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NEUROBIOLOGY Mechanism Found for Migraine Med Research Encourages Patients To Take Triptans Early Migraine patients are acutely aware of time. Their perception of the hours and days they spend secluded in darkened bedrooms is further heightened by the need to brace themselves second-by-second for the pounding pain that shoots through their brain. For the fortunate ones, over-the-counter analgesics may give respite. For others, prescription drugs may help, but more often than not even these fail to stem the throbbing and leave the majority of migraine patients (who make up nearly 10 percent of the population) without a failsafe treatment. Curiously, in most patients, a class of drugs called triptans, which activate the 1B/1D isoform of 5-hydroxytryptamine receptors, works at least some of the time. Providing reliable relief from debilitating migraine attacks may therefore hinge on understanding when and why these drugs work their magic. Rami Burstein, HMS associate professor of neurobiology and of anesthesia at Beth Israel Deaconess Medical Center, may have found the answer. Two types of migraine patient respond to triptans. Those who suffer later in the attack from a skin hypersensitization called cutaneous allodynia (right chart) must take the drugs early for them to be effective. Non-allodynic patients always obtain relief, even when the drugs are taken late (left chart). Red bars show patient's perception of pain before treatment; gray bars, after treatment. In the January 2004 Annals of Neurology, currently available online, Burstein and colleagues report that the success or failure of triptan treatment also depends on time. During a migraine attack, central trigeminovascular neurons situated near the base of the brain are excited by peripheral pain receptors that innervate the dura, the membrane surrounding the cortex. After a period of about 20 minutes, this stimulation can render the trigeminal neurons hypersensitive, at which point they spontaneously begin to fire off action potentials that exacerbate the pain. Burstein has found that if triptans are given before these neurons become hypersensitized, patients can, in most cases, be completely relieved of pain. More specifically, he has found that for triptans to work they must be administered before the manifestation of another migraine symptom, cutaneous allodynia, the sensitization of neurons to normally innocuous stimuli on the skin such as a light touch or gentle warming. "In effect," Burstein said, "treating migraine with triptans is a race against cutaneous allodynia." When that race is won the result is "phenomenal," according to Debra Samuels, a longtime migraine sufferer who has benefited immensely by volunteering for Burstein's studies. Timing Treatment Since 2000, when he was one of the first to scientifically document cutaneous allodynia, Burstein has wondered if the neurological changes responsible for the phenomenon also explain why patients sometimes fail to respond to triptan treatment. Together with Moshe Jakubowski, instructor in anesthesia, and Beth Collins, both at BID, Burstein tested this hypothesis by administering sumatriptan to patients undergoing allodynic and non-allodynic migraine attacks. The results were startling. The drug provided relief in only five of 34 allodynic attacks whereas in 25 of 27 allodynia-free migraines, pain vanished within two hours of treatment. Even in those most susceptible to allodynia (19 of 31 patients enrolled in the study), sumatriptan worked when given early in the attack, before allodynia surfaced. In fact, all 12 patients who were treated in this fashion made remarkable recoveries, though when the same group was treated after onset of allodynia, only three patients responded successfully. "We can now predict with about 90 percent accuracy whether a patient will respond to triptan before we give the drug, and we can increase the success rate from about 40 percent to over 90 percent." --Rami Burstein These data may have a major impact on how primary care physicians and patients deal with migraine. Because of the perception that triptans only work some of the time, and because of the cost (up to $16 for one pill), patients tend to adopt a wait-and-see approach. "If the migraine has not gotten better after four or five hours then the patient may decide to take a pill," explained Burstein. But as his research shows, that may be too late for the drug to be effective, in which case patients may be even less likely to take medication during their next attack. "What we have done is to advance migraine treatment from an empirical approach to a logical one," Burstein said. "We can now predict with about 90 percent accuracy whether a patient will respond to triptan before we give the drug, and we can increase the success rate from about 40 percent to over 90 percent." For Samuels this is nothing short of miraculous. Having taken part in the study, she has learned to recognize the early signs of an attack, such as the discomfort she may feel when brushing her hair or wearing a necklace, and to treat herself before it is too late. Proof of Principle In an accompanying paper, Burstein and Jakubowski describe how they used a rat model of intracranial pain to probe the physiology that underlies triptan treatment. In this model, an inflammatory cocktail is applied directly onto the dura and produces neuronal responses that correspond to many of the symptoms of a migraine attack, including cutaneous allodynia. Rami Burstein (center) and colleagues (from left, Beth Collins, Esther Garcia-Nicas, Moshe Jakubowski, and Dan Levy) have found that timing is crucial when treating a migraine attack with triptans. The findings, which explain why the drugs sometimes fail to provide relief, may have a dramatic impact on how migraines are managed.(Photo by Steve Gilbert) The researchers were able to isolate and record signals from individual rat neurons in the spinal trigeminal nucleus. Eighteen of these were shown to receive input from both skin and dural nociceptors, the pain-sensing neurons. By recording their electrophysiological properties, Burstein shows that they become hypersensitized shortly after the dura has been stimulated, as is postulated to happen during a human migraine attack. This response appeared as a significant increase in the neurons' rate of spontaneous firing. It rose from about three per second at baseline to almost 20 per second after the inflammation was initiated, and a twofold jump occurred in the firing rate normally seen when the animals' skin is brushed. When given at the same time as the inflammatory stimulus, sumatriptan keeps these neurons firing at baseline levels, but if given about two hours later, the drug has little effect. Why nociceptors in the human dura initiate the process that leads to a migraine is still not well understood. "If we knew that, we might be able to develop a prophylactic," said Burstein. For now, patients must rely on their own awareness and quickly respond to the warning signs. Though this is not a perfect solution (a migraine may develop during sleep, for example), it has worked wonders for many, including Samuels. Her attacks have lasted anywhere from three hours to a week. Since she has volunteered for the BID study, she has reduced the frequency of migraines from four or five every month to only one or two. --Tom Fagan