Sumatriptan-Naproxen and Butalbital
Sumatriptan-Naproxen and Butalbital
Objectives.— The primary objective was to compare the efficacy of a sumatriptan and naproxen combination medication (SumaRT/Nap—85 mg sumatriptan and 500 mg naproxen sodium), a butalbital-containing combination medication (BCM—50 mg butalbital, 325 mg acetaminophen, 40 mg caffeine), and placebo when used to treat moderate to severe migraine headache pain in subjects who used BCMs in the past.
Background.— Despite the lack of Food and Drug Administration approval and the absence of placebo-controlled trials to demonstrate efficacy, butalbital-containing medications are among the most commonly prescribed acute migraine treatments in the United States. Butalbital-containing medications are associated with serious and undesirable side effects, and have been linked to the chronification of migraine and development of medication-overuse headaches. This study compares the relative efficacy, safety, and tolerability of a fixed dose SumaRT/Nap versus a BCM and placebo.
Methods.— Enrolled subjects were required to have treated at least 1 migraine with a butalbital medication in the past. Enrolled subjects treated 3 moderate to severe migraines using each of the 3 study treatments once in a randomized sequence. The primary endpoint compared SumaRT/Nap versus BCM for sustained pain freedom at 2–24 hours without the use of any rescue medication. This study combines data from 2 identical outpatient, randomized, multicenter, double-blind, double-dummy, 3 attack crossover studies in adult migraineurs (International Classification of Headache Disorders, 2nd edition).
Results.— A total of 442 subjects treated at least 1 attack with study medication. The majority of the treated subjects were female (88%) with a mean age 43 years, who reported that their migraines had a severe impact on their lives (78% with Headache Impact Test-6 of >59). At screening, 88% of subjects reported current butalbital use; 68% had used butalbital for more than 6 weeks; and 82% reported satisfaction with butalbital. Across treatment groups, 28–29% of subjects took study medication within 15 minutes of migraine onset, 34–37% of subjects took study medication >15 minutes to 2 hours after onset, and 32–36% of subjects took study medication more than 2 hours after onset.
This study did not detect a difference at the nominal 0.05 level in percent sustained pain-free between SumaRT/Nap (8%), BCM (6%), and placebo (3%). SumaRT/Nap was superior to BCM for pain free at 2, 4, 6, 8, 24, 48 hours (P ≤ .044); pain relief (mild or no pain) at 2, 4, 6, 8, 24, 48 hours (P ≤ .01); sustained pain relief 2–24 hours (P < .001); migraine free (pain free with no nausea, photophobia, or phonophobia) at 4, 6, 8, 24, 48 hours (P ≤ .046); and complete symptom free (migraine free with no neck/sinus pain) at 4, 6, 8, 48 hours (P ≤ .031). Adverse event incidence was similar for all treatments (10%, 12%, and 9% for placebo, SumaRT/Nap, and BCM, respectively). Nausea was the most frequent adverse event (2%, 2%, and <1% for placebo, SumaRT/Nap, and BCM, respectively). Five serious adverse events were reported by 3 subjects: viral meningitis and colon neoplasm (placebo); chest pain and hypertension 17 days postdose (SumaRT/Nap); and breast cancer (BCM). Investigators judged no serious adverse events related to study medication.
Conclusions.— This study primarily included subjects whose migraines significantly impacted their lives. Before the study, these subjects used butalbital-containing medications as part of their current migraine treatment regimen and were satisfied with it, suggesting they were butalbital responders who had found a workable treatment strategy for themselves. When treated with SumaRT/Nap versus BCM in this study, however, a significant proportion of subjects reported better treatment outcomes for themselves for both migraine pain and associated symptoms. Use of SumaRT/Nap was also associated with less rescue medication use and a longer time before use of rescue medication compared with both BCM and placebo.
Despite the availability of Food and Drug Administration (FDA) approved migraine-specific treatments, off-label use of nonspecific treatments remains common and, often, controversial. Products containing butalbital, typically in combination with caffeine and aspirin or acetaminophen, fall into this category. Butalbital, along with drugs like phenobarbital and Nembutal, is a sedative derived from barbituric acid. Butalbital-containing combination products do not target migraine pathophysiology specifically, but instead provide indiscriminate analgesic and sedative effects, primarily through the enhancement of a postsynaptic inhibitory response to the neurotransmitter gamma-aminobutyric acid.
Butalbital, like other barbiturates, is associated with a wide range of adverse effects related to general central nervous system (CNS) depression, including intoxication, hangover, tolerance, dependence and addiction, slowness of speech, disinhibition of sexual and aggressive impulses, emotional lability, and difficulty with thinking, judgment, memory, and attention. Doses of barbiturates and butalbital that fail to produce overt effects still have the potential to impair learning, judgment, short-term memory, and driving performance. Butalbital has an average half-life of 35 hours; consequently, drowsiness may last for hours after a dose and residual CNS depression may be evident the following day, manifesting as distortions of mood and impairment of judgment and fine motor skills. Tolerance can develop rapidly with regular use. Reactions following withdrawal of barbiturates vary and generally relate to the dosage and duration of prior exposure. Rapid withdrawal may be associated with seizure, delirium, and even death. Indeed, the risk profile is such that German regulators banned butalbital-containing analgesics. The fact that butalbital use is also strongly associated with the development of medication overuse headaches is of particular importance to migraine patients. Obviously, there are also side effects for triptans and other approved migraine treatments. Triptans, for example, are associated with atypical sensations (burning, heat sensations, numbness, tightness, tingling, etc), jaw or mouth discomfort, dizziness, drowsiness, flushing, lightheadedness and muscle aches and weakness, as well as less common serious cardiac events. Triptan use is restricted in patients with cardio- or cerebrovascular disease, uncontrolled hypertension, liver disease, or those on certain mediations including monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), or lithium. Triptans have also been associated with medication overuse headache. Although neither the FDA, the US Headache Consortium, nor the American Academy of Family Physicians/American College of Physicians-American Society of Internal Medicine endorse the use of butalbital for migraine treatment, the FDA has approved the use of butalbital-containing combination medications (BCMs) for tension headache. As clinicians are known to misdiagnose more than one-third of migraines as tension-type headaches, and the majority of migraineurs also experience tension-type headaches, a risk for inadvertent off-label BCM use for migraine headache exists. Still, despite any prior placebo-controlled trials examining its efficacy, BCMs are widely used as acute migraine treatment, accounting for 14–17% of all prescriptions to migraineurs in the United States.
This article describes the safety and efficacy results of a double-blinded, placebo-controlled, 3-way crossover study comparing a fixed-dose BCM to an approved combination product with proven efficacy in treating migraine pain, sumatriptan and naproxen sodium (SumaRT/Nap), and placebo (PLA), included for assay sensitivity. Efficacy and tolerability were evaluated using parameters typically measured in acute migraine trials. Effects on alertness, cognitive efficiency, and fine motor functioning were also assessed; however, these findings will be published later.
Abstract and Introduction
Abstract
Objectives.— The primary objective was to compare the efficacy of a sumatriptan and naproxen combination medication (SumaRT/Nap—85 mg sumatriptan and 500 mg naproxen sodium), a butalbital-containing combination medication (BCM—50 mg butalbital, 325 mg acetaminophen, 40 mg caffeine), and placebo when used to treat moderate to severe migraine headache pain in subjects who used BCMs in the past.
Background.— Despite the lack of Food and Drug Administration approval and the absence of placebo-controlled trials to demonstrate efficacy, butalbital-containing medications are among the most commonly prescribed acute migraine treatments in the United States. Butalbital-containing medications are associated with serious and undesirable side effects, and have been linked to the chronification of migraine and development of medication-overuse headaches. This study compares the relative efficacy, safety, and tolerability of a fixed dose SumaRT/Nap versus a BCM and placebo.
Methods.— Enrolled subjects were required to have treated at least 1 migraine with a butalbital medication in the past. Enrolled subjects treated 3 moderate to severe migraines using each of the 3 study treatments once in a randomized sequence. The primary endpoint compared SumaRT/Nap versus BCM for sustained pain freedom at 2–24 hours without the use of any rescue medication. This study combines data from 2 identical outpatient, randomized, multicenter, double-blind, double-dummy, 3 attack crossover studies in adult migraineurs (International Classification of Headache Disorders, 2nd edition).
Results.— A total of 442 subjects treated at least 1 attack with study medication. The majority of the treated subjects were female (88%) with a mean age 43 years, who reported that their migraines had a severe impact on their lives (78% with Headache Impact Test-6 of >59). At screening, 88% of subjects reported current butalbital use; 68% had used butalbital for more than 6 weeks; and 82% reported satisfaction with butalbital. Across treatment groups, 28–29% of subjects took study medication within 15 minutes of migraine onset, 34–37% of subjects took study medication >15 minutes to 2 hours after onset, and 32–36% of subjects took study medication more than 2 hours after onset.
This study did not detect a difference at the nominal 0.05 level in percent sustained pain-free between SumaRT/Nap (8%), BCM (6%), and placebo (3%). SumaRT/Nap was superior to BCM for pain free at 2, 4, 6, 8, 24, 48 hours (P ≤ .044); pain relief (mild or no pain) at 2, 4, 6, 8, 24, 48 hours (P ≤ .01); sustained pain relief 2–24 hours (P < .001); migraine free (pain free with no nausea, photophobia, or phonophobia) at 4, 6, 8, 24, 48 hours (P ≤ .046); and complete symptom free (migraine free with no neck/sinus pain) at 4, 6, 8, 48 hours (P ≤ .031). Adverse event incidence was similar for all treatments (10%, 12%, and 9% for placebo, SumaRT/Nap, and BCM, respectively). Nausea was the most frequent adverse event (2%, 2%, and <1% for placebo, SumaRT/Nap, and BCM, respectively). Five serious adverse events were reported by 3 subjects: viral meningitis and colon neoplasm (placebo); chest pain and hypertension 17 days postdose (SumaRT/Nap); and breast cancer (BCM). Investigators judged no serious adverse events related to study medication.
Conclusions.— This study primarily included subjects whose migraines significantly impacted their lives. Before the study, these subjects used butalbital-containing medications as part of their current migraine treatment regimen and were satisfied with it, suggesting they were butalbital responders who had found a workable treatment strategy for themselves. When treated with SumaRT/Nap versus BCM in this study, however, a significant proportion of subjects reported better treatment outcomes for themselves for both migraine pain and associated symptoms. Use of SumaRT/Nap was also associated with less rescue medication use and a longer time before use of rescue medication compared with both BCM and placebo.
Introduction
Despite the availability of Food and Drug Administration (FDA) approved migraine-specific treatments, off-label use of nonspecific treatments remains common and, often, controversial. Products containing butalbital, typically in combination with caffeine and aspirin or acetaminophen, fall into this category. Butalbital, along with drugs like phenobarbital and Nembutal, is a sedative derived from barbituric acid. Butalbital-containing combination products do not target migraine pathophysiology specifically, but instead provide indiscriminate analgesic and sedative effects, primarily through the enhancement of a postsynaptic inhibitory response to the neurotransmitter gamma-aminobutyric acid.
Butalbital, like other barbiturates, is associated with a wide range of adverse effects related to general central nervous system (CNS) depression, including intoxication, hangover, tolerance, dependence and addiction, slowness of speech, disinhibition of sexual and aggressive impulses, emotional lability, and difficulty with thinking, judgment, memory, and attention. Doses of barbiturates and butalbital that fail to produce overt effects still have the potential to impair learning, judgment, short-term memory, and driving performance. Butalbital has an average half-life of 35 hours; consequently, drowsiness may last for hours after a dose and residual CNS depression may be evident the following day, manifesting as distortions of mood and impairment of judgment and fine motor skills. Tolerance can develop rapidly with regular use. Reactions following withdrawal of barbiturates vary and generally relate to the dosage and duration of prior exposure. Rapid withdrawal may be associated with seizure, delirium, and even death. Indeed, the risk profile is such that German regulators banned butalbital-containing analgesics. The fact that butalbital use is also strongly associated with the development of medication overuse headaches is of particular importance to migraine patients. Obviously, there are also side effects for triptans and other approved migraine treatments. Triptans, for example, are associated with atypical sensations (burning, heat sensations, numbness, tightness, tingling, etc), jaw or mouth discomfort, dizziness, drowsiness, flushing, lightheadedness and muscle aches and weakness, as well as less common serious cardiac events. Triptan use is restricted in patients with cardio- or cerebrovascular disease, uncontrolled hypertension, liver disease, or those on certain mediations including monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), or lithium. Triptans have also been associated with medication overuse headache. Although neither the FDA, the US Headache Consortium, nor the American Academy of Family Physicians/American College of Physicians-American Society of Internal Medicine endorse the use of butalbital for migraine treatment, the FDA has approved the use of butalbital-containing combination medications (BCMs) for tension headache. As clinicians are known to misdiagnose more than one-third of migraines as tension-type headaches, and the majority of migraineurs also experience tension-type headaches, a risk for inadvertent off-label BCM use for migraine headache exists. Still, despite any prior placebo-controlled trials examining its efficacy, BCMs are widely used as acute migraine treatment, accounting for 14–17% of all prescriptions to migraineurs in the United States.
This article describes the safety and efficacy results of a double-blinded, placebo-controlled, 3-way crossover study comparing a fixed-dose BCM to an approved combination product with proven efficacy in treating migraine pain, sumatriptan and naproxen sodium (SumaRT/Nap), and placebo (PLA), included for assay sensitivity. Efficacy and tolerability were evaluated using parameters typically measured in acute migraine trials. Effects on alertness, cognitive efficiency, and fine motor functioning were also assessed; however, these findings will be published later.
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