Evaluating the triptans

Transcription

1 The American Journal of Medicine (2005) Vol 118, Suppl 1, 28S 35S Evaluating the triptans Ninan T. Mathew, MD, a Elizabeth W. Loder, MD b a From the Houston Headache Clinic, and Department of Neurology, University of Texas Medical School, Houston, Texas, USA; and the b Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. KEYWORDS: 5-HT 1B/1D ; Headache; Migraine; Patient satisfaction; Triptans The debilitating effect of migraine has fueled the search for more specific agents to treat its characteristic and associated symptoms. Second-generation oral triptans have shown an improved efficacy profile in comparison with the pioneer sumatriptan and with the over-the-counter medications and prescription analgesics that have been staples of migraine treatment. Although all triptans exert effects through the 5-hydroxytryptamine 1B/1D receptors, each triptan has distinctive pharmacokinetic properties that determine its efficacy and tolerability profile. Empirical findings based on clinical trials have led to associations between triptan pharmacology and efficacy. With the expanded treatment choices, the onus is on healthcare providers (especially primary care physicians, who see the majority of patients with migraine) to determine which treatment has an efficacy profile that best suits the individual patient s needs. Patients prefer pharmacotherapy with a rapid onset of action that facilitates complete pain relief and no recurrence. Data from published comparator trials, based on commonly used efficacy end points and pharmacokinetic properties underlying patient-preferred outcomes, are reviewed in this article Elsevier Inc. All rights reserved. Triptans are 5-hydroxytryptamine 1B/1D (5-HT 1B/1D ) receptor agonists. Their development has been a major advance in the treatment of migraine, 1 a neurovascular disorder 2,3 with an economic and emotional burden that places it among the top 20 disabling maladies worldwide. 4 The likely mechanism underlying this type of headache involves the dilation of cranial blood vessels, particularly in the meninges, which is hypothesized to sensitize the central trigeminal neurons, resulting in migraine symptoms. 1 The role of 5-HT in migraine is indicated by its decreasing circulating levels during headache attacks and the concomitant increase in urinary levels of 5-hydroxyindoleacetic acid, a breakdown product of serotonin. 5 Moreover, receptor localization studies using molecular probes have shown substantial messenger RNA for 5-HT 1B receptors on vascular endothelium and human meningeal blood vessels, consistent with vasodilatory mechanisms in migraine. 6 Requests for reprints should be addressed to Ninan T. Mathew, MD, Houston Headache Clinic, 1213 Hermann Drive, Suite 350, Houston, Texas address: ntmathew@houstonheadacheclinic.com. The remarkable efficacy of triptans in relieving the symptoms of migraine 7 supports the hypothesis that 5-HT has a pivotal role in the pathophysiology of this debilitating pain. Triptans have 3 potential mechanisms of action: normalization of dilated intracranial arteries through enhanced vasoconstriction, 8 peripheral neuronal inhibition, 9 and neural inhibition of second-order neurons of the trigeminocervical complex. 10 Of the 7 triptans available on the market, sumatriptan was the pioneer. Recognition of the pharmacologic limitations of sumatriptan, such as its low bioavailability and short half-life (t 1/2 ), led to the development of secondgeneration triptans, including zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan. 11 These agents are the latest additions to the migraine treatment armamentarium, which also includes nonsteroidal antiinflammatory drugs (NSAIDs), combination analgesics, and ergot derivatives. 12,13 Clinical research indicates that triptans have a better efficacy and tolerability profile compared with these agents, 14,15 and these data are supported by patient preference /$ -see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 Mathew and Loder Evaluating the Triptans 29S Table 1 Outcome measures used in evaluating treatment efficacy of triptans Headache response at 2 hr* Percentage of patients with a decrease in headache from severe or moderate to none or mild within 2 hr Pain-free rate at 2 hr Percentage of patients who are pain free at 2 hr, before any rescue medication Headache recurrence Return of headache of any severity within specified time (24 or 48 hr) after a 2-hr painfree stretch posttreatment Sustained relief over 24 hr Headache relief at 2 hr sustained for 24 hr after treatment without use of second-dose of test medication or rescue medication Sustained pain-free rate Pain-free within 2 hr with no use of rescue medication or no recurrence within predetermined time (24 or 48 hr) Associated symptoms Presence of associated symptoms (e.g., nausea, vomiting, photophobia, phonophobia) at time of intake of test medication and after 2 hr Functional disability Patient is asked to account for the impact of headache and associated symptoms on his or her ability to function, using a categorical verbal/numerical scale that measures the level of impairment of the patient during daily activities Use of rescue medication The use of rescue medication 2 hr (or earlier) after the intake of the test drug Intrapatient consistency Treatment success (preferably defined as pain-free within 2 hr) in at least 2 of 3, or 3 of 4 consecutive attacks treated with the active drug Patient satisfaction or preference Patient s expressed satisfaction or preference for treatments *Most common primary efficacy end point in published clinical trials. The primary end point recommended by the International Headache Society (IHS) for use in acute migraine trials. 18 Data from Pain. 19 Adapted from Cephalalgia. 18 Although clinical trials of efficacy and safety (e.g., headto-head trials, meta-analyses, crossover trials, switch studies), case studies, and pharmacoeconomics studies provide an objective basis for treatment choices, the final decision about which triptan to use is typically reached by considering multiple attributes and reflects priorities unique to a particular patient. 17 As the collective experience with triptans increases, the evaluation of treatment efficacy based on a variety of measures reflects our growing knowledge of the benefits and limitations of acute migraine therapy. 17 The efficacy data from randomized clinical trials (RCTs) of triptans are analyzed here, with an attempt to reconcile observational data with pharmacotherapeutic properties that patients consider important for acute migraine treatment. Oral triptans: comparative efficacy in acute migraine treatment With the expansion of the triptan class, the comparative efficacy of the various formulations is of particular interest to clinicians. Of the various routes of administration available for the treatment of migraine (oral, subcutaneous, nasal spray, suppository), patients prefer oral tablets primarily due to convenience; alternative routes are used primarily in patients with severe nausea. 18 Because the tablet is the most common mode of delivery of triptans, subsequent discussion will focus on the oral triptans. When comparing data from different clinical trials, the efficacy parameters that were applied should be noted. A number of outcomes have been used to measure the efficacy of triptans in the treatment of migraine (Table 1). The more commonly used measures are headache response at 2 hours, pain-free rate at 2 hours, headache recurrence, sustained relief at 24 hours, sustained pain-free rate, associated symptoms (nausea, phonophobia, photophobia), functional response, use of rescue medication, intrapatient consistency of response, and patient acceptability or preference. Comparative efficacy according to these measures has been collected from individual head-to-head trial data and meta-analyses. In 2002, 2 systematic reviews were published that compared the analgesic efficacy and adverse effects of pharmacologic treatments for migraine. 7,19 The meta-analysis by Ferrari and colleagues 7 selectively included 53 clinical trials of triptans with a total of 24,089 patients. The review by Oldman and associates 19 included randomized, placebo-controlled studies using a broader range of analgesic agents in a total of 21,022 patients. The conclusions from these analyses will be assessed alongside individual comparative RCTs. Table 2 summarizes the data from head-to-head trials according to the more common end points used. For doseranging studies, efficacy data of the recommended doses were selectively summarized. Most of the studies used sumatriptan as a comparator. Each of these trials blinded patients and investigators to the study medications by methods that included creating placebo tablets to match each active drug or placing one or both active drugs into a capsule and creating a matching placebo capsule. For each of the eletriptan-versus-sumatriptan comparator studies, bioequivalence between the encapsulated and commercial sumatriptan tablets used was demonstrated using standard pharmacokinetic measures. 25 Among the sumatriptan comparative RCTs, the comparator drugs were rizatriptan, 21,23,28 eletriptan, zolmitriptan, 22,31 or almotriptan. 29,30 The efficacy data for frovatriptan are limited, as there are no comparative RCTs to date.

3 30S The American Journal of Medicine, Vol 118, Suppl 1, March 2005 Table 2 Comparative efficacy in triptan head-to-head trials* Study N Comparators by dose (mg) Sumatriptan vs. 2nd-generation triptans Gallagher et al (2000) 31 1,445 Z 2.5, 5 S 25, 50 Geraud et al (2000) 22 1,058 Z 5 Visser et al (1996) R 10, 20, 40 Goldstein et al (1998) 23 1,329 R 5, 10 S 25, 50 Tfelt-Hansen et al (1998) 21 1,099 R 5, 10 Spierings et al (2001) 29 1,173 A 12.5 S50 Dowson et al (2002) A 12.5, 25 Goadsby et al (2000) E 20, 40, 80 Sandrini et al (2002) E 40, 80 S 50, 100 Mathew et al (2003) 26 2,113 E 40 Comparisons between 2nd-generation triptans Bomhof et al (1999) R 10 N 2.5 Pascual et al (2000) R 10 Z 2.5 Garcia-Ramos et al (2003) E 40 N 2.5 Steiner et al (2003) 33 1,337 E 40, 80 Z 2.5 Headache response at 2 hr Z 2.5 S50 (P 0.017) R10 R10 A 12.5 S50 A 12.5 Pain-free at 2 hr Functional improvement at2hr Patient acceptability/ satisfaction by dose (mg) Z 2.5 S50 R10 R10 (P 0.032) S50 A 12.5 (P 0.005) A 12.5 (P ) (P 0.041) R10 (P 0.015) Therapeutic difference in primary outcome by dose (mg) Z 2.5 S50 OR: 1.21 (P 0.017) Z 5 1% R 10 6% HR: 1.14 R 10 HR: 1.2 (P 0.03) A 12.5 S50 0.7% A % (P 0.005) (P 0.025) (P 0.014) (P 0.038) 10% 3% 8% HR: 1.62 HR: % 4% A almotriptan; E eletriptan; HR hazard ratio; N naratriptan; NS not significant; OR odds ratio; R rizatriptan; S sumatriptan; Z zolmitriptan; primary efficacy outcome; secondary efficacy outcome. *Randomized, double-blind trials; comparative emphasis on outcomes pertinent to recommended doses of the various oral formulations. Formulation with numerical advantage and corresponding P-value is indicated. Primary efficacy outcome: complete headache response, defined as a reduction in headache pain from moderate/severe at baseline to mild or no pain 2 hr after taking study medication with no moderate or severe recurrence within 24 hr. Primary efficacy outcome: time to pain relief within 2 hr. Primary efficacy outcome: headache response at 1 hr. Primary efficacy outcome: time to pain-free within 2 hr. Headache response at 2 hours Headache response at 2 hours has been the most common primary efficacy end point in published clinical trials of triptans. It is typically expressed as the percentage of patients with a decrease in headache pain from severe or moderate to mild or none within 2 hours of drug administration and before the use of any rescue medication. 18 When using absolute proportions, the Ferrari meta-analysis, similar to Oldman s, 19 showed that rizatriptan 10 mg and eletriptan 80 mg were superior to sumatriptan 100 mg. 7 However, given that even small differences in study design

4 Mathew and Loder Evaluating the Triptans 31S may affect comparisons of treatment outcomes across studies, using the therapeutic gain or placebo-subtracted proportion as a basis for comparison is considered the better approach, as this may control for between-study variabilities. 7 Using therapeutic gain as the basis for comparison among trials, eletriptan 80 mg (a dose not currently available in the United States) showed the highest headache response at 2 hours, followed by eletriptan 40 mg and rizatriptan 10 mg, which were comparable in the magnitude of headache response (Figure 1). 7 Headache response at 2 hours after using rizatriptan 10 mg was not significantly better than sumatriptan in 3 RCTs. 21,23,28 In 2 of these studies, rizatriptan 10 mg was compared with sumatriptan 100 mg 21,28 ; sumatriptan 50 mg was the highest dose in the third study. 23 In other studies, rizatriptan 10 mg showed significantly better pain response at 2 hours compared with naratriptan 2.5 mg, 20 but not compared with zolmitriptan 2.5 mg. 32 Eletriptan 40 mg showed significantly better headache response at 2 hours compared with sumatriptan 100 mg in 2 of 3 RCTs. 25,26 At 2 hours postdose, eletriptan 40 mg showed superior pain relief over naratriptan 2.5 mg 27 and similar pain relief to zolmitriptan 2.5 mg. 33 Two RCTs compared zolmitriptan with sumatriptan. Zolmitriptan 5 mg was not significantly different from sumatriptan 100 mg in the study by Geraud and coworkers, 22 but results from this particular study may be inconclusive owing to methodologic limitations. In another study, zolmitriptan 2.5 mg was significantly better than sumatriptan based on headache response at 2 hours; however, the highest sumatriptan dose used in this study was 50 mg, 31 which is lower than the recommended dose used in the Ferrari metaanalysis. 7 Two other RCTs, comparing almotriptan 12.5 mg and sumatriptan (one using 50 mg, another using 100 mg), showed comparable headache response at 2 hours. 29,30 Pain-free rate at 2 hours Figure 1 Headache response at 2 hours. (Reprinted with permission from Lancet. 7 ) The International Headache Society (IHS) currently recommends the use of pain-free status at 2 hours as the primary end point to be used in clinical trials of acute migraine, because measurement of this outcome is clinically relevant, is indicative of patients expectations, and is unaffected by rescue medication. 18 Pain-free rate at 2 hours has been shown to be a better indicator of treatment efficacy than headache response at 2 hours. Based on the Ferrari meta-analysis, eletriptan 80 mg, almotriptan 12.5 mg, and rizatriptan 10 mg showed the highest pain-free rate at 2 hours. 7 Two of the 3 rizatriptanversus-sumatriptan RCTs used the pain-free rate as an efficacy end point. One trial showed that rizatriptan 10 mg had a significantly better pain-free rate than sumatriptan 100 mg, 21 and the other showed comparable pain-free rates with sumatriptan 50 mg. 23 In other comparator studies, rizatriptan 10 mg showed better pain-free rates than zolmitriptan 2.5 mg 32 and naratriptan 2.5 mg. 20 The same 2 RCTs showing that eletriptan 40 mg was significantly better than sumatriptan 100 mg on the measure of headache response at 2 hours also demonstrated a superior pain-free rate at 2 hours. 25,26 A study by Garcia-Ramos and colleagues 27 showed higher pain-free rates with eletriptan 40 mg compared with naratriptan 2.5 mg. Zolmitriptan 5 mg was equivalent to sumatriptan 100 mg in pain-free rate at 2 hours, 22 as was almotriptan 12.5 mg in 1 study. 30 However, another study showed that sumatriptan 50 mg was, in fact, superior to almotriptan 12.5 mg in pain-free rate. 29 Headache recurrence and sustained relief Headache recurrence has been defined in most trials as the worsening of headache (to moderate or severe pain) within 24 hours of treatment, subsequent to a headache response (mild or no pain). 18 In clinical trials evaluating posttreatment headache recurrence, the outcome is contingent upon the response rate, because only patients who respond to treatment can recur. 34 This confounding effect can be avoided by measuring sustained relief (headache relief at 2 hours, sustained for 24 hours after treatment, i.e., pain did not return to moderate or severe, and without use of rescue medication or a second dose of study medication). This measure, along with sustained pain-free rate (remaining pain-free over 24 hours without rescue medication), are emerging as important treatment outcomes that are clini-

5 32S The American Journal of Medicine, Vol 118, Suppl 1, March 2005 cally relevant 19 because they are composite measures that integrate initial response, no use of rescue medication, and absence of recurrence. 18 Many of the RCTs comparing a second-generation triptan with sumatriptan showed comparable rates of headache recurrence. Eletriptan 40 mg, however, has been shown to have lower recurrence rates than sumatriptan 100 mg. 25,26 This finding is supported by the significantly higher rates of sustained headache response at 24 hours with eletriptan 40 mg (43% 50%) compared with sumatriptan 100 mg (34% 38%), the eletriptan rates being among the highest that have been reported. 25,26 The Ferrari meta-analysis also indicated that eletriptan 40 mg and eletriptan 80 mg had lower recurrence rates than sumatriptan 100 mg. 7 Consistent with these findings, the Oldman meta-analysis showed that both 40- and 80-mg doses of eletriptan exhibited the highest sustained headache response rates (comparable to subcutaneous sumatriptan 6 mg), followed by rizatriptan 10 mg and sumatriptan 100 mg. 19 Associated symptoms Improvement of associated symptoms is increasingly being evaluated in clinical trials. It is usually used as a secondary efficacy end point. Associated symptoms, such as nausea and vomiting, can amplify the impact of migraine and can influence treatment outcomes from oral medications. 35 Rizatriptan 10 mg 21,23,32 and eletriptan 40 mg 26 have shown better relief of associated symptoms than other active treatments in some comparator studies. Functional disability A functional response pertains to improvement in functionality from a severe baseline condition (reduced activity or bed rest) to normal functioning or slightly reduced activity at 2 hours postdose. 25 The presence of associated symptoms and functional disability can considerably diminish a patient s quality of life. Paying specific attention to patients who present with functional disability at baseline and monitoring this subpopulation throughout the study may produce more meaningful findings than an assessment of all participants regardless of baseline presentation. All 3 eletriptan RCTs showed that eletriptan 40 mg (63% 68%) was significantly better than sumatriptan 100 mg (46% 61%) in improving functional disability at 2 hours Eletriptan 40 mg was associated with superior functional response in comparison with naratriptan 2.5 mg (60% vs. 52%) 27 and similar functional response compared with zolmitriptan 2.5 mg. 33 One of 3 RCTs showed that rizatriptan 10 mg was superior to sumatriptan 100 mg in eliciting functional improvement (42% vs. 33%). 21 In 2 other studies, rizatriptan 10 mg showed better improvement in functional impairment in comparison with zolmitriptan 2.5 mg (45% vs. 37%) 32 and naratriptan 2.5 mg (39% vs. 23%). 20 Improvement in functional disability was not evaluated in any sumatriptan comparator RCTs with zolmitriptan 2.5 mg or almotriptan 12.5 mg. Use of rescue medication The use of rescue medication is influenced by the baseline severity of migraine, but it also depends on the available treatment options. 36 Use of rescue medication is inversely correlated with measures of efficacy and is also related to patient satisfaction. Patients resent the high cost of failed treatment, and they may interpret the need for rescue medication as an indication of lackluster efficacy. 36 As an outcome measure, though, use of rescue medication is less sensitive than pain-free rate at 2 hours because patients may rescue for reasons unrelated to pain response (e.g., anxiety or habit). 18 Intrapatient consistency In RCTs comparing placebo and active drugs, intrapatient consistency is the percentage of individuals in a group who respond in a specific number out of a larger number of treated attacks (e.g., 2 of 3 attacks), maintaining efficacy across consecutive attacks. 18 It is a clinically meaningful measure that patients consider an important criterion in evaluating treatment efficacy. 37 Efficacy in 2 of 3 treated attacks is considered a reasonable estimate of consistency. 38 This end point, however, was not evaluated in the many RCTs of triptans. A post hoc, descriptive analysis based on data from an RCT of 473 patients with moderate or severe migraine who were treated with rizatriptan 10 mg evaluated consistency, which is defined as efficacy in 2 of 3 attacks. Based on this premise, consistent pain relief (86%) and pain-free rates (48%) were observed. 39 A randomized, double-blind, placebo-controlled study (N 1,334) evaluating the efficacy of 3 doses of oral eletriptan demonstrated, among other outcomes, that eletriptan (20, 40, and 80 mg) was consistently effective in treating 3 consecutive migraine attacks in a dose-dependent manner. Of the patients who received eletriptan 40 mg, 77% responded in at least 2 of 3 attacks. 40 Patient satisfaction or preference Complete relief of headache pain, rapid onset of action, and no recurrence are the top attributes that individuals with migraine consider important in choosing among the available pharmacotherapeutic options, 41 including NSAIDs, combination analgesics, and migraine-specific agents. In a questionnaire-based study that was undertaken to assess the history of acute migraine medication use and the relation between prior therapy and patient satisfaction, the results indicate that although analgesics, NSAIDs, and ergot derivatives have been used in the treatment of migraine for a long time, these treatments provided low patient satisfaction. 16 In contrast, the less frequently used triptans were rated with the

6 Mathew and Loder Evaluating the Triptans 33S Table 3 Pharmacokinetic profile of triptans Compound Formulation Recommended dose (mg) t max (hr) t 1/2 (hr) Bioavailability (%) Sumatriptan Oral Subcutaneous Intranasal 20 2 Zolmitriptan Oral Naratriptan Oral * /74 Rizatriptan Oral Eletriptan Oral Almotriptan Oral Frovatriptan Oral t max time to reach peak plasma concentration; t 1/2 terminal elimination half-life. *Data from The Triptans: Novel Drugs for Pain. 44 Determined independently for men/women. Data from J Clin Pharmacol. 46 Range of values for subjects receiving single doses of eletriptan 10, 30, 60, 90, or 120 mg. Adapted from Clin Pharmacokinet. 45 highest patient treatment satisfaction compared with ergot derivatives and nonspecific migraine medications. 16 Such patient preference is consistent with the generally superior efficacy profile of triptans over other agents. 19 Earlier clinical trials evaluating triptans did not use patient acceptance or satisfaction as an efficacy parameter. More recent randomized comparator studies of triptans using this parameter as a secondary end point indicate greater patient satisfaction with rizatriptan 10 mg 20,23,32 and eletriptan 40 mg ,33 It is noteworthy that there are certain pharmacologic characteristics of drugs that are consistently associated with high levels of patient satisfaction, probably because they reflect properties that facilitate relief of headache pain, rapid onset of action, and no recurrence. Pharmacologic properties underlying patientpreferred efficacy outcomes Dose-response studies indicate that, consistent with objective efficacy measures, patients tend to rate higher doses as more efficacious despite corresponding increases in associated adverse effects. 24,42 Quick absorption and adequate bioavailability are important efficacy-associated characteristics of oral triptans. 18 Table 3 summarizes the important pharmacokinetic properties of triptans. As discussed in the previous section, second-generation triptans have demonstrated superior efficacy over oral sumatriptan. Oral sumatriptan has a low bioavailability (14%) 43 due to incomplete oral absorption and first-pass hepatic metabolism 44 ; it takes about 2.5 hours to reach peak plasma drug concentration and has a short half-life of 2 hours. 45 Rizatriptan and eletriptan have the shortest time to peak plasma concentration (t max ), at approximately 1 hour. Almotriptan (70%), naratriptan (63% for men, 74% for women), and eletriptan (50%) have relatively high bioavailability. Eletriptan and rizatriptan rank highest among the triptans according to evidence-based efficacy data, patient preference, and pharmacokinetic benefits. Rapid onset of action Rapid onset of action is a top priority for patients with migraine who seek treatment relief. 41 Bioavailability, relatively short t max, and lipophilicity are pharmacokinetic properties that have been associated with rapid onset of action. Both eletriptan 46,47 and rizatriptan 48 achieve peak plasma concentration in about 1 hour and are rapidly absorbed. 49,50 Approximately 90% of rizatriptan is absorbed, but it undergoes moderate first-pass hepatic metabolism, resulting in a bioavailability of about 47%. 50 The absorptive advantage of eletriptan is attributed to its lipophilicity, which enables transcellular absorption. Physicochemical comparisons indicate that eletriptan is significantly more lipophilic than sumatriptan, naratriptan, rizatriptan, and zolmitriptan. 49 Complete pain relief and no recurrence Headache recurrence may be related to an ongoing, reactivating central nervous system process. It has been speculated that triptans with relatively long terminal elimination half-life and good brain penetration may result in a lower incidence of headache recurrence. 44 The lack of headache recurrence is consistent with complete pain relief. Eletriptan, naratriptan, and frovatriptan have long half-lives, 45 and eletriptan and naratriptan have been associated with lower recurrence rates than sumatriptan 7 ; however, there are no studies to date that compare frovatriptan with sumatriptan. Higher recurrence rates relative to sumatriptan occur with rizatriptan, 7 although concomitant use of rizatriptan and rofecoxib has been shown to lower recurrence. 51 Head-to-head trials have shown that, in comparison with sumatriptan 100 mg, eletriptan 40 mg elicits higher sustained

7 34S The American Journal of Medicine, Vol 118, Suppl 1, March 2005 headache response and sustained pain-free rates. 25,26 Comparative data using these parameters were not reported in published trials of rizatriptan versus sumatriptan. However, a post hoc analysis of data from a study comparing the efficacy of rizatriptan 10 mg with zolmitriptan 2.5 mg showed that rizatriptan had a superior sustained pain-free rate. 32 More recent studies show that pain-free responses are enhanced by early treatment interventions using triptans. In many of the clinical trials for the treatment of acute migraine, 5-HT 1B/1D agonists were reserved for moderate-tosevere migraine. However, there is accumulating evidence that treating acute migraine while the pain is still mild may have an abortive effect on the progression of pain, resulting in improved treatment outcomes. 52,53 Results from a post hoc analysis of a subgroup of patients from a large, randomized, placebo-controlled study of patients with substantial headache-related disability (the Spectrum Study) indicated that the therapeutic gain for pain-free response was statistically higher at 2 and 4 hours postdose with early intervention using sumatriptan 50 mg compared with the same treatment administered during the moderate-to-severe stages of migraine. 54 Similarly, almotriptan 12.5 mg 55 and eletriptan 40 mg 56 have been associated with higher painfree rates with earlier treatment intervention. These findings suggest that early treatment may facilitate the achievement of freedom from migraine pain that may, in turn, lead to improved patient satisfaction. Summary The conclusions from meta-analyses were generally consistent with the findings from individual clinical trials. Based on placebo-subtracted proportions in head-to-head trials and meta-analyses of triptans, eletriptan 40 mg and rizatriptan 10 mg have the highest therapeutic gain compared with sumatriptan 100 mg, according to the most common efficacy variable of headache response at 2 hours. Treatment with eletriptan 40 mg and rizatriptan 10 mg was also associated with substantial functional improvement and patient satisfaction. Patients treated with eletriptan 40 mg demonstrated significantly lower headache recurrence rates compared with those treated with sumatriptan 100 mg. Treatment efficacy is of paramount importance to the patient. Although tolerability is certainly an important consideration, a few studies have shown that patients may opt for the higher effective dose, despite corresponding increases in related side effects. 24,42 Rapid onset of action, complete relief of pain and associated symptoms, and the ability to return to function with no headache recurrence are the top attributes of a drug that patients consider important for the treatment of acute migraine. 41 Bioavailability, lipophilicity, time to reach peak plasma concentration, and terminal half-life are some of the pharmacokinetic parameters that determine these clinical attributes. 44 These pharmacokinetic parameters and patient preferences are important considerations for clinicians in choosing a triptan for treating migraine. A number of comparative studies suggest that eletriptan and rizatriptan have advantages over sumatriptan on many efficacy parameters based on common end points used in clinical trials of acute migraine although, as elaborated upon in preceding sections, eletriptan and rizatriptan are not equivalent in efficacy (e.g., based on headache recurrence). However, more studies are needed that specifically evaluate time to meaningful relief, speed of onset of action, consistency of effect, sustained pain relief, return to function, and sustained pain-free state, as well as the clinical relevance of any differences identified. Such studies will provide the necessary information that physicians and patients need to optimize the treatment of acute migraine. References 1. Tepper SJ, Rapoport AM, Sheftell FD. Mechanisms of action of the 5-HT 1B/1D receptor agonists. Arch Neurol. 2002;59: Hamel E. Current concepts of migraine pathophysiology. Can J Clin Pharmacol 1999;6(suppl A):9A 14A. 3. 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