Migraine Prophylaxis: Pre-emptive Frovatriptan or Topiramate
Migraine Prophylaxis: Pre-emptive Frovatriptan or Topiramate
This pilot study suggests effectiveness for a paradigm of pre-emptive prophylaxis using frovatriptan during the premonitory period of migraine and the daily use of topiramate in reduction of migraineattacks, headache days, and quality-of-life scores as measured by the MSQ over baseline for a population of migraine sufferers with 3 to 6 migraine attacks per month. Subjects utilizing daily topiramate demonstrated somewhat greater reduction in headache days at Month 2. Frovatriptan was associated with fewer AEs that led to study withdrawal. Utilization of a migraine preventive medication and the paradigm of its use is a complex multidimensional process. Efficacy, tolerability, safety, presence of comorbid disease, patient preference, and satisfaction, as well as cost, are all important variables in this equation. The integration of these variables in relationship to the results of this study will be explored in greater detail.
In this pilot study, both topiramate and frovatriptan demonstrated statistical improvement at Months 1 and 2 as measured by reduction in migraine attacks and headache days over the baseline. Topiramate demonstrated a numerical superiority if one evaluated only those able to complete the study and statistical superiority at Month 2 for reduction of headache days. However, this study was not powered to be a drug comparison, and it should be noted that there was a 75% reduction in headache days at Month 2 for the topiramate group. An improvement much greater than one would assume from large clinical trials.
Frovatriptan taken pre-emptively as an intermittent preventative was associated with significantly fewer AEs leading to withdrawal from the study. Topiramate was associated with anxiety, depression, cognitive difficulties, taste aversion, and tingling in extremities in greater than 10% of subjects. Only nausea was reported in slightly greater frequency in the frovatriptan group (7.4% vs 7.1%) compared with the topiramate group. This may well be secondary to migraine rather than an AE to drug.
These AEs are notable, as this study was only of 2-month duration with the first month being a titration period for Group A. Whether there would have been improved tolerance of these AEs or worsening of these events over time leading to increased withdrawal rates is beyond the scope of this study.
Safety analyses are beyond the scope of this pilot study, but several theoretical concerns should be considered. Triptans have been associated with medication overuse headache (MOH) when used as acute treatment. Rarely have they been associated with cardiovascular complications. In this study, there was no evidence of escalating usage of triptans in either group through the 2-month treatment period or cardiovascular AEs. This clearly does not exclude the potential of MOH or cardiovascular safety. Daily preventives for migraine are generally well tolerated, but several have specific important warnings and precautions that need to be considered when prescribing them in clinical practice (see Table 13).
Subjects in both groups treated breakthrough migraine headaches with 2.5 mg of frovatriptan. Subjects rated their pain level following acute treatment at 4 and 24 hours. For Group A (topiramate) at 4 hours, there was no statistical difference in headache intensity comparing baseline with Month 2 (P = .45). Although the sample size is small, this finding argues against improvement in response to acute intervention after successful implementation of a preventive medication. For Group B, there was a statistically significant reduction of headache severity at 4 hours compared with baseline (P = .04). At 24 hours, there was no statistical difference for either group (see Table 14 and Table 15).
The concept of a "twofer" or one drug used to treat 2 different diseases in a migraine patient is well established though little scientific evidence exists to support this treatment paradigm. This is particularly true if dosages used to treat comorbidity are those commonly used in migraine prevention. Topiramate has indications in seizure and has been considered by some to be a mood stabilizer. It is also used off label to assist weight loss. Frovatriptan is indicated in acute migraine and has studies supporting its use as a short-term prophylactic in menstrual migraine. While the concept of a twofer has intuitive merit, little science can support it as an important variable for selection of one migraine preventive over another.
In the daily topiramate paradigm, patients used frovatriptan for acute treatment of breakthrough migraine. In the pre-emptive frovatriptan paradigm, frovatriptan was taken during the premonitory phase when the individual was certain that a disabling migraine would occur. Thus, PPMQ scores compared patient satisfaction with frovatriptan taken during prodrome and frovatriptan used for acute treatment. Interestingly, there was a statistically significant difference in satisfaction in Group A, using frovatriptan for acute treatment (see Table 12). This analysis excluded subjects who withdrew from the study early.
The higher satisfaction in Group A may be explained by the observation that those in Group A appeared to experience fewer prodromes and premonitory symptoms during Month 2 compared with baseline while using topiramate (see Table 16).
In a study using an electronic diary, Giffin et al demonstrated that significant migraine disability occurred for most subjects before the onset of headache. Based on this finding, it would make sense that subjects waiting to use prophylactic intervention until the premonitory period is well developed would endure significant disability. As has been reported in early intervention studies, subjects often wait to see if the headache will evolve into a migraine. It is reasonable to assume that this behavior may also occur when people are asked to treat during the premonitory period. Whether education could alter this behavior is the subject of further study. Whether topiramate or other daily preventives prevent prodromes warrants further investigation.
The MSQ is a validated questionnaire that measures 3 domains of quality of life: Role Function Restrictive, Role function Preventive, and Role Function Emotional. In all 3 domains, there was statistical and clinical improvement for both treatment paradigms over baseline. This was true for Role Function and Emotional Function, and both Months 1 and 2 but only at Month 2 for Role Preventive.
Overall, the paradigm of daily topiramate demonstrated superiority to the pre-emptive paradigm with frovatriptan. However, it should be noted that subjects withdrawing from the study because of AEs were not included in the analyses after study withdrawal. Given the greater number of subjects withdrawing from the topiramate group, it could be argued that the results are biased by the enrichment of retaining subjects only tolerating their respective treatment paradigms.
Cost comparisons favored frovatriptan over topiramate in this pilot study, though it should be observed that since the study was conducted, topiramate has become generic and, hence, is less expensive.
Another factor in comparing these 2 treatment paradigms is access to medication. Topiramate israrely encumbered with quantity limits, whereas frovatriptan like all other triptans frequently has quantity limits and tier stratification. These could significantly impact cost.
Many different medications with unique mechanisms of action have been successfully employed to reduce the frequency of migraine. In general, most of the successfully utilized preventive therapies reduce migraine frequency by 50% in about 50% of subjects. In clinical trials, daily preventive therapies often take weeks to months for the preventive benefits to become apparent and, even in the best of circumstances, rarely prevent all migraine attacks. In addition, there are frequent AEs that become apparent over time that can impair function, especially as medication dosages are increased in pursuit of greater efficacy.
Though difficult to formally assess, one might legitimately assume that there is a unique distinction between onset of efficacy between topiramate and frovatriptan. For example, if a patient treated migraine during a premonitory period whether successfully or unsuccessfully, they would realize the outcome of the intervention in "real" time, whereas subjects using topiramate for prophylaxis would likely be in the titration phase or early in the active treatment phase and may not recognize benefit or failure of treatment until the drug had been used for several weeks to months. Consequently, pre-emptive prophylaxis would define subjects as treatment successes or failures earlier in their course of treatment that potentially could decrease cost and time with disability before treatment change is made. One might argue that subjects experiencing AEs early in treatment with daily preventatives might also be defined early on as treatment failures and thus switched to another therapy. However, this likely reflects a small percent of the treatment failure group for any preventive medication given the standard practice of titrating daily preventive medications.
The present study compared 2 different paradigms for the prevention of the headache phase of migraine. Both frovatriptan and topiramate demonstrated significant reductions in headache episodes and headache days over baseline at 1 and 2 months. Both medications were generally well tolerated though there appeared to be more drug-related AEs leading to study discontinuation for the topiramate Group 5 (18%) vs Group 1 (4%).
There are several important limitations to this study. First, it is a small pilot study that was not designed to adequately test one drug against the other. Instead, it was designed to compare intermittent prophylaxis using an acute medication with an established and widely accepted daily migraine prophylactic medication.
A further limitation was that there was no placebo arm to the study making absolute changes in migraine frequency more difficult to assess. Although, one might argue that using a placebo rather than an active comparator might create ethical concerns given the frequency of migraine attacks in this study population. An addition, another limitation was that the study had only a 2-month active treatment phase that may not have provided sufficient time to adequately compare these 2 unique treatment strategies.
Another important limitation is that not all premonitory periods predict disabling migraine. This might be viewed as people taking medication for migraines that would not occur, and this could lead to overuse of an acute medication. On the other hand, one could argue that using medication daily is the extreme example of using medication on days that no event is likely to occur. It should be kept in mind that quantities of medication provided as guidance of medication overuse in ICHD-2 are established by consensus and do not take into account important variables for specific medications such as their half-life.
Given these limitations, this study does suggest that frovatriptan used as an intermittent prophylactic during the premonitory phase of an attack may prevent headache and provide therapeutic value of migraine prophylaxis for patients with frequent, predictable premonitory symptoms. Further, this strategy was, in this pilot study, associated with fewer AEs and improvement in quality-of-life measures.
Discussion
This pilot study suggests effectiveness for a paradigm of pre-emptive prophylaxis using frovatriptan during the premonitory period of migraine and the daily use of topiramate in reduction of migraineattacks, headache days, and quality-of-life scores as measured by the MSQ over baseline for a population of migraine sufferers with 3 to 6 migraine attacks per month. Subjects utilizing daily topiramate demonstrated somewhat greater reduction in headache days at Month 2. Frovatriptan was associated with fewer AEs that led to study withdrawal. Utilization of a migraine preventive medication and the paradigm of its use is a complex multidimensional process. Efficacy, tolerability, safety, presence of comorbid disease, patient preference, and satisfaction, as well as cost, are all important variables in this equation. The integration of these variables in relationship to the results of this study will be explored in greater detail.
Efficacy
In this pilot study, both topiramate and frovatriptan demonstrated statistical improvement at Months 1 and 2 as measured by reduction in migraine attacks and headache days over the baseline. Topiramate demonstrated a numerical superiority if one evaluated only those able to complete the study and statistical superiority at Month 2 for reduction of headache days. However, this study was not powered to be a drug comparison, and it should be noted that there was a 75% reduction in headache days at Month 2 for the topiramate group. An improvement much greater than one would assume from large clinical trials.
Tolerability
Frovatriptan taken pre-emptively as an intermittent preventative was associated with significantly fewer AEs leading to withdrawal from the study. Topiramate was associated with anxiety, depression, cognitive difficulties, taste aversion, and tingling in extremities in greater than 10% of subjects. Only nausea was reported in slightly greater frequency in the frovatriptan group (7.4% vs 7.1%) compared with the topiramate group. This may well be secondary to migraine rather than an AE to drug.
These AEs are notable, as this study was only of 2-month duration with the first month being a titration period for Group A. Whether there would have been improved tolerance of these AEs or worsening of these events over time leading to increased withdrawal rates is beyond the scope of this study.
Safety
Safety analyses are beyond the scope of this pilot study, but several theoretical concerns should be considered. Triptans have been associated with medication overuse headache (MOH) when used as acute treatment. Rarely have they been associated with cardiovascular complications. In this study, there was no evidence of escalating usage of triptans in either group through the 2-month treatment period or cardiovascular AEs. This clearly does not exclude the potential of MOH or cardiovascular safety. Daily preventives for migraine are generally well tolerated, but several have specific important warnings and precautions that need to be considered when prescribing them in clinical practice (see Table 13).
Efficacy of Acute Intervention
Subjects in both groups treated breakthrough migraine headaches with 2.5 mg of frovatriptan. Subjects rated their pain level following acute treatment at 4 and 24 hours. For Group A (topiramate) at 4 hours, there was no statistical difference in headache intensity comparing baseline with Month 2 (P = .45). Although the sample size is small, this finding argues against improvement in response to acute intervention after successful implementation of a preventive medication. For Group B, there was a statistically significant reduction of headache severity at 4 hours compared with baseline (P = .04). At 24 hours, there was no statistical difference for either group (see Table 14 and Table 15).
Treatment of Migraine Comorbidity
The concept of a "twofer" or one drug used to treat 2 different diseases in a migraine patient is well established though little scientific evidence exists to support this treatment paradigm. This is particularly true if dosages used to treat comorbidity are those commonly used in migraine prevention. Topiramate has indications in seizure and has been considered by some to be a mood stabilizer. It is also used off label to assist weight loss. Frovatriptan is indicated in acute migraine and has studies supporting its use as a short-term prophylactic in menstrual migraine. While the concept of a twofer has intuitive merit, little science can support it as an important variable for selection of one migraine preventive over another.
Comparison of PPMQ Scores
In the daily topiramate paradigm, patients used frovatriptan for acute treatment of breakthrough migraine. In the pre-emptive frovatriptan paradigm, frovatriptan was taken during the premonitory phase when the individual was certain that a disabling migraine would occur. Thus, PPMQ scores compared patient satisfaction with frovatriptan taken during prodrome and frovatriptan used for acute treatment. Interestingly, there was a statistically significant difference in satisfaction in Group A, using frovatriptan for acute treatment (see Table 12). This analysis excluded subjects who withdrew from the study early.
The higher satisfaction in Group A may be explained by the observation that those in Group A appeared to experience fewer prodromes and premonitory symptoms during Month 2 compared with baseline while using topiramate (see Table 16).
In a study using an electronic diary, Giffin et al demonstrated that significant migraine disability occurred for most subjects before the onset of headache. Based on this finding, it would make sense that subjects waiting to use prophylactic intervention until the premonitory period is well developed would endure significant disability. As has been reported in early intervention studies, subjects often wait to see if the headache will evolve into a migraine. It is reasonable to assume that this behavior may also occur when people are asked to treat during the premonitory period. Whether education could alter this behavior is the subject of further study. Whether topiramate or other daily preventives prevent prodromes warrants further investigation.
Comparison of MSQ
The MSQ is a validated questionnaire that measures 3 domains of quality of life: Role Function Restrictive, Role function Preventive, and Role Function Emotional. In all 3 domains, there was statistical and clinical improvement for both treatment paradigms over baseline. This was true for Role Function and Emotional Function, and both Months 1 and 2 but only at Month 2 for Role Preventive.
Overall, the paradigm of daily topiramate demonstrated superiority to the pre-emptive paradigm with frovatriptan. However, it should be noted that subjects withdrawing from the study because of AEs were not included in the analyses after study withdrawal. Given the greater number of subjects withdrawing from the topiramate group, it could be argued that the results are biased by the enrichment of retaining subjects only tolerating their respective treatment paradigms.
Cost and Drug Availability
Cost comparisons favored frovatriptan over topiramate in this pilot study, though it should be observed that since the study was conducted, topiramate has become generic and, hence, is less expensive.
Another factor in comparing these 2 treatment paradigms is access to medication. Topiramate israrely encumbered with quantity limits, whereas frovatriptan like all other triptans frequently has quantity limits and tier stratification. These could significantly impact cost.
Time to Define Treatment Success vs Failure
Many different medications with unique mechanisms of action have been successfully employed to reduce the frequency of migraine. In general, most of the successfully utilized preventive therapies reduce migraine frequency by 50% in about 50% of subjects. In clinical trials, daily preventive therapies often take weeks to months for the preventive benefits to become apparent and, even in the best of circumstances, rarely prevent all migraine attacks. In addition, there are frequent AEs that become apparent over time that can impair function, especially as medication dosages are increased in pursuit of greater efficacy.
Though difficult to formally assess, one might legitimately assume that there is a unique distinction between onset of efficacy between topiramate and frovatriptan. For example, if a patient treated migraine during a premonitory period whether successfully or unsuccessfully, they would realize the outcome of the intervention in "real" time, whereas subjects using topiramate for prophylaxis would likely be in the titration phase or early in the active treatment phase and may not recognize benefit or failure of treatment until the drug had been used for several weeks to months. Consequently, pre-emptive prophylaxis would define subjects as treatment successes or failures earlier in their course of treatment that potentially could decrease cost and time with disability before treatment change is made. One might argue that subjects experiencing AEs early in treatment with daily preventatives might also be defined early on as treatment failures and thus switched to another therapy. However, this likely reflects a small percent of the treatment failure group for any preventive medication given the standard practice of titrating daily preventive medications.
The present study compared 2 different paradigms for the prevention of the headache phase of migraine. Both frovatriptan and topiramate demonstrated significant reductions in headache episodes and headache days over baseline at 1 and 2 months. Both medications were generally well tolerated though there appeared to be more drug-related AEs leading to study discontinuation for the topiramate Group 5 (18%) vs Group 1 (4%).
There are several important limitations to this study. First, it is a small pilot study that was not designed to adequately test one drug against the other. Instead, it was designed to compare intermittent prophylaxis using an acute medication with an established and widely accepted daily migraine prophylactic medication.
A further limitation was that there was no placebo arm to the study making absolute changes in migraine frequency more difficult to assess. Although, one might argue that using a placebo rather than an active comparator might create ethical concerns given the frequency of migraine attacks in this study population. An addition, another limitation was that the study had only a 2-month active treatment phase that may not have provided sufficient time to adequately compare these 2 unique treatment strategies.
Another important limitation is that not all premonitory periods predict disabling migraine. This might be viewed as people taking medication for migraines that would not occur, and this could lead to overuse of an acute medication. On the other hand, one could argue that using medication daily is the extreme example of using medication on days that no event is likely to occur. It should be kept in mind that quantities of medication provided as guidance of medication overuse in ICHD-2 are established by consensus and do not take into account important variables for specific medications such as their half-life.
Given these limitations, this study does suggest that frovatriptan used as an intermittent prophylactic during the premonitory phase of an attack may prevent headache and provide therapeutic value of migraine prophylaxis for patients with frequent, predictable premonitory symptoms. Further, this strategy was, in this pilot study, associated with fewer AEs and improvement in quality-of-life measures.
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