treatment of adults with moderate/severe migraine (Table 2).

In efficacy comparisons with sumatriptan, ALT 12.5 mg was as effective as sumatriptan 100 mg at providing 2-h pain relief and 2-h pain-free in a placebo-controlled trial [32]. Sumatriptan 50 mg was more effective than ALT at achieving pain-free status, but not pain relief, at 2 h in one head to head trial which did not include a placebo group (Table 2) [32,33]. ALT 12.5 mg was as effective as sumatriptan at preventing pain recurrence, with recurrence rates of 18% versus 25% (sumatriptan 100 mg) [32] and 27.4% vs 24.0% (not significant vs. sumatriptan 50 mg) reported [33].

ALT was as effective as zolmitriptan with respect to 2-h pain relief and 2-h pain free rates (Table 2) [34]. This study also evaluated the endpoints of sustained pain relief and sustained pain-free with no adverse events and found that rates were similar for ALT and zolmitriptan (34.2% vs 37.8%, p = 0.220, and 29.2% vs 31.8%, p = 0.357, respectively).

Several meta-analyses comparing a range of triptans have been published. A meta-analysis of 53 clinical trials encompassing six triptans (ALT, eletriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan) found that based on an analysis 2-h pain relief, sustained pain free, consistency of effect and tolerability, ALT 12.5 mg, rizatriptan 10 mg and eletriptan 80 mg had the most favourable profiles [11]. Another meta-analysis of data for the same six triptans found that ALT 12.5 mg had the highest rate of sustained pain-free with no adverse events [38]. Two more recent meta-analyses used multiple treatment comparison meta-analysis (n = 74 trials covering seven triptans including frovatriptan) or network meta-analysis (n = 88 trials covering six triptans) to incorporate indirect evidence [39,40]. Both found that eletriptan and rizatriptan provided better 2-h pain free response than other triptans, including ALT [39,40]. One also evaluated sustained pain-free response at 24 h, and ranked ALT as third most likely to be the best for this endpoint after eletriptan and zolmitriptan [39]. In a pooled analysis of 5 clinical trials in patients with migraine with aura (only one trial involved ALT), all triptans (ALT, frovatriptan, rizatriptan and zolmitriptan) were shown to be efficacious when taken during the headache phase [41]. Frovatriptan had the lowest recurrence rate at 24/48 hours (26/67%) followed by ALT (38/88%), zolmitriptan (38/92%) and rizatriptan (43/89%).

Although meta-analyses have the advantage of larger sample sizes, they should be interpreted with caution because of differences in study comparisons and statistical methods, and, importantly, they do not always take into consideration the tolerability profiles of the drugs involved.

3.1.3. Consistency of effect

ALT demonstrated consistent efficacy when used to treat multiple migraines (with or without aura) over time [30,42]. In a large 1-year, open-label study (n = 762 patients and 13,751 migraine attacks), 61.5% of attacks were treated with a single 12.5-mg dose of ALT, patients were pain-free at 2 h in 58.2% of attacks, and the response rate was similar from the first to the 30^th attack There was no evidence of tachyphylaxis in those patients completing the study [42].

3.2. Early treatment

Several post hoc analyses of initial ALT trials and an open-label study indicated that improved outcomes could be achieved if ALT was administered when the migraine headache was still mild in intensity compared with moderate/severe headaches [43,44], and also that ALT was effective when taken at the onset of a migraine attack (within 1 hour), even if the attack was moderate/severe in intensity [45,46].

As discussed in depth in the previous review [14], several randomized, controlled clinical trials were then conducted to specifically evaluate early intervention with ALT (Table 3) [47–50]. The ALT time versus Intensity Migraine Study (AIMS) found that median total headache duration (the primary endpoint) was significantly shorter following early treatment with ALT 12.5 mg (taken within 1 h of migraine onset, regardless of pain intensity) compared with treatment when pain intensity was moderate/severe (Table 3) [47]. Outcomes, including 2-h pain free and sustained pain free rates, were better when treating mild or moderate pain compared with treating severe pain. Time to treatment (< 1 vs > 1 h) was the best predictor of headache duration, and pain intensity (moderate vs severe) was the best predictor of 2-h pain free and sustained pain free rates [47].

Table 3. Randomized controlled trials of early treatment of acute migraine (with or without aura) with almotriptan 12.5 mg.

Trial/Study design	N	Treatment	Results
AIMS [47] M, CR, OL	1450	Early (<1 h from pain onset) vs standard (moderate/ severe pain)	Early vs standard Median headache duration: 3.18 vs 5.53 h (p < 0.001). 2-h pain free (according to pain intensity at onset and time since onset): <1 h from onset: mild/mod 54% vs severe 18% (p < 0.001); >1 h from onset: mild/mod 37% vs severe 23% (NS). Sustained pain free (according to pain intensity at onset and time since onset): <1 h from onset: mild/mod 24% vs severe 8% (p < 0.076); >1 h from onset: mild/mod 13% vs severe 7% (NS).
AEGIS [48,51] M, R, DB	378	ALT vs placebo; both taken <1 h of onset	ALT vs placebo 2-h pain relief: 72.3% vs 48.4% (p < 0.001); 2-h pain free: 37.0% vs 23.9% (p = 0.01); Sustained pain free: 24.7% vs 16.1% (p = 0.04).
AwM [49,52] M, R, DB	403	ALT early (mild and <1 h) vs ALT standard (moderate/severe pain) vs placebo early vs placebo standard	ALT early/mild vs ALT standard 2-h pain free: 53% vs 37.5% (p = 0.02); Sustained pain free: 45.6% vs 30.5% (p = 0.02); Placebo early/mild vs placebo standard: 24.7% vs 17.5% (p ≤ 0.01 vs respective ALT arms).
Bartolini et al. [50] M, R, DB, CO	133	ALT 12.5 mg vs frovatriptan 2.5 mg	ALT vs frovatriptan 2-h pain relief: 56% vs 54% (NS); 2-h pain free: 32% vs 30% (NS); Sustained pain free: 18% vs 21% (NS).

ALT = almotriptan; CO = crossover; CR = cluster randomized; DB = double-blind; M = multicenter; OL = open = label; N = number of patients; NS = not statistically significant; R = randomized.

The Almotriptan Early Migraine Intervention Study (AEGIS) showed that early treatment with ALT 12.5 mg (taken within 1 h of pain onset, regardless of intensity) achieved significantly better outcomes compared with placebo, including 2-h pain relief, 2-h pain free and sustained pain relief rates (Table 3) [48]. The AEGIS study also found that early ALT reduced the intensity of photophobia and phonophobia versus placebo (p < 0.05) [48], as well as the level of functional disability (54.4% vs 38.1% had normal function at 2 h, p = 0.007) [51]. Another placebo-controlled early intervention clinical trial, Act when Mild (AwM), confirmed that early treatment with ALT 12.5 mg (taken within 1 h when pain was still mild) provided significantly better outcomes, including 2-h pain free and sustained pain free rates, compared with treatment when pain was moderate/severe (Table 3) [49,52].

More recently, a multicenter, randomized, double-blind, crossover trial compared early treatment with ALT 12.5 mg and frovatriptan 2.5 mg (Table 3) [50]. Patients (n = 133) treated 1–3 migraine attacks (with or without aura) with one medication and then switched to the other. Treatment was taken as early as possible after the onset of the migraine attack. The primary endpoint was patients’ treatment preference (measured on a scale from 0 = no preference to 5 = strong preference), but standard efficacy measures were also assessed. ALT and frovatriptan showed similar efficacy with respect to 2-h pain relief, 2-h pain free and sustained pain relief (Table 3), and there was no significant difference in the average preference scores for ALT and frovatriptan (3.4 ± 1.3 vs 3.1 ± 1.3) [50].

3.3. Post-marketing and real-world studies

Postmarketing and other studies in a real-world setting provide information on the use of a drug in everyday clinical practice. Postmarketing surveillance studies of ALT conducted in Europe confirmed the results of clinical trials, finding that ALT was associated with a high response rate, that outcomes were improved when treatment was taken when pain was still mild, and that most patients preferred ALT to their previous acute migraine medication [53–57].

The multinational, open-label, observational Standardised Study with ALT in Early Treatment of Migraine (START; n = 454) confirmed that the benefit of early treatment with ALT 12.5 mg (taken within 1 h of onset when pain was still mild) that had been demonstrated in the secondary-care setting in the AwM study was also seen in an everyday general practice setting [58]. In START, a significantly greater proportion of patients who took ALT early were pain free at 2 h compared with those who did not take it early (65% vs 38%, p < 0.001). Similar clinical benefit was recorded for sustained pain free (59% vs 33%, p < 0.001) and sustained pain free without adverse events (55% vs 31%, p < 0.001) endpoints.

Some additional analyses of START have also been published. At the end of START, patient satisfaction was significantly higher for patients in the early/mild group compared with those who did not receive early treatment (mean score 6.8 vs 6.3 on a 10 cm visual analogue scale, p = 0.049) [59]. It was also found that ALT had been tried by 21% of participants prior to the study and was still being used by 83% of these patients. START also assessed whether trigger factors affected the response to ALT [60]. The most frequent triggers reported during the study were stress (37%), poor sleep (34%) and fatigue (32%), followed by menses (19%). Early ALT treatment maintained its efficacy regardless of the trigger factor(s) involved.

3.4. Special populations

3.4.1. Extent of previous triptan treatment

ALT has been shown to be effective in triptan-naïve patients, with a rate of sustained pain free with no adverse events of 33.7% reported for patients receiving ALT as their first triptan, similar to 32.1% for triptan-experienced patients [61]. ALT has also been shown to be effective in patients with a poor response to sumatriptan. In a study involving 198 sumatriptan non-responders, ALT 12.5 mg provided significantly better 2-h pain relief (47.5% vs 23.2%, p < 0.001), 2-h pain free (33.3% vs 14.1%, p < 0.005) and sustained pain free (20.9% vs 9.0%, p < 0.05) rates than seen with placebo [62].

3.4.2. Allodynia

There is some evidence that the presence of allodynia may increase the risk of an inadequate response to acute migraine medications [63]. As noted by these authors, cutaneous allodynia where the individual perceives normally non-painful stimuli such as brushing hair and wearing glasses as painful occurs in the majority of migraine patients [63]. The regions most affected are the face, scalp, and ears. A placebo-controlled pilot study (n = 112) found that allodynia presence (reported in 34.4% of attacks) did not affect the efficacy of a combination of ALT 12.5 mg plus aceclofenac 100 mg with respect to 2-h pain free or sustained pain free rates [64]. A pooled analysis of data from the AEGIS and AIMS studies of early ALT treatment also found that the presence of allodynia-associated symptoms did not have a significant effect on treatment outcomes, including 2-h pain relief, 2-h pain free and sustained pain free rate, use of rescue medication or headache duration [65].

More recently, analysis of data from the AwM clinical trial, in which 39% of patients reported allodynia, showed that it had no effect on the efficacy of ALT administered early (when pain was mild) in terms of 2-h pain free rate (53.9% vs 52.5% for patients with vs without allodynia), sustained pain free rate (47.2% vs 45.5%) or median headache duration (1.40 vs 1.54 h) [66]. However, allodynia did appear to be associated with impaired ALT efficacy when treatment was delayed until the pain was moderate/severe, with 2-h pain free rates of 31.4% vs 44.3% (p = 0.16) and a median headache duration of 3.17 vs 1.87 h for those with allodynia versus those without allodynia. These results support use of an early treatment strategy and suggest pain intensity may be the main driver of triptan response rather than the presence of allodynia.

3.4.3. Adolescents

Triptans as a class are considered to effective at relieving the pain of acute migraine in children and adolescents [67]. Efficacy has been demonstrated for ALT in several studies in adolescents with migraine (with or without aura). A small, open-label, pilot study reported that it resulted in rapid pain relief in 13 of 15 adolescents aged 11–17 years [68]. A large multicenter, randomized, double-blind trial involving 866 adolescents aged 12–17 years found that ALT 12.5 mg provided significantly higher rates of 2-h pain relief (72.9% vs 55.3%, p < 0.001) and sustained pain relief (66.9% vs 52.4%, p < 0.01) compared with placebo [69].

Another large, long-term, open-label safety study involving 447 adolescents aged 12–17 years (total >8000 migraines) has also reported efficacy data [70]. In this study, ALT 12.5 mg was associated with a 2-h pain relief rate of 61.7% and a sustained pain relief rate of 55.5% among patients with moderate/severe baseline pain. Consistent with studies in adults, better responses were seen when treatment was administered when the pain was mild or moderate rather than severe.

3.4.4. Menstrual migraine

Menses is one of the main triggers of migraine among women of child-bearing age [60,71]. Menstrual migraine tends to be more severe, last longer and be more disabling than non-menstrual migraine [72]. ALT has been shown to be effective in the treatment of menstrual migraine, based on several studies and post hoc analyses [73]. A post hoc analysis of the AEGIS placebo-controlled trial of early ALT 12.5 mg treatment indicated that it was equally effective in the treatment of women with menstrual migraine and non-menstrual migraine [74]. A post hoc analysis of data from 255 women with menstrual migraine who participated in a clinical trial comparing ALT 12.5 mg with zolmitriptan 2.5 mg found no significant difference between the drugs for efficacy endpoints including 2-h pain relief, 2-h pain free and recurrence rates [75].

Studies published since the last review of ALT confirm the efficacy of ALT for menstrual migraine [60,75,76]. A randomized, double-blind, crossover, placebo-controlled trial (n = 147) specifically evaluated the efficacy of ALT 12.5 mg taken at the onset of menstrual migraine [77]. ALT was significantly more effective than placebo with respect to the primary endpoint, 2-h pain free rate (risk ratio 1.81, p = 0.0008; Figure 1), as well as secondary endpoints including sustained pain free (RR 1.99, p = 0.0022), sustained pain free with no adverse events (RR 1.94, p = 0.0061) and duration of migraine (7.5 vs 10.8 h, p = 0.017). Efficacy was maintained during an open-label follow-up phase in which all patients received ALT 12.5 mg. Migraine-associated symptoms tended to decrease over time to a greater extent in patients treated with ALT compared with placebo, with significant differences observed at 2 h for nausea (19% vs 36.7%, p = 0.0007) and photophobia (33.1% vs 49.2%, p = 0.0083) [78].

Figure 1. Efficacy of almotriptan 12.5 mg in the treatment of menstrual migraine: 2 h pain free rate (primary endpoint) and 24 h pain free rate from a randomized double-blind, placebo-controlled study [77].

Another multicenter, randomized, double-blind, crossover trial compared ALT 12.5 mg and frovatriptan 2.5 mg for the acute treatment of menstrual migraine [76]. There were no statistically significant differences between ALT and frovatriptan in terms of pain relief and pain free rates at 2 h (41% vs 36% and 29% vs 19%, respectively) or at 24 h (67% vs 62% and 67% vs 60%). Finally, an analysis of the effect of trigger factors in the START observational study found that the efficacy of ALT administered early was high irrespective of the type of trigger factor present; for menstrual-associated migraine, the 2-h pain free rate was 69% and the sustained pain-free rate was 63% (compared with rates of 38% and 32% with non-early intake) [60].

3.4.5. Vestibular migraine

In a retrospective open-label study involving 26 subjects with vestibular migraine (vertigo attacks occurring in >50% of migraine attacks), oral ALT 12.5 mg within 1-hour of the onset of vertigo was evaluated [79]. In total, 18 patients completed 3 months follow-up and 10 reported complete disappearance of vertigo, 5 over a 50% reduction and 3 less than a 50% reduction of vertigo attacks. The authors concluded that ALT was both safe and effective in patients with vestibular migraine, but recognized the need for a larger controlled clinical trial [79].

4. Tolerability

The tolerability profile of ALT has been reviewed previously [14]. ALT is generally well tolerated and adverse events are uncommon and mild [80]. Based on pooled analysis of double-blind, placebo-controlled trials in adults, the most common adverse events reported with ALT 12.5 mg that occurred at an incidence greater than seen with placebo were nausea (2% vs 1%), dry mouth (1% vs 0.5%) and paresthesia (1% vs 0.5%) [81]. In a pooled analysis of phase 2 and phase 3 studies in moderate/severe migraine the most common adverse events (paresthesia, dizziness, nausea, vomiting, headache, fatigue and somnolence) with ALT were each reported by fewer than 3% of patients, and the overall incidence of adverse events reported with the 12.5 mg dose was not significantly different to that seen with placebo [80]. A similar tolerability profile was seen in studies evaluating early administration of ALT [47–49], and there was no difference in the incidence of adverse events when treating mild migraine early compared with treating moderate/severe pain [49].

ALT was tolerated equally well by patients with menstrual migraine or non-menstrual migraine [74]. In the placebo-controlled study in adolescents aged 12–17 years, the most common adverse events with ALT 12.5 mg were somnolence (4.9% vs 1.7% with placebo), dizziness (3.3% vs 1.7%) and nausea ALT (2.7% vs 0%) [69]. Studies in real-world practice support the good tolerability profile of ALT in the treatment of acute migraine, with somnolence, fatigue and nausea amongst the most common adverse events reported [53,58].

In a meta-analysis of the triptan class (published before frovatriptan data were available), the placebo-subtracted rate of adverse events with sumatriptan 100 mg was 13% (95% confidence interval 8–18). The rates for other triptans overlapped with this, except for ALT 12.5 mg and naratriptan 2.5 mg which had lower rates that were similar to placebo [11]. More recently, a network meta-analysis found that all triptans were associated with a significant increase in the risk of adverse events and/or treatment-related adverse events compared with placebo, except, interestingly, for ALT, naratriptan and frovatriptan [82]. The odds ratios for an adverse event with ALT 12.5 mg was 1.28 (95% CI 0.95–1.72) and for a treatment-related adverse event was 1.15 (95% CI 0.81–1.61). When considering specific adverse events, ALT was the only triptan that was not associated with a significantly increased risk of fatigue, and ALT, frovatriptan and naratriptan were the only ones not associated with a significantly increased risk of dizziness, chest discomfort, somnolence or nausea. However, ALT was associated with an increased risk of vomiting in this analysis (Odds Ratio, 95% Credibility Interval: 6.94, 1.26–33.4) [82].

Individual studies and meta-analyses indicate that ALT 12.5 mg is associated with a low incidence of cardiovascular-related adverse events such as chest symptoms or electrocardiographic abnormalities [11,32,48,52,54,82]. The low lipophilicity coefficient of ALT means that it is not expected to cross the blood-brain barrier to a significant extent [19]. This property, at least theoretically, should be associated with the lowest risk of central nervous system adverse events as was demonstrated for ALT 12.5 mg in a meta-analysis of 53 trials [11], and also with a lower risk of rebound phenomenon and headache chronification, as exemplified by the absence of tachyphylaxis in the long-term study [42].

It is relevant to highlight that no safety signals or new tolerability concerns have been raised by pharmacovigilance systems since ALT was first approved in 1999. During this period, based on the number of tablets dispensed, it is estimated that more than 150 million migraine attacks have been treated with the original patented ALT across EU, US and other countries.

5. Economic considerations

The financial burden of migraine on society is enormous and comprises both direct costs associated with medical care, as well as indirect costs caused by absence from work and reduced productivity. Cost-effectiveness studies involving the triptans highlight wide variations in the average cost-effectiveness ratio between countries [83]. As a consequence, recommendations included in clinical guidelines could have a significant economic impact if they were followed in a number of countries. This European variability is a concern for decision-makers and also for the elaboration of international recommendations and clinical practice guidelines.

Based on patient-level data from the act-when-mild (AwM) study, it was shown with high degree of probability that an early treatment strategy for acute migraine with ALT, when pain was still mild, was cost saving from the French societal perspective and can be considered a cost-effective strategy from the point of view of the French public health system [84].

6. Conclusions

ALT has been available for use in the treatment of acute migraine for almost 20 years. Data published during the last decade reinforce earlier results and confirm that ALT is an effective and well tolerated treatment for patients with acute migraine, including adolescents as well as adults, and patients with menstrual migraine as well as those with non-menstrual migraine. ALT provides rapid and sustained efficacy, particularly when administered early in a migraine attack. Its clinical features compare favorably to other triptans, placing it high on the list of treatment choices when taking both efficacy and tolerability into consideration.

Regarding the use of ALT during pregnancy/lactation no specific data appear to have been published and, in line with the summary of product characteristics, caution should therefore be exercised [85]. A recent publication by Spielmann and colleagues evaluated 432 cases of pregnancy in women treated with triptans and found 9 cases of teratogenicity; however, none of these involved ALT [86]. Following a comparison with control groups the authors concluded that triptans cannot be considered major teratogens. In a separate publication involving 353 pregnant Norwegian women, the authors also reported that there was no evidence that triptans increased the risk of teratogenicity [87]. Finally, sporadic reports of pregnancy while using ALT, after approximately 200 million daily doses have been distributed by the manufacturer, again found no evidence of an increased incidence of pregnancy-related adverse events. Indeed, the incidence of teratogenicity was much lower than the baseline rate in the general population. There are no studies available relating to ALT excretion in milk. Since the bioavailability of triptans is low, minimal quantities would be expected to be excreted in the milk and these low amounts are unlikely to cause any adverse effects in breastfeeding infants [88].

7. Expert opinion

The burden posed by headache disorders cannot be overemphasized. As noted by Steiner and colleagues in an editorial based upon the recently published Eurolight study, migraine is the number one cause of disability in the under 50s [89]. In the Eurolight study, 1175 patients from 10 countries had frequent migraine (>5 attacks per month) and yet <20% had seen a GP or specialist, in the majority of countries <10% were receiving adequate acute treatment, and even fewer patients were prescribed preventative medicines for which they were eligible [90]. In the future, particularly the next 5 years, we must do better. This should not only involve the better use of both preventative medicines and acute treatments such as the triptans (drugs which have been available since the early 1990s), but also the development and introduction of new approaches [91].

The optimal management of patients with migraine involves a stratified approach to treatment, individualization of therapy and administration of medication early during an attack [12,13,92]. Triptans are generally used in patients for whom first-line analgesics have failed to provide adequate relief of headache. ALT is an established drug for the treatment of acute migraine providing both among the highest efficacy and tolerability figures. This article updates our previous review of ALT and confirms that it is an appropriate option for treating acute migraine. Findings with ALT over the last 10 years have reinforced the positive efficacy and tolerability results that were reported during the first 10 years following its introduction. In particular, more recent clinical results have demonstrated the following: ALT is effective in women with menstrual migraine [73]; early administration of ALT improves its effectiveness even in patients with allodynia [66]; and long-term benefit and safety has been reported in adults [42] and, more recently, in adolescents [69,70]. Overall, ALT can be considered a suitable choice for managing acute migraine resistant to first-line drugs.

The response to triptans varies between patients and 30–40% do not experience an adequate response to therapy [93]. Switching to a different triptan can be of benefit in some patients, as demonstrated with ALT in sumatriptan non-responders [56]. However, little is known about the reasons for non-response, and no studies have evaluated whether a subgroup of patients responds poorly to all triptans [93]. Research into triptan non-response could be of benefit to patients and healthcare systems.

With respect to ALT, a second 12.5 mg tablet can be taken within 24 h of the first tablet if symptoms improved after the first dose, but resurfaced (there should be at least a 2-hour interval between doses). However, no data have been published regarding this approach. Likewise, there is little information available concerning how long to treat non-responders to any particular triptan. Taking intraindividual and interindividual variations into consideration it would seem clinically prudent that after a third migraine attack that was inadequately treated (i.e. insufficient pain relief within 2 hours) a switch to an alternative product should be tried. If an effective agent is found then it can be continued long-term, providing it continues to relieve migraine pain within 2 hours and is well tolerated, as evidenced by the data for ALT [42].

The genetic determinants of drug response in migraine are complex; however, several polymorphisms associated with antimigraine drug metabolizing enzymes have been identified [94]. It is possible that in the future, pharmacogenetic considerations could help guide the selection of triptans for a number of individual patients. The variety of pathways involved in the metabolism of ALT may make it less susceptible to genomic variations between patients [95].

Research on new formulations and different routes of administration to improve the bioavailability of triptans is ongoing [96]. New classes of drugs, such as selective 5-HT_1F receptor agonists and small molecule calcitonin gene-related peptide (CGRP) receptor antagonists, are being developed for the treatment of acute migraine [97,98]. It remains to be seen how these drugs will be applied in practice; most likely they will be used in patients who are refractory to current treatments or who have relevant cardiovascular risk factors precluding the use of triptans. From the available data, in terms of pain free at 2 h, the efficacy of oral gepants (small molecule CGRP inhibitors) and 5-HT_1F receptor agonists as well the tolerability of 5-HT_1F receptor agonists in terms of central nervous system adverse events seem to be somewhat inferior to that of the most efficacious and well-tolerated triptans, such as ALT [99].

Article highlights

• ALT, a potent and selective 5-HT_1B/1D receptor agonist, is well established for the treatment of acute migraine with or without aura. Newer findings have reinforced the results of earlier studies.

• A dosage of 12.5 mg provides an optimal balance of both pain control and tolerability.

• In clinical trials in patients with migraine pain of moderate/severe intensity, ALT improved outcomes significantly versus placebo, including 2-h pain relief, 2-h pain free, sustained pain free, sustained pain free with no adverse events, and migraine-related symptoms.

• Other trials showed that early administration of ALT (<1 h when pain was mild) provided better clinical outcomes than later administration.

• ALT demonstrated similar short-term efficacy to other triptans including sumatriptan, zolmitriptan and frovatriptan in comparative clinical trials.

• ALT has been shown to be effective in women with menstrual migraine, adolescents, triptan-naïve and triptan-experienced patients, patients with a poor response to sumatriptan, and patients with allodynia.

• ALT is well tolerated with a low incidence of adverse events, aligned with the best tolerated triptans such as naratriptan. At a dose of 12.5 mg the overall incidence of adverse events in clinical trials with ALT was similar to that seen with placebo.

• Studies in real-world settings have supported the effectiveness and tolerability of ALT for the treatment of patients with acute migraine.

• During the last decade since we last reviewed ALT, large numbers of patients and migraine attacks have been treated with the drug; this not only confirms the confidence it inspires in both physicians and patients, it also supports its role as an evidence-based treatment choice for the management of migraine.

Declaration of interest

C Vila is an employee of Almirall S.A., Barcelona, Spain. J Pascual has received honoraria as a speaker for Allergan, Lilly, Novartis-Amgen, Stendhal and Teva in the last 5 years. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors thank Kathy Croom and Steve Clissold Content Ed Net (Madrid) for editorial assistance that was funded Almirall S.A., Barcelona, Spain.

Additional information

Funding

Editorial assistance was funded by Almirall S.A., Barcelona, Spain.