Pharmacological Synergy: The Next Frontier for Migraine
Pharmacological Synergy: The Next Frontier for Migraine
The burden of migraine significantly impacts the individual sufferer, their families, the workplace, and society. The World Health Organization has identified migraine as an urgent public health priority and has initiated a global initiative to reduce the burden of migraine. Underlying the World Health Organization initiative is the need to discover means of optimizing migraine treatments and make them accessible to the broader portion of the world population.
Development of acute migraine medications over the past several decades has largely centered on engineering highly specific receptor molecules that alter migraine pathophysiological mechanisms to abort or reverse the acute attack of migraine. The first product of this line of discovery was sumatriptan and heralded as a landmark therapeutic breakthrough. Sumatriptan is a 5-HT-1B/D receptor agonist considered to activate receptors involved in the pathophysiology specific to migraine. Large-scale regulatory/clinical studies demonstrated statistical superiority for sumatriptan over placebo in reduction or elimination of headache, nausea, photophobia, and phonophobia. Since the introduction of sumatriptan, 6 other triptan products have been released in the United States as acute treatments for migraine, all having the same mechanism of action and similar efficacy. Despite their utility as migraine abortive medications, the triptans do not successfully treat all attacks of migraine or necessarily treat all migraine associated symptoms. In fact, in less than 25% of attacks do subjects obtain and maintain a migraine-free response to treatment for at least beyond 24 hours.
A wide range of non-triptan medications also have demonstrated efficacy in acute migraine. These include non-steroidal anti-inflammatory drugs (NSAIDs), opioids, phenothiazines, and valproic acid to name a few. Given the distinctly different mechanisms of actions of these various medications, it is likely that several unique pathophysiological mechanisms are involved in terminating acute episodes of migraine. Clinicians now capitalize on this observation and use migraine medication in combination with another to improve patient outcomes, for example, using an antiemetic with an opioid or a triptan and NSAIDs.
More recently, the Food and Drug Adminstration has approved a combination product containing 85 mg of sumatriptan plus 500 mg of naproxen sodium for acute treatment of migraine. Clinical trials conducted prior to approval demonstrated that the combination of sumatriptan and naproxen was more effective as a migraine abortive than either of its components but that each component and the combination were more effective than placebo. Exactly how sumatriptan and naproxen interact to create therapeutic synergism is unknown though its mere occurrence suggests that models assisting medical understanding and prediction of pharmacological synergism may improve clinical outcome over products acting through a single receptor mechanism.
Migraine is a syndrome, meaning it is defined by observed symptoms rather than known pathophysiology. Multiple pathogenic mechanisms are likely involved in generating this diverse array of symptoms understood as the migraine symptom complex. Sumatriptan and naproxen have independent mechanisms of action and target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine. Sumatriptan acts on the 5-HT1B and 5-HT1D receptors, whereas naproxen inhibits the COX-1 and COX-2 enzymes. Sumatriptan has vasoconstricting effects as well as effects on neurogenic inflammation by decreasing the release of substance P and calcitonin gene-related peptide. In contrast, naproxen affects prostaglandins and other inflammatory mediators. Because sumatriptan and naproxen both relieve migraine yet interact with different cellular targets within the migraine pathway, it is reasonable to assume there is a unique synergy between these medications that improves treatment outcomes. Clinical trials supported this contention by demonstrating the combination of sumatriptan/naproxen alleviated migraine pain quickly (primarily based on the sumatriptan mechanism of action), and sustained the response longer (primarily based on the naproxen mechanism of action) than is possible when either drug is given alone. The working hypothesis is that when sumatriptan and naproxen are given at the same time, they affect different mechanisms of the migraine pathway and produce an enhanced therapeutic effect.
The purpose of this article is to apply statistical analyses to data from phase II and phase III studies of the combination of sumatriptan and naproxen to determine if this enhanced therapeutic effect is synergistic. This methodology of accessing synergy can be used in the development of future combination migraine treatments to improve treatment outcomes.
Migraine is not just a debilitating disease for the individual sufferer, it also places a significant burden on affected families, workplaces, and society as a whole. The World Health Organization considers migraine to be an urgent public health priority and has initiated a global initiative to reduce the burden of migraine. Underlying the World Health Organization initiative is the need to optimize migraine treatments and make them accessible to a broader portion of the world population.
Development of acute migraine medications over the past several decades has largely centered on engineering highly specific receptor molecules that alter migraine pathophysiological mechanisms to abort or reverse the acute attack of migraine. The first product of this line of development was sumatriptan and heralded as a landmark therapeutic breakthrough. Sumatriptan is a 5-HT1B/1D receptor agonist considered to activate receptors involved in the pathophysiology specific to migraine. Large-scale clinical studies demonstrated statistical superiority for sumatriptan over placebo in reduction or elimination of headache, nausea, photophobia, and phonophobia. Since the introduction of sumatriptan, 6 other triptan products have been released in the United States as acute treatments for migraine, all having the same mechanism of action and similar efficacy. Despite their utility as migraine abortive medications, the triptans do not successfully treat all attacks of migraine or necessarily treat all migraine-associated symptoms. In fact, subjects obtain and maintain a migraine-free response to treatment for at least 24 hours in less than 25% of attacks.
A wide range of non-triptan medications also have demonstrated efficacy in acute migraine. These include non-steroidal anti-inflammatory drugs (NSAIDs), opioids, phenothiazines, and valproic acid to name a few. Given distinctions in the scientifically understood mechanisms of action of these various medications, it is likely that several unique pathophysiological mechanisms are involved in terminating acute episodes of migraine. Clinicians now capitalize on this observation and use migraine medication in combination with another to improve patient outcomes, for example, using an antiemetic with an opioid or a triptan and NSAIDs.
More recently, the Food and Drug Administration (FDA) has approved a combination product containing 85 mg of sumatriptan and 500 mg of naproxen sodium for acute treatment of migraine. Clinical trials demonstrated that the combination of sumatriptan and naproxen was more effective as a migraine abortive than either of its individual components. Exactly how sumatriptan and naproxen interact to create an improved therapeutic benefit is unknown though its mere occurrence suggests that models assisting medical understanding and prediction of pharmacological synergism may aid in the development of combination products that improve clinical outcome over products acting through a single receptor mechanism.
Migraine is a syndrome; thus it is defined by observed symptoms rather than known pathophysiology. Multiple pathogenic mechanisms are likely involved in generating this diverse array of symptoms understood as the migraine symptom complex. Sumatriptan and naproxen have independent mechanisms of action and target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine. Sumatriptan acts on the 5-HT1B and 5-HT1D receptors, whereas naproxen inhibits the COX-1 and COX-2 enzymes. Sumatriptan has vasoconstricting effects as well as effects on neurogenic inflammation by decreasing the release of substance P and calcitonin gene-related peptide. In contrast, naproxen affects prostaglandins and other inflammatory mediators. Because sumatriptan and naproxen both relieve migraine yet interact with different cellular targets within the migraine pathway, the 2 drugs have recently been studied in combination to determine if there is a unique synergy between these medications that improves treatment outcomes. Clinical trials of the combination support the conclusion that the combination of sumatriptan and naproxen alleviates migraine pain quickly (primarily based on the sumatriptan mechanism of action), and sustains the response longer (primarily based on the naproxen mechanism of action) than is possible when either drug is given alone. In addition, pharmacokinetic studies suggest a therapeutically advantageous pharmacokinetic profile when sumatriptan and naproxen are administered in combination. The working hypothesis is that when sumatriptan and naproxen are given at the same time, they affect different mechanisms of the migraine pathway and produce an enhanced therapeutic effect.
The purpose of this article is to apply statistical analyses to data from phases II and III studies of the combination of sumatriptan and naproxen to determine if this enhanced therapeutic effect is synergistic. This methodology of accessing synergy can be used in the development of future combination migraine treatments to improve treatment outcomes.
Smith et al contains a detailed description of the protocol used, data collected, and analyses conducted in the phase II study of combination treatment of sumatriptan and naproxen for migraine. The study was designed to determine if the sustained pain response rate in subjects treated with the combination of sumatriptan 50 mg and naproxen sodium 500 mg was superior to that of subjects treated with the individual components (sumatriptan 50 mg or naproxen sodium 500 mg) or placebo. This was a phase II, randomized, double-blind, placebo-controlled, multicenter study consisting of a screening visit, at home treatment of a single migraine attack, and a follow-up visit occurring 24–72 hours after the treated migraine attack.
At the time of an eligible migraine attack (pain of moderate or severe intensity), subjects recorded their pain intensity and associated migraine symptoms on a diary card prior to taking study medication and at pre-defined intervals after taking study drug. Subjects recorded the pain intensity scores (none [0], mild [1], moderate [2], or severe [3]) just prior to taking study medication, and every 15 minutes for 2 hours, every 30 minutes until 4 hours and then hourly while awake for the next 20 hours.
The primary efficacy endpoint was sustained pain response, defined as a pain score of 0 (no pain) or 1 (mild pain) at 2 hours post-dose, which did not return to a pain score of 2 (moderate pain) or 3 (severe pain) for the succeeding 22 hours, and no rescue medication was taken during the 24 hours following dosing with study medication. Several secondary efficacy endpoints were assessed, including sustained pain-free response, which was defined as a pain score of 0 (no pain) at 2 hours, which remained at 0 at all subsequent time points, and no rescue medication was taken during the 24 hours. Smith et al concluded that the combination group produced significantly greater initial pain relief at 2 hours post-dose, sustained pain response, and sustained pain-free effects than did sumatriptan alone, naproxen alone or placebo. The combination was particularly superior to its components in subjects with severe baseline migraine pain. The combination was also effective for the relief of the secondary symptoms of migraine: nausea; phonophobia; and photophobia. Smith et al did not, however, analyze whether the combination group showed synergistic therapeutic efficacy for any of the efficacy endpoints (because the study was prospectively designed to compare data from the combination group with the individual components [sumatriptan or naproxen] alone or placebo).
Brandes et al contains a detailed description of the protocol used, data collected, and analyses performed for the phase III studies of combination treatment of sumatriptan and naproxen for migraine. Brandes et al report 2 clinical studies that were identically designed and concurrently conducted at 118 clinical study centers. These studies were designed to demonstrate the superiority of the combination of sumatriptan 85 mg and naproxen 500 mg vs the individual components (sumatriptan 85 mg or naproxen 500 mg) and placebo in the acute treatment of migraine.
At the time of an eligible migraine attack (pain of moderate or severe intensity), subjects recorded their pain intensity and associated migraine symptoms on a diary card prior to taking study medication and at pre-defined intervals after taking study drug. Subjects recorded the pain intensity scores (none [0], mild [1], moderate [2], or severe [3]) just prior to taking study medication; 0.5, 1, and 1.5 hours after dosing; and hourly from 2 to 24 hours after dosing.
Various primary and secondary efficacy endpoints were assessed in the phase III studies, including both 2- and 24-hour endpoints. The most rigorous endpoint evaluated was sustained pain-free response, defined as no pain at 2 hours and no relapse of pain (to mild, moderate, or severe) and no use of rescue medication during the 24-hour period after dosing.
Brandes et al concluded that the combination of sumatriptan plus naproxen for the acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy. These phase III studies did not analyze whether the combination group showed synergistic therapeutic efficacy for any of the efficacy endpoints.
Synergy is a biological process by which 2 factors act together, or interact, to produce an enhanced effect that would not be predicted by the effects of the individual components. While synergy is a biological effect, not a numerical value, biostatisticians use mathematical models to evidence the synergistic effect of biological interactions such as those that take place with combination drug therapies. That is, statistical analyses are useful to find evidence, by analyzing the available data, that drugs are producing a synergistic effect in a biological system. To analyze synergy, statisticians use various reference models to predict the effect of the combination based on the effects of the individual components. If the actual (or observed) effect of the combination is the same as the predicted effect based on the effects of the individual components, the drugs do not interact.
Thus, the reference model for the no interaction case predicts the effect of the combination from the effects of the individual components. Combinations that have merely an additive effect (meaning their effect can be predicted from the effects of the individual components) demonstrate no interaction between the individual components of the combination. Alternatively, if the actual effect of the combination is different from the effect predicted by the reference model, the 2 drugs are understood to interact with one another, either synergistically or antagonistically. Combinations that have a greater than additive effect demonstrate a synergistic interaction. Combinations that have a less than additive effect demonstrate an antagonistic interaction.
There are 2 general approaches used to assess synergy in biological systems: the independent action approach and the dose addition approach. Independent action assumes that the probability of an effect from one drug is independent of the probability of an effect from a second drug. Dose addition assumes the dose–response relationship of one drug does not change the dose–response relationship of another drug when given in combination. In both approaches, departure from the reference model (ie, independent action or dose addition) that enhances the effects is considered to be evidence of an underlying biological process that is synergistic.
An independent action model is based on the idea of statistically independent action of each component. The independent action model is particularly appropriate for assessing synergy in the combination of sumatriptan and naproxen because these 2 drugs act on different mechanisms within the migraine pathway. It is commonly used to evaluate 2 or more agents that are assumed to act on different sites (eg, in evaluating the effects associated with various carcinogenic compounds).
Under the independent action approach, the probability of a response from a combination of drugs A and B considers the probability of response from drug A plus the probability of response from drug B minus the probability of response to both drug A and drug B (because some patients will respond to both drug A and drug B).
When 2 drugs, say A and B, act independently (and there is no interaction) we can predict the probability (P) of therapeutic response from the combination by knowing the probability of A and the probability of B. Mathematically, independent action is calculated according to the following formula:
***
where P(AorB) is the probability of response to either A or B, PA is the probability of response to A, and PB is the probability of response to B. This model subtracts the overlap between the probability of responding to A, and the probability of responding to B (this overlap correction is analogous to correcting for overlapping Venn diagrams). This basic model can be adjusted to take into account various factors, such as the observed placebo effect.
If the effect of the combination is greater than the probability of response to either drug A or B (as calculated under the independent action model), then the combination is synergistic.
Abstract and Introduction
Abstract
The burden of migraine significantly impacts the individual sufferer, their families, the workplace, and society. The World Health Organization has identified migraine as an urgent public health priority and has initiated a global initiative to reduce the burden of migraine. Underlying the World Health Organization initiative is the need to discover means of optimizing migraine treatments and make them accessible to the broader portion of the world population.
Development of acute migraine medications over the past several decades has largely centered on engineering highly specific receptor molecules that alter migraine pathophysiological mechanisms to abort or reverse the acute attack of migraine. The first product of this line of discovery was sumatriptan and heralded as a landmark therapeutic breakthrough. Sumatriptan is a 5-HT-1B/D receptor agonist considered to activate receptors involved in the pathophysiology specific to migraine. Large-scale regulatory/clinical studies demonstrated statistical superiority for sumatriptan over placebo in reduction or elimination of headache, nausea, photophobia, and phonophobia. Since the introduction of sumatriptan, 6 other triptan products have been released in the United States as acute treatments for migraine, all having the same mechanism of action and similar efficacy. Despite their utility as migraine abortive medications, the triptans do not successfully treat all attacks of migraine or necessarily treat all migraine associated symptoms. In fact, in less than 25% of attacks do subjects obtain and maintain a migraine-free response to treatment for at least beyond 24 hours.
A wide range of non-triptan medications also have demonstrated efficacy in acute migraine. These include non-steroidal anti-inflammatory drugs (NSAIDs), opioids, phenothiazines, and valproic acid to name a few. Given the distinctly different mechanisms of actions of these various medications, it is likely that several unique pathophysiological mechanisms are involved in terminating acute episodes of migraine. Clinicians now capitalize on this observation and use migraine medication in combination with another to improve patient outcomes, for example, using an antiemetic with an opioid or a triptan and NSAIDs.
More recently, the Food and Drug Adminstration has approved a combination product containing 85 mg of sumatriptan plus 500 mg of naproxen sodium for acute treatment of migraine. Clinical trials conducted prior to approval demonstrated that the combination of sumatriptan and naproxen was more effective as a migraine abortive than either of its components but that each component and the combination were more effective than placebo. Exactly how sumatriptan and naproxen interact to create therapeutic synergism is unknown though its mere occurrence suggests that models assisting medical understanding and prediction of pharmacological synergism may improve clinical outcome over products acting through a single receptor mechanism.
Migraine is a syndrome, meaning it is defined by observed symptoms rather than known pathophysiology. Multiple pathogenic mechanisms are likely involved in generating this diverse array of symptoms understood as the migraine symptom complex. Sumatriptan and naproxen have independent mechanisms of action and target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine. Sumatriptan acts on the 5-HT1B and 5-HT1D receptors, whereas naproxen inhibits the COX-1 and COX-2 enzymes. Sumatriptan has vasoconstricting effects as well as effects on neurogenic inflammation by decreasing the release of substance P and calcitonin gene-related peptide. In contrast, naproxen affects prostaglandins and other inflammatory mediators. Because sumatriptan and naproxen both relieve migraine yet interact with different cellular targets within the migraine pathway, it is reasonable to assume there is a unique synergy between these medications that improves treatment outcomes. Clinical trials supported this contention by demonstrating the combination of sumatriptan/naproxen alleviated migraine pain quickly (primarily based on the sumatriptan mechanism of action), and sustained the response longer (primarily based on the naproxen mechanism of action) than is possible when either drug is given alone. The working hypothesis is that when sumatriptan and naproxen are given at the same time, they affect different mechanisms of the migraine pathway and produce an enhanced therapeutic effect.
The purpose of this article is to apply statistical analyses to data from phase II and phase III studies of the combination of sumatriptan and naproxen to determine if this enhanced therapeutic effect is synergistic. This methodology of accessing synergy can be used in the development of future combination migraine treatments to improve treatment outcomes.
Introduction
Migraine is not just a debilitating disease for the individual sufferer, it also places a significant burden on affected families, workplaces, and society as a whole. The World Health Organization considers migraine to be an urgent public health priority and has initiated a global initiative to reduce the burden of migraine. Underlying the World Health Organization initiative is the need to optimize migraine treatments and make them accessible to a broader portion of the world population.
Development of acute migraine medications over the past several decades has largely centered on engineering highly specific receptor molecules that alter migraine pathophysiological mechanisms to abort or reverse the acute attack of migraine. The first product of this line of development was sumatriptan and heralded as a landmark therapeutic breakthrough. Sumatriptan is a 5-HT1B/1D receptor agonist considered to activate receptors involved in the pathophysiology specific to migraine. Large-scale clinical studies demonstrated statistical superiority for sumatriptan over placebo in reduction or elimination of headache, nausea, photophobia, and phonophobia. Since the introduction of sumatriptan, 6 other triptan products have been released in the United States as acute treatments for migraine, all having the same mechanism of action and similar efficacy. Despite their utility as migraine abortive medications, the triptans do not successfully treat all attacks of migraine or necessarily treat all migraine-associated symptoms. In fact, subjects obtain and maintain a migraine-free response to treatment for at least 24 hours in less than 25% of attacks.
A wide range of non-triptan medications also have demonstrated efficacy in acute migraine. These include non-steroidal anti-inflammatory drugs (NSAIDs), opioids, phenothiazines, and valproic acid to name a few. Given distinctions in the scientifically understood mechanisms of action of these various medications, it is likely that several unique pathophysiological mechanisms are involved in terminating acute episodes of migraine. Clinicians now capitalize on this observation and use migraine medication in combination with another to improve patient outcomes, for example, using an antiemetic with an opioid or a triptan and NSAIDs.
More recently, the Food and Drug Administration (FDA) has approved a combination product containing 85 mg of sumatriptan and 500 mg of naproxen sodium for acute treatment of migraine. Clinical trials demonstrated that the combination of sumatriptan and naproxen was more effective as a migraine abortive than either of its individual components. Exactly how sumatriptan and naproxen interact to create an improved therapeutic benefit is unknown though its mere occurrence suggests that models assisting medical understanding and prediction of pharmacological synergism may aid in the development of combination products that improve clinical outcome over products acting through a single receptor mechanism.
Migraine is a syndrome; thus it is defined by observed symptoms rather than known pathophysiology. Multiple pathogenic mechanisms are likely involved in generating this diverse array of symptoms understood as the migraine symptom complex. Sumatriptan and naproxen have independent mechanisms of action and target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine. Sumatriptan acts on the 5-HT1B and 5-HT1D receptors, whereas naproxen inhibits the COX-1 and COX-2 enzymes. Sumatriptan has vasoconstricting effects as well as effects on neurogenic inflammation by decreasing the release of substance P and calcitonin gene-related peptide. In contrast, naproxen affects prostaglandins and other inflammatory mediators. Because sumatriptan and naproxen both relieve migraine yet interact with different cellular targets within the migraine pathway, the 2 drugs have recently been studied in combination to determine if there is a unique synergy between these medications that improves treatment outcomes. Clinical trials of the combination support the conclusion that the combination of sumatriptan and naproxen alleviates migraine pain quickly (primarily based on the sumatriptan mechanism of action), and sustains the response longer (primarily based on the naproxen mechanism of action) than is possible when either drug is given alone. In addition, pharmacokinetic studies suggest a therapeutically advantageous pharmacokinetic profile when sumatriptan and naproxen are administered in combination. The working hypothesis is that when sumatriptan and naproxen are given at the same time, they affect different mechanisms of the migraine pathway and produce an enhanced therapeutic effect.
The purpose of this article is to apply statistical analyses to data from phases II and III studies of the combination of sumatriptan and naproxen to determine if this enhanced therapeutic effect is synergistic. This methodology of accessing synergy can be used in the development of future combination migraine treatments to improve treatment outcomes.
Phase II Study Analysis
Smith et al contains a detailed description of the protocol used, data collected, and analyses conducted in the phase II study of combination treatment of sumatriptan and naproxen for migraine. The study was designed to determine if the sustained pain response rate in subjects treated with the combination of sumatriptan 50 mg and naproxen sodium 500 mg was superior to that of subjects treated with the individual components (sumatriptan 50 mg or naproxen sodium 500 mg) or placebo. This was a phase II, randomized, double-blind, placebo-controlled, multicenter study consisting of a screening visit, at home treatment of a single migraine attack, and a follow-up visit occurring 24–72 hours after the treated migraine attack.
At the time of an eligible migraine attack (pain of moderate or severe intensity), subjects recorded their pain intensity and associated migraine symptoms on a diary card prior to taking study medication and at pre-defined intervals after taking study drug. Subjects recorded the pain intensity scores (none [0], mild [1], moderate [2], or severe [3]) just prior to taking study medication, and every 15 minutes for 2 hours, every 30 minutes until 4 hours and then hourly while awake for the next 20 hours.
The primary efficacy endpoint was sustained pain response, defined as a pain score of 0 (no pain) or 1 (mild pain) at 2 hours post-dose, which did not return to a pain score of 2 (moderate pain) or 3 (severe pain) for the succeeding 22 hours, and no rescue medication was taken during the 24 hours following dosing with study medication. Several secondary efficacy endpoints were assessed, including sustained pain-free response, which was defined as a pain score of 0 (no pain) at 2 hours, which remained at 0 at all subsequent time points, and no rescue medication was taken during the 24 hours. Smith et al concluded that the combination group produced significantly greater initial pain relief at 2 hours post-dose, sustained pain response, and sustained pain-free effects than did sumatriptan alone, naproxen alone or placebo. The combination was particularly superior to its components in subjects with severe baseline migraine pain. The combination was also effective for the relief of the secondary symptoms of migraine: nausea; phonophobia; and photophobia. Smith et al did not, however, analyze whether the combination group showed synergistic therapeutic efficacy for any of the efficacy endpoints (because the study was prospectively designed to compare data from the combination group with the individual components [sumatriptan or naproxen] alone or placebo).
Phase III Study Analysis
Brandes et al contains a detailed description of the protocol used, data collected, and analyses performed for the phase III studies of combination treatment of sumatriptan and naproxen for migraine. Brandes et al report 2 clinical studies that were identically designed and concurrently conducted at 118 clinical study centers. These studies were designed to demonstrate the superiority of the combination of sumatriptan 85 mg and naproxen 500 mg vs the individual components (sumatriptan 85 mg or naproxen 500 mg) and placebo in the acute treatment of migraine.
At the time of an eligible migraine attack (pain of moderate or severe intensity), subjects recorded their pain intensity and associated migraine symptoms on a diary card prior to taking study medication and at pre-defined intervals after taking study drug. Subjects recorded the pain intensity scores (none [0], mild [1], moderate [2], or severe [3]) just prior to taking study medication; 0.5, 1, and 1.5 hours after dosing; and hourly from 2 to 24 hours after dosing.
Various primary and secondary efficacy endpoints were assessed in the phase III studies, including both 2- and 24-hour endpoints. The most rigorous endpoint evaluated was sustained pain-free response, defined as no pain at 2 hours and no relapse of pain (to mild, moderate, or severe) and no use of rescue medication during the 24-hour period after dosing.
Brandes et al concluded that the combination of sumatriptan plus naproxen for the acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy. These phase III studies did not analyze whether the combination group showed synergistic therapeutic efficacy for any of the efficacy endpoints.
Testing for Synergy From Combination Treatment
Synergy is a biological process by which 2 factors act together, or interact, to produce an enhanced effect that would not be predicted by the effects of the individual components. While synergy is a biological effect, not a numerical value, biostatisticians use mathematical models to evidence the synergistic effect of biological interactions such as those that take place with combination drug therapies. That is, statistical analyses are useful to find evidence, by analyzing the available data, that drugs are producing a synergistic effect in a biological system. To analyze synergy, statisticians use various reference models to predict the effect of the combination based on the effects of the individual components. If the actual (or observed) effect of the combination is the same as the predicted effect based on the effects of the individual components, the drugs do not interact.
Thus, the reference model for the no interaction case predicts the effect of the combination from the effects of the individual components. Combinations that have merely an additive effect (meaning their effect can be predicted from the effects of the individual components) demonstrate no interaction between the individual components of the combination. Alternatively, if the actual effect of the combination is different from the effect predicted by the reference model, the 2 drugs are understood to interact with one another, either synergistically or antagonistically. Combinations that have a greater than additive effect demonstrate a synergistic interaction. Combinations that have a less than additive effect demonstrate an antagonistic interaction.
There are 2 general approaches used to assess synergy in biological systems: the independent action approach and the dose addition approach. Independent action assumes that the probability of an effect from one drug is independent of the probability of an effect from a second drug. Dose addition assumes the dose–response relationship of one drug does not change the dose–response relationship of another drug when given in combination. In both approaches, departure from the reference model (ie, independent action or dose addition) that enhances the effects is considered to be evidence of an underlying biological process that is synergistic.
An independent action model is based on the idea of statistically independent action of each component. The independent action model is particularly appropriate for assessing synergy in the combination of sumatriptan and naproxen because these 2 drugs act on different mechanisms within the migraine pathway. It is commonly used to evaluate 2 or more agents that are assumed to act on different sites (eg, in evaluating the effects associated with various carcinogenic compounds).
Under the independent action approach, the probability of a response from a combination of drugs A and B considers the probability of response from drug A plus the probability of response from drug B minus the probability of response to both drug A and drug B (because some patients will respond to both drug A and drug B).
The Reference Model for Independent Action
When 2 drugs, say A and B, act independently (and there is no interaction) we can predict the probability (P) of therapeutic response from the combination by knowing the probability of A and the probability of B. Mathematically, independent action is calculated according to the following formula:
***
where P(AorB) is the probability of response to either A or B, PA is the probability of response to A, and PB is the probability of response to B. This model subtracts the overlap between the probability of responding to A, and the probability of responding to B (this overlap correction is analogous to correcting for overlapping Venn diagrams). This basic model can be adjusted to take into account various factors, such as the observed placebo effect.
If the effect of the combination is greater than the probability of response to either drug A or B (as calculated under the independent action model), then the combination is synergistic.
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