Abstract
Professor Goadsby
Now that we have discussed the development of naratriptan, it falls upon Roger Cady to talk about the use of sumatriptan and naratriptan in a broader context. Roger has been involved in the headache business for quite some time and is intimately involved in teaching about headache. His US-based primary care network has shown us some ways to disseminate information to general practitioners. For that and many other contributions, I thank you, and invite you to give your presentation; Roger Cady?
Roger Cady
Thank you. I am honoured to have been asked to speak to you today. I am going to talk about the expanding applications for the triptans, specifically sumatriptan and naratriptan. It has been said that great accomplishments breed great expectations and this is especially true when we speak of sumatriptan. One great accomplishment of sumatriptan is that it validated migraine as a physiological rather than a psychological disorder. In early clinical trials, after receiving the first injection of sumatriptan, people with the hitherto vague diagnosis of migraine almost seemed to magically improve before our eyes. Most physicians can recall their first patient treated with sumatriptan in whom they witnessed this response and this did much to validate migraine as a ‘real’ disease.
The discovery of sumatriptan also gave us insights into migraine pathophysiology. It has acted as a molecular scalpel, teasing out the mechanisms of migraine, and opened our eyes to the importance of the neuronal rather than the vascular mechanisms of migraine, which had preoccupied earlier thinking. Triptan therapy has been important in the lives of our patients because today we can help them restore control to their lives. I have watched patients who were disabled with migraine become functional, go to school, launch a career. I have heard mothers in tears tell me the burden of caring for a child during a migraine, yet with the control quality treatment has brought to their lives, those concerns are gone. They are free be the kind of parent, spouse or worker they wanted to be.
But despite these great accomplishments, other expectations have not been met. Migraine is still under-diagnosed, under-treated and, I suspect, misunderstood. In this presentation, I want to concentrate on three questions:
What is the spectrum of headache activity that can be effectively treated?
When should we intervene pharmacologically in migraine?
How should we treat migraine?
1. What is the spectrum of headache activity that can be effectively treated?
In 1996, Donna Gutterman, M.E. Beach and I did a retrospective analysis of over 1900 migraine attacks to assess whether sumatriptan could treat a broader spectrum of migraine than was defined by the IHS criteria (1). This was followed by a rigorous placebo-controlled study (the Spectrum Study) designed by Richard Lipton, Walter Stewart, Stephen O'Quinn and myself that explored this question in detail (2, 3). We started with the assumption that among patients experiencing high level of headache-related disability, we could define three distinct populations of headache sufferers. The first population was one of subjects with IHS 1.1 or 1.2 migraine (migraine with and without aura). We theorized that in addition to these headaches they may be experiencing other headache presentations as well, such as migrainous and episodic tension-type headaches, so experiencing a spectrum of headache activity.
A second population comprised people with headaches that appeared to be migraine, but lacked some of the features required to meet the 1.1 or 1.2 diagnostic categories. These headaches met criteria for migrainous headache (IHS 1.7). It is doubtful that any of these patients would have been included in clinical trials. This population could also have episodic tension-type headache but not IHS migraine 1.1 or 1.2. Finally, we theorized a third population with only episodic tension type headache. We then gave all the subjects diaries and asked them to treat up to 10 headaches with oral sumatriptan, 50 mg over a 6-month period.
In the study (3) 249 patients treated 1576 headaches – migraine, ‘migrainous’ and tension-type (Table 1) and we found that the responses to sumatriptan for all headache types were equal (Fig. 1). Moreover, headaches in the migrainous population, those who failed to qualify for the 1.1 or 1.2 category, also responded to sumatriptan. We concluded that sumatriptan effectively treats the full spectrum of headaches in a population with IHS migraine.
Response to sumatriptan vs. headache diagnosis; Spectrum Study, ∗P<0.001.
Overview of the Spectrum Study
Among the population with only episodic tension-type headache diagnosed by clinical history (a population difficult to find in clinical practice), the treatment diaries showed that about 40% were experiencing some migraine features during their tension-type headaches, and they had to be reclassified. However, when migrainous features were identified, the headaches responded to sumatriptan. The remaining few patients, who only had episodic tension-type headache, also responded to sumatriptan but with a high placebo response; the difference was not statistically significant. It appears from this study that many disabling headaches not conforming to classical diagnostic guidelines are treatable with sumatriptan, yet we have excluded this population from the original clinical trials and I suspect that many of these patients are denied triptan therapy in clinical practice at the present time.
2. When can we treat?
Clinical trials have focused on treating migraine during moderate to severe pain. However, the migraine attack begins before moderate to severe pain is experienced (Fig. 2). The progression from a well-functioning nervous system to one in the throes of a migraine is evidenced by predictable changes, beginning with a premonitory or prodromal phase, followed sometimes by an aura, and then by headache. This generally intensifies over time from mild to moderate to severe pain and our clinical trials have focused only upon this stage of the headache process.
Clinical phases of migraine.
As a subanalysis of the Spectrum data we studied the efficacy of treatment when the headache was mild (2). Could early intervention abort the migraine process and prevent the ensuing disability documented from clinical trials? We evaluated a subset of protocol violators from the Spectrum data, who had treated some of their headaches during mild rather than moderate-to-severe pain. In the overall population, about 10% of the 265 subjects had treated a migraine during mild pain. Overall, this group treated 46 attacks while the pain was mild and 212 attacks while the pain was moderate or severe. In treating during mild pain, placebo had been taken six times and 50 mg sumatriptan on 40 occasions. This may be a small group of patients, but the results were dramatic. At 2 h about half the patients, and by 4 hs 85%, were pain-free compared with a placebo response of 17%.
An intragroup analysis found an 85% response rate at 4 h for headaches treated when mild, compared to a 47% response rate if the same patients delayed treatment until they were experiencing moderate or severe pain. While statistically it is certainly easier to get to zero from one rather than from three or two, the clinical reality is that this mild-treatment population avoided disability and suffering. I should also point out that in the population treating mild pain with placebo, four of eight patients had progressed to moderate or severe headaches at 1 h. In addition, the recurrence rate for those treating at the stage of mild pain was 13% (vs. 18% with moderate to severe pain). Another curious observation was that investigators associated no sumatriptan-related adverse events when patients treated during mild pain but the rate was 5.2% when the same patients treated migraine during moderate or severe pain. It may be that ‘triptan sensations’ are more obvious to patients during fully developed migraine, much in the same way sensory symptoms of photo- and phonophobia are heightened during the intense pain phase.
In summary, it appears that sumatriptan is excellent therapy for early migraine, and treatment during mild pain offers superior efficacy over treatment during moderate or severe pain. Early treatment may also prevent disability and appears to carry no therapeutic penalty in terms of recurrence rates or adverse events.
The next question is obvious. If we can treat during mild pain, maybe we can start treatment in the pre-headache phase. We studied naratriptan in this capacity as it has better access to the central 5-HT1B,D receptors. We selected 20 patients who said that they could always tell that a migraine was on its way and who reported having a well-defined prodrome or premonitory phase with their migraines (Fig. 3). To document the association of premonitory phase and headache, the patients kept diaries through three migraine attacks that they treated with their usual therapy. The diary correlation was 100% between prodrome and onset of migraine.
Overview of the prodrome study.
The patients then treated three migraine attacks with naratriptan during the premonitory phase at the point they knew the headache of migraine was inevitable. Analysis of this group showed a 63% reduction in the anticipated number of migraine attacks. When headaches did occur, they were generally less intense than those experienced during the usual therapy treatment phase of the study (4). During the usual therapy treatment phase, 5% of migraines were reported as mild and 95% as moderate or severe, but when treatment was initiated during the premonitory phase, 44% of the ensuing headaches were reported as mild. In addition, 70% of patients who prevented migraine successfully repeated their success three times in three attempts. We concluded from this study that naratriptan may be effective in preventing migraine if taken during a premonitory phase and may be effective in reducing the severity of migraine. This therapeutic strategy undoubtedly improves quality of life and has pharmacoeconomic benefit.
3. How to treat migraine?
We lack a clear scheme of headache management for primary care providers, general neurologists and people who do not treat migraine everyday. If we use the research-driven IHS criteria in the acute situation we can diagnose the current headache, as is done so effectively in clinical trials. However, in the out-patient setting, where most migraine patients are evaluated, people are not in the midst of a migraine attack. They come to their primary care physicians between headaches and with a multitude of symptoms. In addition, their histories reflect a spectrum of headaches experienced over a lifetime. As a result, physicians find the diagnostic picture confusing when they try to apply the IHS classification. We need to explore a more practical diagnostic paradigm.
Realistically, patients come to the doctor to explain the impact of headaches on their lives. The qualities of individual attacks are less important to them than whether they can establish headache control and can function normally. Patients with frequent headaches are often experiencing comorbidities, such as mood disorders, muscle tension states or irritable bowel syndrome. When patients talk about their anxieties and fears, mood disruption and irritability, many clinicians are quick to diagnose depression or anxiety and prescribe an SSRI and non-specific headache medication. After all, physicians have been schooled to listen for stress symptoms that imply a mood disorder. The consequence is that headache frequently goes unrecognized and under-treated.
In reality, it is the impact of headaches on a person's life that best defines the treatment needs for headache sufferers. Future research should explore the idea of a disability or impact-based diagnostic scheme in primary care. Primary care physicians should regard any established pattern of recurrent disabling headache as being migraine, until proven otherwise. Currently, physicians often think that disabling headaches not accompanied by aura or not completely fulfilling migraine diagnostic criteria are not ‘real’ migraine. The Spectrum study suggests that primary headaches that are disabling respond to sumatriptan, and perhaps that is where diagnostic thinking should begin.
Extracting this information in a clinical setting needs to be done in a time-efficient manner for acceptance in primary care. Several points may assist in clarifying clinically relevant information. First, by asking an individual how the headaches interfere with life in many ways determines the necessary next step of therapy. When headaches interfere with a patient's ability to parent, work or meet important social obligations, the need for effective abortive therapy is obvious.
Second, physicians need the reassurance that a stable headache pattern rules out most serious secondary headaches. Over-using acute medications (including OTCs) happens too often by patients who are not experiencing a clear episodic recurrent headache pattern. Thus, it is important to address headache frequency as part of the patient evaluation. In addition, assessment needs to be made of medication usage and response to therapy. Finally, asking for ‘comfort signs’, such as a menstrual association or a positive family history, provides reassurance to both the patient and the physician. These simple approaches can assist recognition and treatment of patients with disabling headaches.
In the future, we will expand the treatment population by increasing the types of headaches that we can treat and by changing the diagnostic and treatment paradigms that we have been using. The notion that patients must wait for moderate to severe pain before we intervene with effective therapy is at odds with almost every other disorder we treat. We don't wait for hypertension to get out of hand before we start therapy, nor for blood sugars to go far above normal before we treat a diabetic, but we ignore headache until it incapacitates. This must change. Finally, we need to merge the best medical science and the best clinical practices in treating patients with migraine. There are 500 opinion leaders here today who must lead the educational charge to help primary care physicians adopt a pragmatic, practical approach to this disease. That will do more than anything else to ensure success.
Thank you.