Category: Headaches

Scientists are reporting the development and successful initial testing of a new form of methotrexate — the mainstay anticancer drug — designed to be given as nose drops rather than injected. It shows promise as a more effective treatment for brain cancer, they say.

The report appears in ACS' Molecular Pharmaceutics.

Tomotaka Shingaki and colleagues note that brain cancer is difficult to treat, partly because current anticancer drugs have difficulty reaching the brain. That's because the so-called blood-brain barrier (a protective layer of cells surrounding the brain) prevents medication in the blood from entering the brain. But new evidence indicates that some drugs administered through the nose, either as nose drops or nasal spray, can bypass this barrier and travel directly into the brain. Among them are drugs for migraine headaches. Until now, however, nobody knew if methotrexate might do the same.

The scientists tested methotrexate nose drops on laboratory rats with brain cancer. Compared to cancer treated with an injectable form of the drug, the nose drop drug reduced the weight of tumors by almost one-third, the scientists said. "The strategy to utilize the nose-brain direct transport can be applicable to a new therapeutic system not only for brain tumors but also for other central nervous system disorders such as neurodegenerative diseases," the article noted.

New hope has arrived for migraine sufferers following a Griffith University study with the people of Norfolk Island.

Led by Professor Lyn Griffiths from the University's Griffith Health Institute, the team has identified a new region on the X chromosome as playing a role in migraine.

The research provides compelling evidence for a new migraine susceptibility gene involved in migraine. The study also indicated that there may be more than one X chromosomal gene involved and implicated a gene involved in iron regulation in the brain.

All females have two X chromosomes whilst males have an X and a Y chromosome.

"These results provide more support for the role of the X chromosome in migraine and may explain why so many more females suffer from the disorder," said Professor Griffiths.

Tracking down and identifying the various genes that cause migraine is very important as it provides insights to allow us to develop better means of diagnosis and more targeted treatments.

"Currently, 12 per cent of the population suffers from migraine. Even though we have some very good treatments for this very debilitating disease, they certainly don't work for everyone and can have some adverse side effects. Hence there is a real need to develop new migraine treatments."

This National Health and Medical Research Council funded work involved a unique population study of the remote Norfolk Island where 80 per cent of inhabitants are able to trace their ancestry back to the famous historical event, The Mutiny on the Bounty.

"This population was used due to its unusual pedigree structure in which genetic relationships can be traced through genealogical data to the island's original founders, and also the high incidence of migraine sufferers in this population. It's very useful for gene mapping purposes because of the reduced genetic and environmental diversity," said Professor Griffiths.

A comprehensive chromosome analysis of around 300 Norfolk participants from a large multigenerational Norfolk family, including many who are affected by migraine, was conducted using DNA samples obtained from the islanders.

A study of mothers and their young babies by neurologists at the University of California, San Francisco (UCSF) has shown that mothers who suffer migraine headaches are more than twice as likely to have babies with colic than mothers without a history of migraines.

The work raises the question of whether colic may be an early symptom of migraine and therefore whether reducing stimulation may help just as reducing light and noise can alleviate migraine pain. That is significant because excessive crying is one of the most common triggers for shaken baby syndrome, which can cause death, brain damage and severe disability.

"If we can understand what is making the babies cry, we may be able to protect them from this very dangerous outcome," said Amy Gelfand, MD, a child neurologist with the Headache Center at UCSF who will present the findings at the American Academy of Neurology's 64th Annual Meeting, which takes place in New Orleans in April.

Colic, or excessive crying in an otherwise healthy infant, has long been associated with gastrointestinal problems — presumably caused by something the baby ate. However, despite more than 50 years of research, no definitive link has been proven between infant colic and gastrointestinal problems. Babies who are fed solely breast milk are as likely to have colic as those fed formula, and giving colicky babies medication for gas does not help.

"We've known about colic for a really long time," Gelfand said, "but despite this fact, no one really knows why these babies are crying."

How the Study was Conducted

In the UCSF study, Gelfand and her colleagues surveyed 154 new mothers bringing their infants to the pediatrician for routine check ups at two months, the age when colicky crying typically peaks. The mothers were surveyed about their babies' crying patterns and their own history of migraine, and those responses were analyzed to make sure the reported crying did indeed fit the clinical definition of colic.

Mothers who suffered migraines were found to be two-and-a-half times more likely to have colicky babies. Overall, 29 percent of infants whose mothers had migraines had colic compared to 11 percent of babies whose mothers did not have migraines.

Gelfand and her colleagues believe colic may be an early manifestation of a set of conditions known as childhood periodic syndromes, believed to be precursors to migraine headaches later in life.

Babies with colic may be more sensitive to stimuli in their environment just as are migraine sufferers. They may have more difficulty coping with the onslaught of new stimuli after birth as they are thrust from the dark, warm, muffled life inside the womb into a world that is bright, cold, noisy and filled with touchy hands and bouncy knees.

The UCSF team next plans to study a group of colicky babies over the course of their childhood to see if they develop other childhood periodic syndromes, such as abdominal migraine.

The presentation "Infant Colic is Associated with Maternal Migraine" by Amy Gelfand, Katherine Thomas, and Peter Goadsby will be made on April 25 in New Orleans.

A migraine is the most common type of headache that propels patients to seek care from their doctors. Roughly 30 million Americans suffer from migraine headaches, with women affected almost three times more often than men, according to statistics from the National Headache Foundation in Chicago.

"Hormonal changes are a big contributor to the higher female incidence," said Michael A. Moskowitz, MD, Professor of Neurology at Harvard Medical School at the Massachusetts General Hospital in Boston. "There are lines of evidence that support this from lab to clinical evidence and a decrease (although not abolished) incidence in post-menopausal females."

Migraine headaches can vary from person to person, but they typically last from four hours up to 72 hours. Some people get them several times per month, while others experience them much less frequently. Many migraine sufferers report throbbing or pulsating pain on one side of the head, blurred vision, sensitivity to light and sound, nausea, and vomiting. Roughly one in five migraine sufferers experience an aura, or visual or sensory disturbance, before the onset of the headache. Examples of an aura include: flashes of light, loss of vision, zig-zag lines, pins and needles in an arm or leg, and speech and language problems.

Several risk factors have been identified that increase a person's chance of having migraines:

• Family history: A significant majority of migraine sufferers have a family history of migraine attacks. For a person who has one or more first-degree relatives with migraine headaches, the likelihood rises substantially.

• Age: Migraines typically affect people between the ages of 15-55. Most people have had their first attack by 40 years old.

• Gender: Women are more likely to suffer from migraines than men.

• Certain medical conditions: depression, anxiety, stroke, epilepsy, and high blood pressure are all associated with migraine headaches.

• Hormonal changes: Women who suffer from migraines often find that the headaches have a pattern of recurrence just before or shortly after the onset of menstruation. The headaches may also change during pregnancy and/or menopause.

Migraines are vascular headaches but the exact cause is not fully understood. Some researchers believe that migraines occur when there are abnormal changes in the brain. When these changes occur, inflammation causes blood vessels to swell and press on nerves, which can result in pain.

Researchers have learned that certain triggers can set off migraine attacks. These triggers vary from person to person and can include: sleep disturbances, stress, weather changes, low blood sugar, dehydration, bright lights and loud noises, hormonal changes, foods that contain aspartame, foods that contain tyramine (fava beans, aged cheeses, soy products, etc.), caffeine, and alcohol.

Unfortunately, migraines have no known cure, but they can be managed effectively with the help of a health care provider. A variety of drugs can be used for pain relief and for prevention. Lifestyle changes are often recommended to identify and eliminate possible triggers that can set off an attack.

"Until recently there have been no treatments available to treat people who suffer from chronic migraines," said Moskowitz. "Recently, a new medication has become available specifically to treat chronic migraine headaches, called onabotulinumtoxinA (Botox). Chronic migraine sufferers can derive significant benefit from this new form of therapy."

Chronic migraine sufferers have also found relief in certain vitamins and other homeopathic remedies. But patients should check with their doctors for proper treatment protocols.

Treating chronic migraines with behavioral approaches — such as relaxation training, hypnosis and biofeedback — can make financial sense compared to prescription-drug treatment, especially after a year or more, a new study found.

Longtime behavioral therapy researcher and practitioner Dr. Donald Penzien, University of Mississippi Medical Center professor of psychiatry, coauthored the study. He said the costs of prescription prophylactic drugs — the kind chronic migraine sufferers take every day to prevent onset — may not seem much even at several dollars a day.

"But those costs keep adding up with additional doctor visits and more prescriptions," Penzien said. "The cost of behavioral treatment is front-loaded. You go to a number of treatment sessions but then that's it. And the benefits last for years."

Published in the June issue of the journal Headache, the study compared the costs over time of several types of behavioral treatments with prescription-drug treatments. The research team included investigators from Wake Forest University, UMMC and the University of Mississippi.

The researchers found that after six months, the cost of minimal-contact behavioral treatment was competitive with pharmacologic treatments using drugs costing 50 cents or less a day. Minimal-contact treatment is when a patient sees a therapist a few times but largely practices the behavioral techniques at home, aided by literature or audio recordings.

After one year, the minimal-contact method was nearly $500 cheaper than pharmacologic treatment.

"We have a whole armamentarium of behavioral treatments and their efficacy has been proven. But headache sufferers are only getting a tip of these options," said Dr. Timothy Houle, associate professor of anesthesiology and neurology at Wake Forest University, and the study's principal investigator.

"One reason is people think behavioral treatment costs a lot. Now with this study, we know that the costs are actually comparable, if not cheaper, in the long run."

At a time when health-care costs are under national scrutiny, the study offers a framework for comparing costs that researchers can update and use for years to come.

"We thought, 'Wouldn't it be fun to model this and see how it comes out over time?'" Penzien said. "All the figures are there so if someone disagrees with it, they can plug in their own numbers."

The researchers didn't compare the effectiveness of methods, nor did they calculate the costs over time of individual drugs, since dosages and prices vary widely. Rather, they figured the per-day costs of each method based on fees of physicians and psychologists. For the physician group, they added in the cost of prescription beta-blocker drugs at various prices.

For instance, among the psychologists surveyed, one-on-one behavioral sessions cost between $70 and $250 for the intake visit and $65 and $200 for follow-up visits. That put the median intake cost at $175 and median follow-up cost at $125 for a median 10 visits.

The researchers calculated the median cost of pharmacologic approaches at $250 for the intake session and a professional fee of $140 per session. Median time to the first follow-up was 52.2 days, rising to 60 for the second with a median five visits per year.

To get information on behavioral treatments, the researchers surveyed members of the Behavioral Issues Group of the American Headache Society. For figures on pharmacologic treatments, the researchers surveyed a group of Headache Society-member physicians they knew treated substantial numbers of headache sufferers.

The most expensive behavioral treatment method — individual sessions with a psychologist in clinic — cost more than pharmacologic treatment with $6-a-day drugs in the first months. But at about five months, individual sessions become competitive. After a year, they are cheaper than all methods except treatment with drugs costing 50 cents or less a day.

Overall, group therapy and minimal-contact behavioral treatment were cost-competitive with even the cheapest medication treatment in the initial months. At one year, they become the least-expensive headache treatment choice.

Grant funding from the National Institute of Neurological Disorders and Stroke supported the research.

---

Journal Reference:

1. Allison M. Schafer, Jeanetta C. Rains, Donald B. Penzien, Leanne Groban, Todd A. Smitherman, Timothy T. Houle. Direct Costs of Preventive Headache Treatments: Comparison of Behavioral and Pharmacologic Approaches. Headache: The Journal of Head and Face Pain, 2011; 51 (6): 985 DOI: 10.1111/j.1526-4610.2011.01905.x

Familial hemiplegic migraine is a rare and severe subtype of migraine with aura, an unusual sensory experience preceding the migraine attack. Researchers from the San Raffaele Scientific Institute in Milan, and CNR Institute of Neuroscience in Pisa, Italy, have developed a mouse model of Familial Hemiplegic Migraine type 2 (FHM2) and used it to investigate the migraine's cause.

The study will be published June 23 in the open-access journal PLoS Genetics.

The researchers developed a knock-in animal model for FHM2 by inserting the W887R mutation of the ATP1A2 gene into the mouse genome. Mutations of this gene have previously been identified in patients as leading to a mutation of the α2 Na,K-ATPase protein with loss of function. As migraine is a complex phenotype, the research focused on a specific endophenotype that is functionally linked to migraine: cortical spreading depression (CSD). CSD is a wave of neuronal and glial depolarisation that progresses slowly across the cortex and frequently causes migraine aura.

The in vivo analysis of the FHM2 mouse model indicated an increased CSD susceptibility. This increase is a consequence of the accelerated degradation of the mutant protein by means of the cellular proteasome system, resulting in a decreased amount of functional α2 Na,K-ATPase protein. Since several lines of evidence involve a specific role of the α2 Na,K pump in active reuptake of glutamate from the synaptic cleft operated by glial cells, the authors hypothesize that CSD facilitation in the FHM2 mouse model is sustained by inefficient glutamate clearance by astrocytes and consequent increased cortical excitatory neurotransmission. The authors therefore propose that episodic disruptions of the excitation-inhibition balance underlie the vulnerability to "spontaneous" CSD ignition in both the rare form of FHM and, probably, at least a fraction of common migraine cases.

---

Journal Reference:

1. Loredana Leo, Lisa Gherardini, Virginia Barone, Maurizio De Fusco, Daniela Pietrobon, Tommaso Pizzorusso, Giorgio Casari. Increased Susceptibility to Cortical Spreading Depression in the Mouse Model of Familial Hemiplegic Migraine Type 2. PLoS Genetics, 2011; 7 (6): e1002129 DOI: 10.1371/journal.pgen.1002129

A recently published paper highlights that while the risk of post-traumatic stress disorder (PTSD) is more common in those with migraine than those without migraine irrespective of sex, the risk is greater in male migraineurs than female migraineurs.

Study details are now available in Headache: The Journal of Head and Face Pain, published by Wiley-Blackwell on behalf of the American Headache Society.

In this paper, lead author B. Lee Peterlin and colleagues review the epidemiology of PTSD and migraine, underscoring the established sex differences. While individually both migraine and PTSD are more common in women than men, a recent study by Peterlin and colleagues — the only study to date to look at sex differences in the PTSD-migraine association — suggests that men with migraines had up to a four-fold greater odds of PTSD than females who experience migraine headaches. This finding suggests that sex hormones play an important role in the PTSD-migraine association.

The age of the traumatic life event resulting in PTSD may also be an important factor for the sex differences in the PTSD-migraine association. When a traumatic life event occurs before 13 years of age, the risk of depression is greater than the risk of PTSD; however, when the traumatic life event occurs after 12 years of age, the risk of PTSD is greater.³⁷ Although the migraine population has a documented high prevalence of abuse, the peak age of vulnerability for childhood sexual abuse, is under 13 years of age. In contrast transportation accidents and combat, (two of the most common traumatic events reported by migraineurs with PTSD in one study), may be more commonly experienced by those older than 12 years of age. It is therefore possible that in the migraine population, sex differences in the type and age of traumatization contributes to the sex differences in the risk of PTSD.

Studies have also shown that the presence of PTSD in those with migraine is associated with greater headache-related disability than in migraine sufferers without PTSD. Dr. Peterlin explains, "The current data indicate that behavioral PTSD treatment alone can positively influence chronic pain conditions and disability. Therefore, physicians should consider screening migraine sufferers for PTSD, and men in particular. Further, in those migraineurs with PTSD, behavioral therapy should be considered, alone or in combination with pharmacological treatment." The authors suggest that further research investigating the sex differences in the association between PTSD and migraine is necessary to validate the sex differences found in their study, as well as to determine suitable treatment options in those migraineurs suffering with PTSD.

A second related article published this month in Headache also reviews sex and gender differences in those with headache. Todd Smitherman, PhD, from the University of Mississippi and Thomas Ward, MD, of the Dartmouth Medical School in New Hampshire reviewed extant medical literature to examine the psychosocial factors of gender and social role expectations, and coping strategies as they relate to sex and gender differences in headache pain.

A distinction was made in this paper between sex — the biologically-based indicators of male or female; and gender — "the traits and behaviors characteristic of and appropriate to members of each sexual category" (Unger, 1976) given that pain-related differences between men and women established in the medical literature cannot be reduced solely to biological determinants.

The authors suggest that women's pain experiences, multiple role responsibilities, and coping strategies likely influence the sex and gender differences in pain perception and response. "Gender-based differences are not strictly biological and important psychosocial issues are involved with headache pain as well," Dr. Smitherman concluded. "Further research of the impact of sex and gender on psychosocial variables may help clinicians tailor treatment plans that reduce pain and disability for headache patients."

---

Journal References:

1. B. Lee Peterlin, Satnam S. Nijjar, Gretchen E. Tietjen. Post-Traumatic Stress Disorder and Migraine: Epidemiology, Sex Differences, and Potential Mechanisms. Headache: The Journal of Head and Face Pain, 2011; DOI: 10.1111/j.1526-4610.2011.01907.x
2. Todd A. Smitherman, Thomas N. Ward. Psychosocial Factors of Relevance to Sex and Gender Studies in Headache. Headache: The Journal of Head and Face Pain, 2011; DOI: 10.1111/j.1526-4610.2011.01919.x

Headache is a very common complaint, with over 90% of all persons experiencing a headache at some time in their lives. Headaches commonly are tension-type (TTH) or migraine. They have high socioeconomic impact and can disturb most daily activities. Treatments range from pharmacologic to behavioral interventions. In a study published online in the Journal of Manipulative and Physiological Therapeutics, a group of Dutch researchers analyzed 119 randomized controlled clinical trials (RCTs) and determined the magnitude of placebo effect and no treatment effect on headache recovery rate.

"Although the intention of control and placebo interventions in research studies is to be relatively ineffective, the question rises as to what factors might cause improvement seen in these groups," commented corresponding investigator Arianne P. Verhagen, PhD, Assistant Professor, Department of General Practice, Erasmus Medical Center, Rotterdam, The Netherlands. "The aim of this study was to analyze the observed effects in the 'no treatment' and placebo control groups in clinical trials with TTH and migraine patients."

In the headache clinical trials studied, the "no treatment" and placebo groups had a high overall recovery rate of 36%. Control groups in pharmacological trials showed a higher response rate than the behavioral (non-pharmacological) trials (38.5% vs. 15.0%). Patients had higher recovery rates in the acute treatments compared with the prophylactic treatments (39.6% vs. 32.8%). Knowing that a substantial portion of patients improve without treatment is important when considering the benefits and risks of daily headache treatment.

Pharmacological treatment typically starts when non-pharmacological treatments like lifestyle changes, relaxation therapy, cognitive therapy, and reassurance do not work. Many of the prescribed or over-the-counter medications, such as non-steroidal anti-inflammatory drugs (NSAIDs), may lead to adverse events and medication overuse headache. Considering the risks of adverse events, the authors recommend that "the prescription of medication needs to be carefully considered and evaluated with each individual patient. Because of the recovery results in 'no treatment' control groups in pharmacological trials, the question rises whether or not this way of prescription is always preferable over no treatment (wait and see) especially in the TTH population."

---

Journal Reference:

1. Femke M. de Groot, Annieke Voogt-Bode, Jan Passchier, Marjolein Y. Berger, Bart W. Koes, Arianne P. Verhagen. Headache: the Placebo Effects in the Control Groups in Randomized Clinical Trials; an Analysis of Systematic Reviews. Journal of Manipulative and Physiological Therapeutics, 2011; DOI: 10.1016/j.jmpt.2011.04.007

Scientists at the University of Granada have confirmed that injecting a local anesthetic or botulinum toxin (botox) into certain points named "trigger points" of the pericraneal and neck muscles reduce migraine frequency among migraine sufferers. University of Granada researchers have identified the location of these trigger points -which activation results in migraine- and their relationship with the duration and severity of this condition.

Headache is a universal experience. At present, there are more than 100 different types of headache and one of the most recurring ones is migraine, which affects approximately 10-12% of the population, being three times more common in women than in men. When migraine becomes chronic -occurring more than 15 days a month-, it can disrupt patients' daily life in a great degree.

This research study is one of the three studies that have been conducted by Juan Miguel García Leiva -a researcher at the University of Granada Institute for Neuroscience "Federico Oloriz" — and coordinated by professor Elena Pita Calandre.

Trigger Points in Migraine Sufferers

In the first study, researchers examined a sample of healthy subjects and patients with a diagnosis of migraine -any frequency-, and analysed the presence of trigger points and their location, many of the explorations resulting in a migraine crisis. The most interesting findings of this study were: 95% of migraine sufferers have trigger points, while only 25% of healty subjects have them. The most common locations of trigger points are the anterior temporal and the suboccipital region, both billateral, of the head. Furthermore, researchers found a positive correlation among the number of trigger points in a patient, the number of monthly crises and the duration in years of the condition.

Subsequently, researchers conducted another study with 52 migraine sufferers (with migraine refractory to common pharmacological treatments). During three months, patients received a weekly subcutaneous injection of 1mL of a local anesthetic into their trigger points.

After the injection of the anesthetic, 18% of patients experienced a 50% or higher reduction in the frequency of migraine crises, as compared with the basal period. Additionally, an 11-49% reduction of frequency was observed in 38% of patients. Two thirds of the patients treated reported to feel "better or much better."

Few Side Effects

In the third study, 25 patients with chronic migraine were injected with 12.5 doses of botox into each trigger point twice, during a period of 3 months. Frequency (main variable), intensity and scales of migraine crises were recorded one month before and one month after the treatment to compare the changes experienced. In addition, side effects were also recorded during the experiment, and they were found to be mild and temporary.

After the injections, the most significant decrease in crisis frequency was observed at week 20. Similar results were obtained in those crises labelled as "moderate" and in the frequency of analgesic use by patients.

García Leiva specified that this treatment "is not a first-choice treatment for migraine sufferers, but it can only be applied in patients with chronic migraine who have tried several treatments with poor results, and who show peripheral sensitization of muscles. Recently, the Foods and Drugs Administration (USA) has approved botulinum toxin as a therapeutical drug for the treatment of chronic migraine.

---

Journal References:

1. E. P. Calandre, J. Hidalgo, J. M. Garcia-Leiva, F. Rico-Villademoros. Trigger point evaluation in migraine patients: an indication of peripheral sensitization linked to migraine predisposition?European Journal of Neurology, 2006; 13 (3): 244 DOI: 10.1111/j.1468-1331.2006.01181.x
2. Juan M. García-Leiva, Javier Hidalgo, Fernando Rico-Villademoros, Vicente Moreno, Elena P. Calandre. Effectiveness of Ropivacaine Trigger Points Inactivation in the Prophylactic Management of Patients with Severe Migraine. Pain Medicine, 2007; 8 (1): 65 DOI: 10.1111/j.1526-4637.2007.00251.x
3. Hidalgo J, Rodríguez-López CM, García-Leiva JM, Rico-Villademoros F, Calandre EP. Effectiviness botulinum toxin type A in the prophylaxis of severe and treatment–refractory migraine. Journal of Headache and Pain, 2006; 7 (S-1): S-18 [link]