Sumatriptan: Pharmacological Basis and Clinical Results

Carl G. H. Dahlöf

Disclosures

Curr Med Res Opin. 2001;17(1s) 

In This Article

Sumatriptan vis-à-vis Sumatriptan-like Triptans

Several other 5-HT1B/1D agonists such as naratriptan, zolmitriptan and rizatriptan have recently been introduced for the acute treatment of migraine. The relative features and benefits of these newer 5-HT1B/1D agonists and sumatriptan will become established as they are more extensively studied in clinical trials and used in clinical practice. The 2.5-mg dose of naratriptan tablets, for example, is known to provide efficacy with a slower onset of action but to have excellent tolerability.

Experience with the newer 5-HT1 agonist tablets to date suggests that, generally speaking, they have similar peak efficacies and times to onset of action to those of sumatriptan tablets, with no tablet showing an onset of action before 30 min post-dose[53,54,55,56,57,58,59].

A recently published direct comparison suggested that eletriptan tablets 40 mg and 80 mg could be more effective than sumatriptan tablets 100 mg for some measures[60], but this effect appears to be an artifact of the administration of sumatriptan in an encapsulated form in this study. The suggestion that the results of the eletriptan-sumatriptan comparator study are artifactual arose from the observation that headache relief 2 h after dosing with sumatriptan in comparator trials with zolmitriptan tablets[53,54], rizatriptan tablets[55,56,57,58] and eletriptan tablets[59] was lower when encapsulated sumatriptan was used as a comparator (46-54% headache response) than it was when conventional sumatriptan tablets were used as a comparator (61-68% headache response). Pharmacokinetic studies, showing that in both healthy volunteers and migraine patients, that sumatriptan absorption was delayed with an over-encapsulated form, compared with the tablet, support the hypothesis that encapsulation appears to delay absorption of sumatriptan during migraine and that the effect may be exacerbated by migraine-associated gastric stasis[61].

Recent data suggest that acute treatment successes and failures are not randomly distributed among migraineurs[62]. Rather, individual migraineurs are more or less likely to respond to a given treatment. For example, in an analysis of data from controlled clinical trials where three attacks were treated with sumatriptan tablets 50 mg or 100 mg, it was demonstrated that two preceding treatment successes with respect to pain relief and pain free at 2 h were followed by a successful response during the third attack in more than 70% of the patient population (Glaxo Wellcome data on file). On the other hand, in the minority of patients who had experienced two treatment failures in the preceding attacks, about 70% failed to respond also during the third attack. The clinical implication of these findings is that if the migraineur does not respond to treatment for the first two attacks, she/he should probably try another treatment alternative. The probability of response in an individual migraine is related to whether or not the individual responded on a previous attack. Withinpatient consistency of response for two of three attacks occurs in 89%, 67%, 64% and 71% of patients with sumatriptan injection, nasal spray, tablets and suppository, respectively. Within-patient consistency of response for three of three attacks occurs in 73%, 35%, 32% and 41% of patients treated with sumatriptan injection, nasal spray, tablets and suppository, respectively. Thus, the injection is associated with higher intra-individual response consistency than the other formulations of sumatriptan. Similar results might be expected to apply between triptans, a hypothesis that is being researched.

Whereas the incidence of headache relief 2 h post-dose is similar among triptan tablets, their tolerability profiles may distinguish them. The least lipophilic, sumatriptan does not readily cross the blood-brain barrier[2], and it has a low incidence of central nervous system side-effects such as somnolence or dizziness. More lipophilic triptans such as rizatriptan, on the other hand, may be hampered by higher incidences of these neurological side-effects than does placebo in controlled clinical trials. The incidence of any neurological adverse event as reported in product labelling is 20% for rizatriptan tablets 10 mg and 17% for zolmitriptan tablets 2.5 mg compared with 8% for sumatriptan tablets 50 mg and 12% for sumatriptan tablets 100 mg[9,63,64]. Dizziness and somnolence are reported at incidences of 9% and 8%, respectively for rizatriptan 10 mg compared with 3% and 1%, respectively, for sumatriptan 50 mg. This tolerability penalty of more lipophilic triptans, however, is not always confirmed by data in head-to-head comparative trials.

Recently the concept of patient preference was incorporated into the design of an open-label, independent trial in a clinic setting[65]. Like the tolerability data, patient preference data may help to assess differences among the triptans. Consecutive patients consulting at the headache clinic for migraine treatment and who were either previous or current users of some triptan were enrolled into the study. Patients were randomized to treat two migraine attacks with each of three triptans: sumatriptan 50 mg or 100 mg, naratriptan 2.5 mg or 5mg and zolmitriptan 2.5 mg or 5 mg. Patients who for historical reasons received the higher dose of a particular medication for the first two attacks, received the higher dose of the other two triptans for the subsequent four migraine attacks. For example, if a patient received 100 mg of sumatriptan for the first two attacks, they would receive 5mg of naratriptan or zolmitriptan for the next two attacks. Finally on the last two attacks they would receive the remaining triptan (5 mg of zolmitriptan or naratriptan). After the patients had treated two attacks with each treatment, they assessed their preference.

In this cross-over study, more patients indicated that they were rather or very satisfied with the efficacy of sumatriptan (93%) than naratriptan (71%) or zolmitriptan (61%)[65]. Similarly, more patients were satisfied with the onset of action of sumatriptan (89%) than naratriptan (54%) or zolmitriptan (61%). With respect to the primary objective, 50% of patients preferred sumatriptan, 32% preferred naratriptan and 18% preferred zolmitriptan. While there are several design issues with this study, such as small patient numbers (n=28), the use of an unregistered 5-mg dose of naratriptan, and the open-label design, it does serve as an example of an approach to the comparison of the triptans that might provide a more real-life perspective than the randomized clinical trial.

In another recent trial, treatment satisfaction with and preference of sumatriptan 50 mg tablets and sumatriptan 20 mg nasal spray in the acute treatment of migraine were evaluated in migraineurs naive to either formulation. The study was open and employed a randomized two-period cross-over design. The primary objective was to determine which formulation of sumatriptan the patients preferred. The results demonstrate that the tablets and nasal spray were equally preferred. The proportion of migraineurs preferring nasal spray was 53% (95% confidence interval 43-64%), and the proportion preferring the tablet was 47% ( 95% confidence interval 36-57%) (Glaxo Wellcome data on file). The conclusion from this study was that about half of the migraineurs prefer the nasal spray and half of the patients prefer the tablets. The nasal spray has a faster onset of action but is associated in some cases with an unpleasant taste. The tablets have a somewhat slower onset of action than the nasal spray but are in the opinion of many patients easier to take. Like the patient preference data that differentiate among the doses of sumatriptan tablets, these results show that patient preference can help to differentiate among formulations where standard clinical efficacy measures do not.

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