- Email: [email protected]
Sumatriptan versus eletriptan: which is best?
Reflection & Reaction Sumatriptan versus eletriptan: which is best? The triptans are the drugs of choice for the acute treatment of moderate to severe migraine attacks. Sumatriptan, the first selective 5HT1B/1D receptor agonist to be developed, has served as the standard to which all “secondgeneration triptans” have been compared. Although eletriptan is still awaiting approval by the US Food and Drug Administration (FDA), it is currently marketed in at least 42 countries worldwide A double-blind, placebo-controlled, multiple migraine attack study, reported in the Oct 22 issue of Neurology, showed that 80 mg of eletriptan is significantly more effective than both placebo and 50 mg of sumatriptan for headache response at 1 h, the primary efficacy endpoint.1 Sandrini and colleagues1 also showed that both doses of eletriptan (40 mg and 80 mg) were more effective than sumatriptan (50 mg and 100 mg) for other key endpoints including 2 h painfree, 2 h headache response, sustained headache, and sustained pain-free responses at 24 h. The results of this study add to the findings of a previous head-to-head study in which there was a significant 1 h and 2 h efficacy advantage for 80 mg of eletriptan compared with 100 mg of sumatriptan.2 The 2 h headache response— which is the primary efficacy endpoint used in the majority of triptan clinical trials—in Sandrini’s study mirrors the results of a recent meta-analysis of placebo-controlled eletriptan studies, which calculated a headache response at 2 h of 60% (95% CI: 58 to 64%) for 40 mg of eletriptan and of 66% (62 to 70%) for the 80 mg dose.3 However, the 2 h headache response rates for sumatriptan in Sandrini’s study—50% for 50 mg and 53% for 100 mg of sumatriptan—differed from the results of the meta-analysis where the corresponding 2 h headache response rates were 63% (60 to 64%) and 59% (57 to 61%) for the 50 mg and 100 mg doses of sumatriptan, respectively. Some people have argued that the consistently lower efficacy rates for sumatriptan in the head-to-head studies with eletriptan are due to the encapsulation of sumatriptan in these
474
studies.4 As Sandrini and colleagues suggest, encapsulated sumatriptan has similar dissolution rates in vitro when compared with the commercially available formulation. In addition, the bioequivalence of the encapsulated formulation of sumatriptan to the unencapsulated commercial tablets was confirmed in a study consistent with FDA and European Agency for the Evaluation of Medicinal Products (EMEA) guidelines. Nevertheless, the consistent relative underperformance of sumatriptan in the head-to-head trials is notable but the reasons remain unclear. Does Sandrini and colleagues’ study help a physician to decide which triptan to use for an individual patient? It is important to keep in mind that patients often choose medications not simply on the basis of a single efficacy criterion, but on a variety of factors including speed and completeness of relief, sideeffect profile, and the ability to return to normal function. In addition, the availability of different formulations is often important. Sumatriptan, for example, offers non-oral formulations that allow tailor-made treatments; the 6 mg subcutaneous formulation is the most effective acute migraine treatment, but is also associated with more intense adverse events and the need for self-injection. What is clear is that although all of these medications are safe and effective, patient preferences vary, individual responses to a triptan cannot be predicted, and the response to one triptan does not predict the response to another. Finding the best therapy may involve a process of trial and error as the physician establishes a reasonable but aggressive expectation (eg, restoration of normal function at 2 h) and one or more medications are tried until this expectation is met. It is also important to understand that the timing of administration in a clinical trial does not mean that the same protocol should be used in clinical practice. Like all clinical trials of the triptans, patients were obliged not to treat themselves until the pain became moderate or severe in intensity. In practice, it has long been recognised
that early treatment substantially improves the efficacy of any acute antimigraine drug. Recent long-term open-label and placebo-controlled studies of triptans have confirmed this clinical observation, and very recent data suggests that as the migraine attack is allowed to evolve, central sensitisation develops and triptans fail to abort the attack.5,6 The Sandrini study confirms previous reports and demonstrates that eletriptan is very effective for the acute treatment of migraine. Ultimately, preference for individual triptans should remain the patient’s decision. In the final analysis, because migraine is a paroxysmal disorder with periods of normality between attacks, neither the clinician nor the patient needs to restrict themselves to any single triptan long-term and the opportunity to “trial” a different triptan for the next attack gives patients the opportunity to find the medication which best suits them. Perhaps more important than drug selection is ensuring that the proper dosage and formulation is used and that patients are properly instructed on the importance of administering the medication early during the course of an attack once the patient recognises that a migraine headache is imminent. Conflict of interest DWD has consulted for, received honoraria from, or received research grants from the following pharmaceutical companies: Allergan, Abbott, Merck, Pfizer, GlaxoSmithKline, OrthoMcNeil, Eli Lilly, Pharmacia, and AstraZeneca.
David W Dodick Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA. Email [email protected] References 1
2
3
4
5 6
Sandrini G, Farkkila M, Burgess G, Forster E, Haughie S for the Eletriptan Steering Committee. Eletriptan vs sumatriptan: a double-blind, placebocontrolled, multiple migraine attack study. Neurology 2002; 59: 1210–17. Goadsby PJ, Ferrari MD, Olesen J, et al. Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Neurology 2000; 54: 156–63. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001; 358: 1668–75. Fuseau E, Petricoul O, Sabin A, et al. Effect of encapsulation on absorption of sumatriptan tablets: data from healthy volunteers and patients during a migraine. Clin Ther 2001; 23: 242–51. Pascual J. Clinical benefits of early triptan therapy for migraine. Headache 2002; 42 (suppl 1): 10–17. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000; 47: 614–24.
THE LANCET Neurology Vol 1 December 2002
http://neurology.thelancet.com
For personal use. Only reproduce with permission The Lancet Publishing Group.
474
studies.4 As Sandrini and colleagues suggest, encapsulated sumatriptan has similar dissolution rates in vitro when compared with the commercially available formulation. In addition, the bioequivalence of the encapsulated formulation of sumatriptan to the unencapsulated commercial tablets was confirmed in a study consistent with FDA and European Agency for the Evaluation of Medicinal Products (EMEA) guidelines. Nevertheless, the consistent relative underperformance of sumatriptan in the head-to-head trials is notable but the reasons remain unclear. Does Sandrini and colleagues’ study help a physician to decide which triptan to use for an individual patient? It is important to keep in mind that patients often choose medications not simply on the basis of a single efficacy criterion, but on a variety of factors including speed and completeness of relief, sideeffect profile, and the ability to return to normal function. In addition, the availability of different formulations is often important. Sumatriptan, for example, offers non-oral formulations that allow tailor-made treatments; the 6 mg subcutaneous formulation is the most effective acute migraine treatment, but is also associated with more intense adverse events and the need for self-injection. What is clear is that although all of these medications are safe and effective, patient preferences vary, individual responses to a triptan cannot be predicted, and the response to one triptan does not predict the response to another. Finding the best therapy may involve a process of trial and error as the physician establishes a reasonable but aggressive expectation (eg, restoration of normal function at 2 h) and one or more medications are tried until this expectation is met. It is also important to understand that the timing of administration in a clinical trial does not mean that the same protocol should be used in clinical practice. Like all clinical trials of the triptans, patients were obliged not to treat themselves until the pain became moderate or severe in intensity. In practice, it has long been recognised
that early treatment substantially improves the efficacy of any acute antimigraine drug. Recent long-term open-label and placebo-controlled studies of triptans have confirmed this clinical observation, and very recent data suggests that as the migraine attack is allowed to evolve, central sensitisation develops and triptans fail to abort the attack.5,6 The Sandrini study confirms previous reports and demonstrates that eletriptan is very effective for the acute treatment of migraine. Ultimately, preference for individual triptans should remain the patient’s decision. In the final analysis, because migraine is a paroxysmal disorder with periods of normality between attacks, neither the clinician nor the patient needs to restrict themselves to any single triptan long-term and the opportunity to “trial” a different triptan for the next attack gives patients the opportunity to find the medication which best suits them. Perhaps more important than drug selection is ensuring that the proper dosage and formulation is used and that patients are properly instructed on the importance of administering the medication early during the course of an attack once the patient recognises that a migraine headache is imminent. Conflict of interest DWD has consulted for, received honoraria from, or received research grants from the following pharmaceutical companies: Allergan, Abbott, Merck, Pfizer, GlaxoSmithKline, OrthoMcNeil, Eli Lilly, Pharmacia, and AstraZeneca.
David W Dodick Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA. Email [email protected] References 1
2
3
4
5 6
Sandrini G, Farkkila M, Burgess G, Forster E, Haughie S for the Eletriptan Steering Committee. Eletriptan vs sumatriptan: a double-blind, placebocontrolled, multiple migraine attack study. Neurology 2002; 59: 1210–17. Goadsby PJ, Ferrari MD, Olesen J, et al. Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Neurology 2000; 54: 156–63. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001; 358: 1668–75. Fuseau E, Petricoul O, Sabin A, et al. Effect of encapsulation on absorption of sumatriptan tablets: data from healthy volunteers and patients during a migraine. Clin Ther 2001; 23: 242–51. Pascual J. Clinical benefits of early triptan therapy for migraine. Headache 2002; 42 (suppl 1): 10–17. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000; 47: 614–24.
THE LANCET Neurology Vol 1 December 2002
http://neurology.thelancet.com
For personal use. Only reproduce with permission The Lancet Publishing Group.