Pharmacological Synergy: The Next Frontier for Migraine
Pharmacological Synergy: The Next Frontier for Migraine
Migraine is a complex neurobiological process capable of generating a wide array of clinical symptoms. Clinical trials have demonstrated that not all attacks or all symptoms of specific attacks are always relieved by intervention with triptans, even within the same subject. Further, certain aspects of migraine pathophysiology do not appear to be altered by triptan intervention (eg, aura). Consequently, there is a clinical need to explore the potential synergy of different medications presumed to act on different pathways of migraine pathophysiology in successfully treating acute migraine.
Migraine is an excellent disease model for exploring synergistic mechanisms of pharmacological agents used in its treatment. Given the divergence of symptomatology frequently observed during an attack, it is reasonable to assume that no single receptor mechanism can fully explain the totality of symptom expression. The FDA has recently supported a concept of migraine specific medications for acute interventions whereby the intervention demonstrates statistical superiority over placebo in relief of headache, nausea, photophobia, and phonophobia. While each endpoint is considered independent, it is important to note that only a minority of subjects treated during moderate to severe headache experience complete relief of all acute symptoms. This strongly underscores the limitations of single receptor pharmacology and the hope of finding a "magic bullet" to treat a complex disease like migraine.
It is advantageous to use multiple drugs working in synergy to relieve migraine. The complexity and diversity of migraine symptoms that are observed during episodes of migraine suggest that physiological "networks" rather than single receptors are generating these diverse symptoms. Considering the "process of migraine" as developing over time, specific drug interventions may be more or less effective depending on the pathophysiological phase of migraine when they are delivered. This has been demonstrated in part by numerous "early intervention" studies that clearly demonstrate better efficacy for multiple migraine related symptoms when oral triptans are delivered early in the mild headache phase of migraine. Likewise, Burstein presented data that demonstrated ketorolac was more efficacious than sumatriptan when migraine had evolved to a point where central sensitization had developed. This again suggests that as migraine progresses, so too does the pathophysiology that drives the symptom expression observed clinically.
Additionally, independent mechanisms of pharmacological intervention appear to have varying effects on specific symptoms associated with migraine. For example, while triptans appear more efficacious for migraine associated nausea than placebo, there are no peer-reviewed published studies to suggest that triptans have efficacy in treating nausea unrelated to migraine. This suggests that relief of nausea by triptans during migraine is mediated through an indirect mechanism(s). Similarly, there are no peer-reviewed published studies to suggest that triptans have efficacy in other primary headache disorders such as tension-type headache.
The analysis of the studies described in this article clearly support differences in various aspects of migraine relief using a combination of sumatriptan and naproxen. As demonstrated in the analysis in this article there is a clear example of synergism among medications with different mechanisms of action that resolve migraine-associated symptoms. Designing studies that explore synergistic interaction is of paramount importance for the welfare of patients. Unfortunately, while the advent of sumatriptan was indeed a breakthrough innovation for the treatment and scientific understanding of migraine, it is not a "magic bullet" for treating migraine, and its development was followed by 2 decades of drug development that focused on improving the triptan molecule rather than advancing new therapeutic directions.
Development of pragmatic approaches that tangibly improve patient care requires an understanding that treating a complex clinical conundrum such as migraine may often require a combination of medications rather than a single drug. Standards of care for other disease states appear to have already recognized this principle. For example, treatment of hypertension is frequently accomplished with combinations of medications working through different mechanisms of action.
Demonstrating strategies to evaluate the potential synergy of unique and different pharmacological interventions for migraine has value for both patient outcome and future drug development. Utilization of a predictive model such as described in this article could be a significant step forward in defining potentially synergistic migraine interventions and improving treatment outcome.
Discussion
Migraine is a complex neurobiological process capable of generating a wide array of clinical symptoms. Clinical trials have demonstrated that not all attacks or all symptoms of specific attacks are always relieved by intervention with triptans, even within the same subject. Further, certain aspects of migraine pathophysiology do not appear to be altered by triptan intervention (eg, aura). Consequently, there is a clinical need to explore the potential synergy of different medications presumed to act on different pathways of migraine pathophysiology in successfully treating acute migraine.
Migraine is an excellent disease model for exploring synergistic mechanisms of pharmacological agents used in its treatment. Given the divergence of symptomatology frequently observed during an attack, it is reasonable to assume that no single receptor mechanism can fully explain the totality of symptom expression. The FDA has recently supported a concept of migraine specific medications for acute interventions whereby the intervention demonstrates statistical superiority over placebo in relief of headache, nausea, photophobia, and phonophobia. While each endpoint is considered independent, it is important to note that only a minority of subjects treated during moderate to severe headache experience complete relief of all acute symptoms. This strongly underscores the limitations of single receptor pharmacology and the hope of finding a "magic bullet" to treat a complex disease like migraine.
It is advantageous to use multiple drugs working in synergy to relieve migraine. The complexity and diversity of migraine symptoms that are observed during episodes of migraine suggest that physiological "networks" rather than single receptors are generating these diverse symptoms. Considering the "process of migraine" as developing over time, specific drug interventions may be more or less effective depending on the pathophysiological phase of migraine when they are delivered. This has been demonstrated in part by numerous "early intervention" studies that clearly demonstrate better efficacy for multiple migraine related symptoms when oral triptans are delivered early in the mild headache phase of migraine. Likewise, Burstein presented data that demonstrated ketorolac was more efficacious than sumatriptan when migraine had evolved to a point where central sensitization had developed. This again suggests that as migraine progresses, so too does the pathophysiology that drives the symptom expression observed clinically.
Additionally, independent mechanisms of pharmacological intervention appear to have varying effects on specific symptoms associated with migraine. For example, while triptans appear more efficacious for migraine associated nausea than placebo, there are no peer-reviewed published studies to suggest that triptans have efficacy in treating nausea unrelated to migraine. This suggests that relief of nausea by triptans during migraine is mediated through an indirect mechanism(s). Similarly, there are no peer-reviewed published studies to suggest that triptans have efficacy in other primary headache disorders such as tension-type headache.
The analysis of the studies described in this article clearly support differences in various aspects of migraine relief using a combination of sumatriptan and naproxen. As demonstrated in the analysis in this article there is a clear example of synergism among medications with different mechanisms of action that resolve migraine-associated symptoms. Designing studies that explore synergistic interaction is of paramount importance for the welfare of patients. Unfortunately, while the advent of sumatriptan was indeed a breakthrough innovation for the treatment and scientific understanding of migraine, it is not a "magic bullet" for treating migraine, and its development was followed by 2 decades of drug development that focused on improving the triptan molecule rather than advancing new therapeutic directions.
Development of pragmatic approaches that tangibly improve patient care requires an understanding that treating a complex clinical conundrum such as migraine may often require a combination of medications rather than a single drug. Standards of care for other disease states appear to have already recognized this principle. For example, treatment of hypertension is frequently accomplished with combinations of medications working through different mechanisms of action.
Demonstrating strategies to evaluate the potential synergy of unique and different pharmacological interventions for migraine has value for both patient outcome and future drug development. Utilization of a predictive model such as described in this article could be a significant step forward in defining potentially synergistic migraine interventions and improving treatment outcome.
Source...