The Sumatriptan Nasal Spray: A Review of Clinical Trials

Professor Goadsby

We are going to move now onto the sumatriptan nasal spray, the option in between, and the presenter is Dr Alan Rapoport, Co-Director of The New England Centre for Headache. You will have noticed that so far all the speakers have been European – you can make any number of inferences you like about that – but Alan has a kind of honorary European position due to a close association with Finland that he may or may not care to explain. Alan is one of the major opinion leaders in the United States, has been involved in clinical trials right across the range, and treats a great number of patients with headache.

Alan Rapoport

When sumatriptan was released, it revolutionized the management of headache, as the city of Rome has revolutionized my life; in 1965 as a student travelling through Europe I met my future Finnish wife in a Tavola Calda in Rome. So it gives me great pleasure to be here, and I'd like to thank Bob Ingram, Pat Humphrey and GlaxoSmithKline for sumatriptan, and the city of Rome for being here.

Why a nasal spray? Well, it expands the versatility of the compound, provides an additional delivery route, bypasses the GI tract and starts to work in about 15 min, so it can be used in patients who are vomiting. It offers patients most of the speed but less of the discomfort and adverse events of the injection. Of the 11 studies performed in adults since 1990 and reviewed by Dahlof (1), nine were controlled, two were not. The primary end point in each trial was headache relief at 2 h. Secondary end-points included headache relief at other time-points, complete relief, meaningful headache relief as determined by the patient, improvement in clinical disability (or lack of it) at 2 h, reduction of associated migraine symptoms and headache recurrence.

The results in five studies of the 20 mg intranasal dose (1–5) show that up to 64% of patients on active drug obtained headache relief compared to 25% on placebo; these results being significant at the P ≤ 0.05 level. The figures for achievement of pain-free status at 2 h were as good as 42%, compared with 12% or less with placebo (Fig. 1). As an example of the improvement in associated symptoms, photophobia was significantly decreased by 15 min in patients on active drug compared to placebo (5) (Fig. 2). The figures for clinical disability at 2 h are similar, with 64–74% of patients having no, or only mild clinical disability, significantly better P ≤ 0.05 than the results with placebo (2, 4, 5) (Fig. 3).

Figure 1

Percentages of patients pain-free 2 h postdose in placebo-controlled studies of sumatriptan nasal spray (n = 3225).

Figure 2

Associated symptoms: presence of photophobia/all attacks following IN sumatriptan (n = 1077). ∗P < 0.05 vs placebo; +data for all attacks combined.

Figure 3

Percentage of patients with no or mild clinical disability 2 h post-dose in placebo-controlled studies of sumatriptan nasal spray (n = 2464). ∗P < 0.05 vs. placebo.

The time to onset of headache relief varied between 15 and 60 min There was also intrapatient consistency of response (relief obtained in two out of three attacks), as 67% of the patients who took the 20 mg nasal spray, but only 34% of those taking placebo, achieved this mark (Fig. 4) (1, 5). In a one-year open trial, the overall response at 2 h was 77% and the number of AEs was low at 20%, comprising mainly disturbances of taste, nausea and vomiting (Table 1). Disorders of the nasal cavity or sinuses and throat, burning sensations, dizziness and vertigo all occurred in less than 4% of the subjects on sumatriptan nasal spray.

Figure 4

Consistency of response with IN sumatriptan in placebo-controlled trials (n = 1077). ∗P < 0.05 vs. placebo for ≥2/3 attacks; +P < 0.05 vs. 5 mg for ≥2/3 attacks.

TABLE 1

Adverse events ≥ 1% in placebo-controlled studies of IN sumatriptan

Event	Placebo n=704	Sumatriptan nasal spray
		5 mg n=496	10 mg n=1007	20 mg n=1212
Bad/unusual taste (%)	1.7	13.5	19.3	24.5
Nausea and/or vomiting (%)	11.3	12.2	11.0	13.5
Disorder/discomfort of nasal cavity/sinuses (%)	2.4	2.8	2.5	3.8
Throat discomfort (%)	0.9	0.8	1.8	2.4
Burning sensation (%)	0.1	0.4	0.6	1.4
Dizziness/vertigo (%)	0.9	1.0	1.7	1.4

The recurrence rates for sumatriptan-treated patients varied between 30 and 45% (compared with 33–55% for the placebo-treated patients (Table 2). The median time to recurrence was slightly shorter than for the tablet or the injection. There was no benefit from doses over 20 mg, nor from dividing the dose between the two nostrils. Sumatriptan plasma concentrations reach a peak most rapidly after sc. injection. The nasal spray gives higher plasma levels than the tablet early on but they approximate by 2 h (Fig. 5). The nasal spray gives significant pain relief at 15 min, the tablet at 30 min (Fig. 6).

Figure 5

Sumatriptan plasma concentration vs. time following subcutaneous, oral and intranasal administration to healthy volunteers.

Figure 6

Onset of effect: comparisons between formulations of sumatriptan.

TABLE 2

Headache recurrence rates following IN sumatriptan

Recurrence rates for sumatriptan-treated patients ranged from 30% to 46%

Recurrence rates for placebo-treated patients ranged from 33% to 55%

Median time to recurrence was 6.3–7.3 h

I am going to mention just one comparative study, the sumatriptan vs. DHE nasal spray (1, 6). The Imitrex dose was 20 mg, and that of DHE 1 mg followed by another 1 mg 30 min later if required. Significant efficacy from sumatriptan is seen by 20 min and relief was obtained at 2 h with sumatriptan in 63% compared with 51% with DHE.

I conclude that sumatriptan nasal spray is as effective as the tablets in the acute treatment of migraine. The onset of action may occur as early as 15 min. The 20 mg sumatriptan nasal spray dose provides the best overall efficacy and is well tolerated.

Thank you.