Sumatriptan: Pharmacological Basis and Clinical Results

Carl G. H. Dahlöf


Curr Med Res Opin. 2001;17(1s) 

In This Article

The Sumatriptan Formulations

Sumatriptan was first introduced in an injectable formulation, which was followed in many countries by the introduction of tablet and nasal spray forms. In some countries, sumatriptan is also available in a suppository form. Each of the formulations has unique attributes, which allow therapy to be tailored to the needs of the individual patient (Table 1).

Of the sumatriptan formulations, the injection is the most rapidly and potently effective. Sumatriptan injection is more effective than placebo at conferring headache relief beginning 10 min after dosing[13,14]. Two hours after dosing with the injection, approximately 80% of patients report headache relief.

Sumatriptan injection is similarly effective at alleviating nausea, photophobia and phonophobia and at reducing clinical disability. Intra-patient response consistency between attacks is high with sumatriptan injection: in a study in which patients treated up to three attacks with sumatriptan injection, headache relief 2 h post-dose was reported by 73% of patients for all three attacks and 89% of patients for two of three attacks[15].

Sumatriptan injection is also effective with long-term use. In one open-label, 6-month study in which patients could treat all attacks with sumatriptan injection 6 mg, the mean percentage of attacks with headache relief 1 hour post-dose over 6 months was 77%[16]. There was no evidence of tachyphylaxis over 6 months of use of sumatriptan injection.

Across studies with sumatriptan injection, approximately 35% of patients reporting relief 2 h post-dose experienced headache recurrence, or return of headache within 24 h of dosing[13,14]. The mechanism of headache recurrence, which occurs at a similar frequency with other sumatriptan formulations and with other triptans, has not been determined. Headache recurrence can be effectively alleviated (but not prevented) by taking a second dose of sumatriptan[17].

The most common adverse event with sumatriptan injection is burning or stinging at the injection site, which occurs in approximately 60% of patients in clinical trials[17]. Patients may also experience warm/hot sensation, tightness, tingling, flushing and feelings of heaviness or pressure in areas such as the face, limbs and chest. These events have been designated 'triptan sensations', because they appear to occur with all sumatriptan-like compounds developed to date[19]. The observation that 1-5% of patients experienced these symptoms in the chest area prompted investigations into their mechanism, which was determined not to be attributable to coronary artery vasoconstriction in the vast majority of cases (see Safety, below).

Sumatriptan injection is well-tolerated with long-term use. In a 2-year study in which 412 patients treated 13 277 migraines, no adverse event was reported in more than 3% of migraine attacks[18]. The long-term safety of sumatriptan was assessed in a 12-month study in which 12 339 migraineurs were followed as they took sumatriptan in a manner consistent with ordinary clinical use[20]. All adverse events were recorded regardless of suspected causality. No fatalities or myocardial infarctions were assessed as being attributable to sumatriptan, and sumatriptan was well-tolerated.

The high degree of efficacy and favourable tolerability of the injection are realized in improvements in patients' health-related quality of life measured with either generic instruments such as the Short Form-36 Health Survey or disease-specific instruments such as the Migraine-Specific Quality of Life Questionnaire[21]. Sumatriptan injection is associated with improvements in physical, social and mental dimensions of health-related quality of life after as few as 3 months of use for the acute treatment of migraine.

Sumatriptan injection also reduces migraine-associated productivity loss in the workplace. In the only double-blind, placebo-controlled studies in migraine specifically designed to test effects of a medication on migraine-associated workplace productivity loss, sumatriptan injection reduced productivity loss across an 8-hour work shift by approximately 50% compared with placebo[22,23].

Sumatriptan has been available in tablet form since 1991. Sumatriptan tablets are effective compared with placebo at alleviating headache beginning 30 min post-dose[24]. Approximately 65% of patients report headache relief 2 h after dosing[24,25,26]. Headache recurrence within 24 h of initial dosing occurs in approximately 35% of patients[24]. Intra-patient consistency of response between attacks is relatively high: in a three-attack study, 64% of patients reported headache relief 2 h post-dose for two of three attacks, and 32% reported headache relief for all three attacks[15]. Like the injection, sumatriptan tablets have been shown to be effective and well-tolerated with long-term use[16], to improve patients' health-related quality of life[27], and to reduce migraine-associated lost workplace productivity[27].

Aside from the suppository, which is not widely used around the world, the tablet is the best tolerated sumatriptan dosage form. In several clinical studies, the adverse event profile of sumatriptan tablets does not differ significantly from that of placebo[25,26]. In studies in which adverse events are reported more frequently with sumatriptan tablets than with placebo, the most common adverse event is nausea, which is possibly attributed to the migraine rather than to sumatriptan[26]. Triptan sensations occur less frequently with sumatriptan tablets than with the injection[28].

Like the availability of several sumatriptan formulations, the availability of several sumatriptan tablet doses (25 mg, 50 mg and/or 100 mg) in many countries allows flexibility in tailoring therapy to the needs of the individual patient and the individual attack. Sumatriptan tablet doses of 25 mg, 50 mg and 100 mg have been extensively studied to determine the optimal tablet dosing regimen. Small, early studies revealed no differences in efficacy between the three doses, though all doses of sumatriptan were more effective than placebo[25,26]. These early studies were not sufficiently powered to detect differences between sumatriptan doses. A large, definitive study (Glaxo Wellcome protocol S2CM09) of 1003 patients treating up to three migraine attacks with sumatriptan tablets 25 mg, 50 mg, or 100 mg (same dose for all three attacks) shows that the 50 mg and 100 mg doses were similarly effective 2 h post-dose (incidence of headache relief 61% and 62%, respectively) and 4 h post-dose (incidence of headache relief 78% and 79%, respectively) and that both doses were more effective than sumatriptan tablets 25 mg (incidence of headache relief 52% 2 h post-dose and 67% 4 h post-dose) and placebo (incidence of headache relief 27% 2 h post-dose and 38% 4 h post-dose) (Figure 1)24. The incidence of freedom from pain 2 h post-dose (attack 1), which increased directly with dose of sumatriptan, was 21%, 31% and 35% for the 25 mg, 50 mg and 100 mg doses, respectively, compared with 9% for placebo. Both 50 mg and 100 mg doses were more effective than placebo at conferring headache relief beginning 30 min after dosing. While the 50 mg and 100 mg doses were equally effective, the 100 mg dose was associated with a higher incidence of adverse events than the 50 mg dose (37% vs 27%; Table 2).

Percentage of patients reporting headache relief as a function of time after dosing with placebo or sumatriptan tablets 25 mg, 50 mg, or 100 mg23. 25 mg, 50 mg, 100 mg vs placebo: *p<0.05; 50 mg, 100 mg vs 25 mg: †p<0.001; 100 mg vs 25 mg; #p<0.05

These data, collected using standard clinical endpoints, are supplemented by results of studies examining patients' preferences for particular sumatriptan tablet doses[29,30]. In an open-label trial, patients' preference for particular doses of sumatriptan tablets was assessed by giving them the opportunity to increase the dose to 100 mg or decrease it to 25 mg after treating three migraine attacks with 50 mg[29]. Half of patients (50%) chose to increase the dose to 100 mg, 12% decreased the dose to 25 mg, and 37% continued taking 50 mg. Given the opportunity to increase or decrease the dose again by one dose interval after treating three additional attacks, most (58%) selected the 100 mg dose for treatment of future attacks, while 33% chose the 50 mg dose and 8% the 25 mg dose. Thus, in conditions reflecting those found in ordinary clinical practice, patients tended to gravitate toward the 100 mg dose, although many also found the 50 mg dose satisfactory.

Patient preference for sumatriptan tablet doses was also assessed in a double-blind, randomized, cross-over study in which 257 patients treated three migraines, each with a different dose of sumatriptan (25 mg, 50 mg, or 100 mg)[30]. The results demonstrate that 35% of patients preferred the 100 mg dose; 31% preferred the 50 mg dose; and 25% preferred the 25 mg dose. The two main reasons for preferring the higher doses were efficacy and speed of action.

Considered together, the efficacy, tolerability and patient preference data suggest that 50mg is an appropriate dose for most patients, although many find optimum relief with and prefer the 100mg dose. Though efficacy and tolerability data have not always distinguished among the sumatriptan doses, individual patients often clearly prefer one dose to the other. This observation suggests that data on traditional clinical efficacy and tolerability endpoints should be supplemented with information on patient preference in tailoring therapy to individual patient's needs.

In 1996 and 1997 sumatriptan was approved for use by intranasal administration in North America and Europe. Sumatriptan nasal spray is rapidly effective with an onset of efficacy beginning as early as 15 min post-dose compared with placebo. The 5 mg, 10 mg and 20 mg doses of sumatriptan nasal spray have been assessed thoroughly in five randomized, double-blind clinical studies[31]. Across the studies, all three doses of sumatriptan nasal spray were significantly more effective than placebo, but a higher incidence of headache relief 2 h post-dose was reported with the 20 mg dose compared with either the 5mg or the 10 mg dose. For sumatriptan nasal spray 20 mg, 55- 64% of patients reported headache relief 2 h post-dose compared with 25-36% of placebo patients. Headache recurrence is reported in 30-40% of patients treated with sumatriptan nasal spray[31]. In a study in which patients used the same dose of sumatriptan nasal spray for up to three attacks, 67% of patients responded for two of three attacks, and 35% of patients responded for all three attacks[15,32]. Like sumatriptan injection and tablets, sumatriptan nasal spray is effective and well-tolerated with long-term use for up to a year[31].

Across placebo-controlled studies, few adverse events occurred in 1% or more of the patients (Table 3). The most common of these events was a disturbance of taste, usually described as bad, bitter, unpleasant, or unusual. This adverse event was reported in about one-fourth of patients receiving sumatriptan nasal spray 20 mg. Other than disturbance of taste, adverse events with sumatriptan nasal spray were reported at frequencies similar to those of placebo.

The results of these clinical trials are consistent with data from clinical practice[33]. The patients' opinion of sumatriptan nasal spray treatment was obtained from 118 migraineurs (94 women and 24 men) with previous experience of subcutaneous sumatriptan and/or sumatriptan tablets. They were asked to compare this new formulation with the older formulations with respect to onset of action, total efficacy, tolerability and user friendliness. Sumatriptan nasal spray (20 mg) was perceived to have a faster onset of action than sumatriptan tablets. Compared with sumatriptan injection, the nasal spray was perceived as less effective in reducing symptoms of migraine attacks but as causing fewer adverse events. A bitter taste, reported by 68% (80 of 118) of the migraineurs, was the most commonly reported side-effect of sumatriptan nasal spray. The overall impression of sumatriptan nasal spray was reported to be better or equal to that of the tablet and the injection by 57% and 46% of patients, respectively.

A recent randomized double-blind, double-dummy, parallel-group trial compared the efficacy and tolerability of sumatriptan nasal spray 20 mg with rizatriptan wafer 10 mg (Glaxo Wellcome data on file). In terms of speed of onset, sumatriptan nasal spray was statistically superior to rizatriptan wafer in conferring freedom from pain 30 min post-dose. Efficacy was comparable between the two formulations at all other measured time points. As expected, taste disturbance was the most commonly reported adverse effect for sumatriptan nasal spray. Tolerability of the two products was similar overall.

Sumatriptan suppository is not widely available, but is marketed in several countries including Germany, Sweden, Switzerland and Greece. Like sumatriptan tablets, sumatriptan suppositories are effective compared with placebo beginning 30 min post-dose. Across five placebo-controlled studies, the incidence of headache relief 2 h post-dose ranged from 64-74% with the 25 mg suppository dose and 43-69% with the 12.5 mg dose compared with 21-48% with placebo[34]. Headache recurrence was reported in approximately 35% of patients. The tolerability

sumatriptan group than in the corresponding placebo group. profile of the suppository was similar to that of placebo. Ano-rectal adverse events such as burning, itching, or irritation were reported in less than 1% of patients.

The availability of several sumatriptan formulations provides an opportunity to tailor therapy to individual patient's needs. For the majority of patients, sumatriptan tablets, which offer consistent efficacy within 30 min of administration in a convenient dosing form, may be an appropriate choice. Although clinical trials do not demonstrate robust differences in efficacy between the 50 mg and the 100 mg tablet doses, individual patients do distinguish them and often have a preference for one dose over the other. For patients who desire particularly rapid relief that cannot be provided by a tablet form, sumatriptan injection with a 10-minute onset of action or sumatriptan nasal spray with a 15-minute onset of action may be appropriate choices. Patients with very severe attacks and those with vomiting may also benefit from the injection. For patients with nausea who do not wish to take tablets or who fear injections, the suppository or nasal spray are appropriate options.


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