INTERVIEW WITH F. MICHAEL CUTRER, MD

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1 ASIM Mar p /18/01 9:19 AM Page 107 INTERVIEW WITH F. MICHAEL CUTRER, MD Dr. Cutrer is Director of the Partners Headache Center at Massachusetts General and Brigham and Women s Hospitals in Boston. He is also Assistant Professor of Neurology at Harvard Medical School. Dr. Cutrer received his medical degree from the University of Mississippi and was a resident in neurology at the University of California Los Angeles Medical Center. He was also a fellow at Massachusetts General Hospital, where his area of specialization was migraine mechanisms. Boardcertified in psychiatry and neurology, his major clinical interests are primary headache disorders and trigeminal pain syndromes. Advanced Studies in Medicine (ASiM) Senior Clinical Editor for this issue interviewed Dr. Cutrer about his experience with treating and managing migraine and other headache disorders, as well as his opinions regarding newer treatment options, such as antiepileptic drugs. Highlights of the interview follow. RESPONSE RATES TO ACUTE AND PROPHYLACTIC THERAPIES ASiM: Currently available drug therapies are often not effective enough or have too many untoward side effects for many patients with migraine or other types of headache. To approximately what percentage of patients with headache does this apply (both in the headache population as a whole and in your practice/experience)? Dr. Cutrer: The first distinction we need to make is whether it is acute or prophylactic therapy. In the headache population as a whole, which includes mild low-grade headaches treated with drugs that are available over the counter, acute therapies are, in general, fairly effective. More than 90% of patients will have some response to a nonsteroidal antiinflammatory drug (NSAID) or acetaminophen. As the intensity and frequency of the attacks increase, however, the response to acute therapy drops, probably to below 60% in patients who have consistently severe headaches. As the headaches become chronic, or start to occur on a 5-days-per-week basis, the response rate drops even further. If patients take analgesic medications on a daily basis, they may begin to have analgesic rebound. What frequently happens is that the patient will experience a partial or transient response, with return of the headache after a few hours. Response rates in patients with migraine and more classical tension or more severe tension-type headaches fall along that percentage scale, somewhere between 60% and 85%. Drug trials of standard antimigraine therapies have response rates of about 65% to 70% at about 2 hours and even higher than that at about 4 hours. While acute therapies are not perfect, they re fairly good for the majority of people. Prophylactic therapies are medications that are taken on a daily basis to suppress the frequency and severity of attacks. In general, they are not standard analgesic drugs. They are usually given to people who are having attacks more than 1 or 2 days a week. For years, the premise was that somebody having headaches more often than 2 days per month would qualify for prophylaxis. With the advent of the triptans, which are more consistently effective against migraine, many patients don t receive prophylactic treatment until their headaches are occurring at least 1 day a week. Because prophylactic agents are used empirically, they have a spottier response rate. Even in the best prophylactic trials, one seldom sees a greater than Advanced Studies in Medicine 107

2 ASIM Mar p /18/01 9:19 AM Page % response or greater than 50% improvement. About 60% or, at the very best, in the upper 60% to lower 65% range is seen, but it s lower than that in most cases. But you have to remember that, from the start, prophylactic drugs are used in patients who have more frequent, and generally more severe, attacks. When you move down from the general population to the population included for prophylactic drug trials and then to a specialty practice like mine, the response rates decrease. Many patients in my practice have already seen 3 or 4 other neurologists. Sometimes they have already tried and failed or not tolerated every drug, except for the newest one. In patients with intermittent attacks who come to the Headache Unit, we eventually have about a 60% response rate, not necessarily with the first drug we try, but usually within the first 2 or 3 drugs. Patients don t always get a permanent or complete improvement, but they often go from 20 attacks per month to less than 10, or even lower. In some instances, patients actually become headachefree for periods of time, and that allows me to try to wean them off prophylaxis after several months. That s what I always aim for, but it occurs only about 25% to 30% of the time. It is difficult to know in advance who will and who will not be able to come off prophylaxis permanently. In patients with chronic headaches headaches 5 days or more per week that are very often constant the response rate drops to well below 50%. When daily analgesic use is involved, the rate is probably below 30% or even lower than that. As long as they re taking a daily Fioricet, or daily Vicoden, or daily Stadol, their chances of improvement, even with aggressive prophylactic therapy, drop to less than 5%. For those patients, the situation is very grim. If they are willing to come off daily analgesics and actually do get off them, their response rate increases to between 30% to 40%. Bear in mind that some patients at the Headache Unit have had a headache every day for 35 years. Even though their response is less than perfect, sometimes we are able to reduce the severity of their Many patients in my practice have already seen 3 or 4 other neurologists. Sometimes they have already tried and failed or not tolerated every drug, except for the newest one. attacks and enable them to function again. We might be able to give them occasional days off, or break them from constant pain to intermittent pain. There s a gradient of response. ASiM: Do these proportions hold true for patients with migraine, cluster, transformed migraine, chronic daily headache, and tension-type headache, or is one group more refractory to available drug therapies than another? Dr. Cutrer: Intermittent migraineurs have a fairly good prognosis. Going through the first 4 or 5 prophylactic treatments we have, 70% to 80% show some response. Patients with intermittent and nonchronic cluster headaches also respond pretty well. However, there is always a question with cluster because it is episodic by nature. Very often, a patient will go into remission for months and it s difficult to know what the exact response is because what you re doing primarily is trying to shorten the duration of the cluster period. Almost all of them respond, but it s difficult to determine in a formal study if you ve decreased the duration. A fairly large majority eventually come out of their cluster, and the patient usually feels that the duration has been shortened by prophylactic intervention. The response to acute treatment of cluster headache is actually quite good. Very few patients that I see, and I think in general, fail to show some response to acute therapy with either ergotamines or the triptans, which are the drugs of choice. Another available therapy is inhaled oxygen, which has a reasonable response rate, about 50% to 60% in my patients. I always try it, especially in patients who are having nocturnal attacks, because it has no side effects and it s safe. It s not unusual to treat the attack with oxygen first and then, if there is no response, to use one of the triptans, usually injectable sumatriptan, which is probably the drug of choice at this time. Prophylactic therapies for patients who have more chronic attacks or chronic cluster headaches include verapamil, lithium, and tapering doses of steroids. I m always a little apprehensive about using steroids, although I do have patients who have failed to respond 108 Vol. 1, No. 3 March 2001

3 ASIM Mar p /18/01 9:19 AM Page 109 to other therapies but do respond to steroids. You start with prednisone 80 mg and then taper down. In the past, physicians prescribed ergotamine derivatives such as methysergide or even daily Cafergot and other ergotamines. The use of that therapy makes me very nervous because it combines the same type of drug for prophylactic therapy and acute therapy. It s almost like you re double dosing on breakthrough attacks. Some of my colleagues do it, but I m apprehensive about putting someone on, for example, methysergide, which is an ergot derivative, and then giving him acute therapy with another vasoconstrictive drug like sumatriptan, especially since cluster headache patients are often middle-aged men with risk factors for coronary disease. Nevertheless, these patients show a pretty good response to both acute and prophylactic therapy. In my view, transformed migraine is the largest subset of chronic daily headache, which is any headache that lasts for more than 5 days a week (or more than 15 days per month under proposed criteria). Patients in this group have at least some head pain every day. They seem to have a baseline of mild to moderate headaches with intermittent superimposed severe attacks, which occur 2 to 3 days per week. They re included in the group of patients with a generally poorer prognosis. One major determining factor for prognosis among those patients is frequent analgesic use. Sometimes, just the process of recurrent withdrawal from analgesics (which can be a very potent factor for reactivation of the headache) can render the headaches refractory to treatment. So these patients have 2 strikes against them. In terms of acute therapy, what often happens in this population is that they ll have a transient response or an incomplete response to their analgesics, whether it s an opiate or a combination analgesic that contains caffeine. Then they become emotionally dependent on the drug as well as somewhat physically dependent. They re not experiencing euphoria or any of the responses that are usually associated with abuse, but they become imprisoned by their fear that they won t be able to function or take care of their family or go to work if they stop taking their analgesics. You add to that the fact that analgesic withdrawal can be a potent trigger for headaches and you can understand why they become nonresponsive to therapy. It s a very sad story. However, if you can get patients with transformed migraine off analgesics, they have a much better prognosis. Another category of chronic daily headache is new persistent daily headache, which is something that just starts out of the blue. Often, patients can name the day that their constant headache started. This kind of headache always prompts me to do a more aggressive search for an underlying primary cause, such as a tumor, arteriovenous malformation or thrombosis, or some medication effect that s just starting. Many patients with persistent daily headache are somewhat less responsive or even unresponsive to treatment. Patients with chronic tension-type headaches show some response, probably more than 50% of the time, but there are fewer treatment options available to them. They include amitriptyline, which is the most consistently helpful, other tricyclics, and the muscle relaxant tizanadine, which was found to be effective in one small study, but I ve seen a checkered response to it in my patients. After those 3 options, you don t have much left to offer. Patients whose daily headaches have migraine features tend to be more refractory, but that probably speaks to the pathophysiology. Daily cluster headache is a matter of terminology. I do not consider cluster headaches that occur every day to have the same relationship as cluster headaches that are usually associated with spontaneous remissions. The final category of chronic daily headache includes headaches of short duration, chronic paroxysmal hemicrania, hemicrania continua, and nocturnal hypnic headaches, which are related to cluster headaches in many ways. Some of these headaches have fairly uncommon syndromes, like hemicrania continua or chronic paroxysmal hemicrania, and are exclusively responsive to indomethacin. ASiM: Is any one group more prone to develop side effects from available drug therapies? Dr. Cutrer: With any prophylactic treatment, the group most prone to side effects, even side effects that aren t written in the books, are the patients you are trying to wean from daily analgesics. They will report side effects you never heard of, saying that the only treatment that they can tolerate or are not allergic to is their currently overused opiate analgesic. Headache patients in general are more prone to side effects. I don t know why that is, but if you compare the frequency of side effects of patients Advanced Studies in Medicine 109

4 ASIM Mar p /18/01 9:19 AM Page 110 treated with beta-blockers for hypertension with the frequency of side effects in patients you re treating with migraine prophylaxis, you ll find it s much, much higher in those with migraine. Whether that represents a heightened sensitivity to any sort of drug effect, or something else, I don t know. DEPRESSION AND CHRONIC HEADACHE ASiM: How often is depression a component of chronic headache, and how often is chronic headache a component of depression? Dr. Cutrer: There has been some research in this area and also in genetic epidemiology suggesting comorbidity of migraine and depression. I suspect that the incidence of depression in patients with chronic headaches, chronic migraine, or other chronic forms of headache is greatly increased. It s a complex issue because, at some level, there is probably a genetic linkage between the 2 disorders. There is also a distinct reactive component. If your life is altered and your existence contracted to the point where you can t leave the house or can t function, depression increases. That happens with any sort of chronic pain. I think there also may be a small segment of patients with depression who are more prone to have some somatic expression of their mood disorder. However, in my experience, somatic expression is overestimated by many physicians. They refer patients on the assumption that the headaches are caused by depression, and I usually don t find that to be the case, although it can be a factor in treatment response. If a patient is extremely depressed and if it is not dealt with, his or her response to prophylactic therapy decreases. ASiM: Are primary care physicians referring patients with headache because they think the headache is masking depression? Dr. Cutrer: They refer because the patients are calling them 12 times a week or using analgesics every day or they have gone through 2 or 3 prophylactic regimens and they just don t know what to do now. Often in the referral letter, there will be a passing reference to the patient s history of depression ; this is very important information but I find that it is usually not the cause of the patient s headaches. ASiM: To what extent is headache misattributed (and consequently mistreated or suboptimally treated) to depression? Dr. Cutrer: There s a widespread impression that any antidepressant is effective in migraine. Actually, there is strong evidence to support prophylaxis in migraine for only 1 antidepressant, amitriptyline. There is an assumption that other tricyclics or related tricyclics like nortriptyline and some others are also effective, but it s been my experience that they re not as effective as amitriptyline. That is probably because amitriptyline has many different receptor effects. On the other hand, I don t find that the selective serotonin reuptake inhibitors (SSRIs), which are considerably better tolerated antidepressants than the tricyclics, are particularly helpful in treating the migraine itself. ANTICONVULSANTS AND OTHER DRUG CLASSES FOR PROPHYLAXIS ASiM: The significant number of headache patients who do not benefit sufficiently from currently available drug therapies has prompted investigators to test other medications, such as anticonvulsants, that might provide relief. Why are anticonvulsants a good choice in this regard? Dr. Cutrer: First, anticonvulsants frequently have some gamma-aminobutyric acid (GABA) activity. GABA is a widely distributed and potent inhibitory neurotransmitter system that, among other things, modulates pain. Anticonvulsants that stabilize GABA levels or increase endogenous GABA levels are likely to have a suppressive effect on the pain system. We ve shown this in some animal models. Second, many of the newer anticonvulsants exert non-n-methyl-d-asparate (NMDA) modulation of the glutamate, which is the primary neurotransmitter for the trigeminal pain (headache). The third reason is that anticonvulsants do not generally have modulatory effects on vascular smooth muscle. The last thing you want is for your prophylactic agent and your most effective acute treatments to be vasoconstricting. With anticonvulsants, you are often able to treat your patient with a prophylactic agent that doesn t alter blood pressure, doesn t alter vascular caliber, and doesn t affect coronary arteries. Then, when you need to, you can use serotonin-related drugs. 110 Vol. 1, No. 3 March 2001

5 ASIM Mar p /18/01 9:19 AM Page 111 ASiM: How promising are anticonvulsants in the treatment and prophylaxis of migraine and other headaches? Dr. Cutrer: Anticonvulsants are the most promising category of new drugs. They are promising because they have many different receptor activities. Traditionally, the best antimigraine drugs are those that have a lot of nonspecific effects, and that betrays our essentially limited understanding of the way the drugs work. If you push all the buttons, you get a better response than if you push the wrong button. ASiM: Do anticonvulsants have any potential utility in neurological disorders other than epilepsy and headache? In non-neurological disorders? Dr. Cutrer: They are being used in many psychiatric disorders, in mood disorders, and in nonheadache pain. Almost any condition that is paroxysmal is a potential treatment target. ASiM: Studies of topiramate found that it was associated with weight loss. Is it being investigated for use in obesity? Dr. Cutrer: Weight loss is the best side effect you can have in the headache population because many drugs used for headache, such as antidepressants and valproic acid, are associated with weight gain. Many of my patients have weight problems when they come to the Headache Unit, so weight loss is a feature I don t have to sell too hard. ASiM: What other drug classes might be suitable for investigation of their possible efficacy in the treatment and prophylaxis of migraine and other headaches? Dr. Cutrer: The one that comes to mind first would be the dopaminergic drugs, because we know that some of these drugs are effective for the treatment of status migrainous persistent headache, at least acutely. The feeling is that this effect is beyond the straight antiemetic effect and perhaps beyond the sedative effect. We don t know exactly why, but that s interesting to me because it opens up a new way to investigate what s going on with the system. Other drugs that might be interesting to investigate are the selective cyclooxygenase-2 (COX-2) inhibitors, a subpopulation of the NSAIDs. What makes me nervous about using any NSAID chronically is that they have gastrointestinal and renal effects. I rarely let patients stay on an NSAID, including a COX-2 inhibitor, for more than a year. Sometimes, though, it s the one thing that works, so you re sort of trapped. ATYPICAL PRESENTATIONS ASiM: What is your management approach to patients with atypical presentations of migraine (eg, acephalgic migraine)? Dr. Cutrer: You should rule out the other causes of transient neurological symptoms. I m much more likely to scan atypical patients. I investigate anybody with an atypical presentation and follow up. If they re having prolonged neurological symptoms, they get a computerized tomography scan or magnetic resonance imaging scan; if the scans are normal or the symptoms suggest a vascular lesion, I may order magnetic resonance angiography to look at the vessels. Atypical presentations would include onset of headaches after the age of 40, or a prolonged neurological or very rapid acceleration of head pain. Some of the abnormalities that I might investigate include collagen vascular disorder or clotting abnormalities. One test that is often advocated looks for the presence of antiphospholipid antibodies or the lupus anticoagulant, but in my experience, the incidence of these abnormalities in the migraine population is very low, lower than what the literature might suggest. In acephalgic migraine, the patient s age is important. In patients under 40, if the visual symptom has the classical migratory quality, I usually do not image them. If the quality of the visual disturbance is static, persists for more than 1 hour, or occurs only in 1 eye or the patient has no family history, I often image them. I don t push it much more than that. However, if somebody over 40 presents with almost any atypical feature, I investigate further because there is an increasing risk of stroke and other brain abnormalities as a person ages. PTH Advanced Studies in Medicine 111