U.S. adults who reported a history of migraine or severe headache were 25% more likely to develop hypertension compared with those with no migraine history, with a higher risk for women vs. men, researchers reported.
“Elevated blood pressure is more frequently detected in patients with headaches during admission to the emergency department than in those without headaches,” Jing Zhang, MBBS, PhD, of the department of cardiology at the First Affiliated Hospital of Nanjing Medical University, China, and colleagues wrote in the study background. “Migraineurs also tend to have a higher risk of cardio-cerebrovascular diseases. In addition, several BP-lowering drugs, including beta-blockers, ACE inhibitors and angiotensin II receptor blockers, have been demonstrated to be effective in the prophylactic treatment of migraine. Collectively, these findings provide a rationale for elucidating the association between migraine and hypertension.”
U.S. adults who reported a history of migraine or severe headache were 25% more likely to develop hypertension vs. those with no migraine history, with a higher risk for women vs. men. Data were derived from Zhang J, et al. Nutr Metab Cardiovasc Dis. 2022;doi:10.1016/j.numecd.2022.11.014.
In a cross-sectional study, Zhang and colleagues analyzed data from 5,716 adults who completed the National Health and Nutrition Examination Survey between 1999 and 2004. Self-reported migraine was identified from yes/no responses to the question, “Has a doctor ever said that you suffer or have suffered from migraine or severe headache?” Researchers assessed the association between migraines, severe headaches and hypertension.
Within the cohort, 19.8% of respondents reported migraine or severe headaches. Participants with migraine were predominantly younger women and had a higher BMI, lower education level and lower dietary intake of potassium and calcium compared with participants without migraine. Those reporting migraines also had lower serum levels of total cholesterol, creatinine and hemoglobin, as well as a higher estimated glomerular filtration rate (P for all < .05).
After adjustment for potential confounders, a history of migraine or severe headaches was positively associated with hypertension (OR = 1.25; 95% CI, 1.03-1.53).
In subgroup analyses, positive associations between migraine or severe headache and hypertension were detected in women (OR = 1.39; 95% CI, 1.07-1.82), those with a lower BMI, defined as 25 kg/m2 or less (OR = 1.51; 95% CI, 1.09-2.08) and those without diabetes (OR = 1.27; 95% CI, 1.05-1.55). However, there was no statistically significant association among migraine, severe headache and hypertension across all subgroup characteristics.
The researchers noted that the association of migraine with hypertension may differ between patients with or without aura and between patients with different headache frequencies.
“Further prospective and mechanistic studies are needed to elucidate the causality of these associations,” the researchers wrote.
Acetaminophen (Paracetamol) and non-steroidal anti-inflammatory drugs (NSAID) like Ibuprofen have been shown to effectively relieve migraine pain. The commonly used dosage of these drugs to treat migraine are as follows:
In children and teenagers, Ibuprofen and Acetaminophen can be administered. For children aged 12 years and above, Acetaminophen also in combination with Metoclopramide can be used.[1]
Ibuprofen:
It is rapidly absorbed by the gastrointestinal tract
Rapid onset of action
In comparison to the tablet formulation, the solubilised liquid-containing capsules show a faster onset of action and a superior response rate for headache relief at 1 hour.
Short half-life (2 hours) and thus multiple doses are required.
Higher doses are not more effective than the standard 400-mg dose.
For acute migraine headaches, Paracetamol 1000 mg alone is helpful, and the addition of 10 mg Metoclopramide provides short-term efficacy.
Acetaminophen causes fewer gastric side effects
Does not affect platelet function
Short half-life of 2-3 hours and thus multiple doses are required.
To minimise hepatotoxic side effects, the total daily dose should not exceed 4000 mg.
Acetaminophen can also be used with other medications. When given in comparable doses, the combination of Aspirin, Paracetamol, and caffeine has been shown to be more effective. To avoid the medication-overuse headache, Acetaminophen or NSAIDs should be used for not more than 14 days per month when used alone; the use of a combination of these drugs should be limited to 10 days a month.
Sleep is vital for you to function at your best and give your body and brain a chance to rest. Unfortunately, over half of all migraines occur between 4:00 and 9:00 a.m. Not only can a lack of sleep trigger a migraine, but a migraine can also interfere with your ability to sleep, creating a vicious cycle. Try to create a calm environment before bed and get at least seven or eight hours of sleep a night to head off migraines in future.
Uncontrolled Stress
2/10
Almost 70% of people with migraines report stress as a trigger. Although it can be difficult to avoid stress with the hectic pace of life today, try keeping track of situations that cause you stress and lead to migraines. If you can’t avoid stressful people and situations, focus on relaxation methods such as meditation and deep breathing.
A Sedentary Lifestyle
3/10
Exercise causes your body to release substances that block pain and decrease anxiety and depression. It also helps you maintain a healthy weight, which can help reduce migraines. Start off slowly, though, since vigorous exercise can cause a migraine if you aren’t used to it.
Eating the Wrong Foods
4/10
Keeping a migraine diary that includes what you ate before a migraine is the best way to identify what foods trigger your migraines. While everyone is different, many people report that the following foods trigger their migraines:
Chocolate
Cheese and other dairy products
Caffeine
Cured meat
Artificial sweeteners
Foods that contain MSG or histamine
Not Eating Regularly
5/10
Just as eating the wrong foods can cause a migraine, not eating regularly can, too. Fasting increases your risk of a migraine. Eat breakfast early and try to keep a regular schedule for meals. Eating too late in the day can interfere with your sleep, so have dinner several hours before bed.
Drinking Too Much Alcohol
6/10
Red wine is the most commonly reported alcohol trigger, but other types of alcoholic beverage are also associated with migraines. Drinking alcohol can trigger a migraine within a few hours, or you may have a delayed hangover headache. Although you can drink alcohol in moderation if it doesn’t affect you, avoid it completely if it triggers your headaches.
Overscheduling
7/10
Trying to cram too much into your day sets you up for migraines in several ways. Running around from one activity to another is stressful and doesn’t allow you time to relax. At the end of a stressful day, it can be hard to get a good night’s sleep. Try to simplify your life as much as possible so you have plenty of downtime to take care of yourself.
Being Unprepared for the Weather
8/10
Common weather-related migraine triggers include storms, heat, and changes in barometric pressure. You can’t control the weather, of course, but staying inside during storms or the hottest part of the day can help you avoid triggering a migraine.
Not Drinking Enough Water
9/10
About one-third of those who deal with migraines report dehydration as a trigger. Make it a habit to carry a water bottle with you and stay hydrated. At the first sign of a migraine, drink a glass of water to try to head it off.
Taking Too Much Medication
10/10
If your doctor has prescribed medicine for acute headaches, taking it more than 10 times per month can trigger rebound headaches. These are called medication overuse headaches. Talk to your doctor to find out what else you can do to control your migraines so that you don’t need to take the medicine so often.
While the exact mechanisms behind migraines remain unclear, a number of different hypotheses have been raised. It appears to be a disorder of your central nervous system. Mitochondrial dysfunction also appears to be part of the puzzle
The influence of neurotransmitters may also play a role, as may nutritional deficiencies. Studies have identified several nutritional deficiencies that significantly raise your risk of migraines, including riboflavin (vitamin B2) deficiency
Riboflavin has been shown to ameliorate hallmarks of migraine, including oxidative stress, mitochondrial dysfunction, neuroinflammation, homocysteine neurotoxicity and glutamate excitotoxicity
Foods rich in riboflavin include spinach, beet greens, crimini and portabella mushrooms, pastured eggs, asparagus, almonds, organic turkey, grass fed beef liver and beef tenderloin
In one study, 400 milligrams of riboflavin per day reduced migraine frequency by 50%, from four days a month to two days a month, after three months of use.
Migraine affects an estimated 1 billion people worldwide, and is the third most common disease globally.1 In the U.S., self-reported migraine and severe headache affects 1 in 62 Women are up to three times more likely to suffer with migraines than men, likely due to hormone fluctuations.3
Despite its high prevalence, decades of research have failed to pin down the exact mechanisms behind the attacks — most of which tend to recur once or twice a month.4 The pain, which often occurs on one side of the head only, can be moderate to severe in intensity.
Along with throbbing, piercing or “burning” pain, other common symptoms include nausea, visual disturbances, dizziness, numbness in your extremities or face, and extreme sensitivity to light, sound, smell and touch.5 Attacks typically last from four hours to three days,6 often requiring bed rest in complete darkness and silence.
Reigning Migraine Hypotheses
While the exact mechanisms remain unclear, a number of different hypotheses have been raised. Over the last decade or two, researchers have started leaning toward migraine being a disorder of your central nervous system, most likely originating in your brain stem.7,8,9,10 While most brain regions do not register or transmit pain signals, the trigeminal nerve network does.
Pain is relayed through the trigeminal network to an area in your brain stem called the trigeminal nucleus. From there, it is conveyed to the sensory cortex in your brain that is involved in awareness of pain and other senses. As explained by Migrainedisorders.com:11
“[P]eople with migraine illness have a nervous system that is not working normally. It overreacts … when stimulated, there is an unusual wave of brain activity that leads to a headache.
Almost all migraine sufferers have a problem with a specific part of the nervous system, called the trigeminal nerve. The trigeminal nerve is a network of wiring that attaches to special sensors.
When stimulated, they send electrical signals to the brainstem with connections to nerves of the cortex and its covering, the dura. Normally this system allows us know what is going on in the world. When the system does not work properly, electrical signals set off a slowly moving wave of electrochemical activity across the surface of the brain.
People with migraine start to experience odd sensations, such as white sparks in an eye (a misfiring of the ocular nerve) followed by an intense pain in some part of the head and concluding with a long period of nausea (activation of the gastrointestinal system) and exhaustion (general inflammation and swelling of the cortex).”
The initial activation of your trigeminal nerve is thought to be triggered by a variety of internal and external stimuli, ranging from stress, hormone fluctuations and irregular sleep to a variety of foods, flashing lights, noise and weather changes.12
Still, migraines can sometimes occur even in the absence of an apparent trigger, suggesting we still don’t have a complete picture of the phenomenon. Mitochondrial dysfunction also appears to be part of the puzzle. As noted in one 2013 paper:13
“Abnormal [mitochondrial] function translates into high intracellular penetration of Ca(2+), excessive production of free radicals, and deficient oxidative phosphorylation, which ultimately causes energy failure in neurons and astrocytes, thus triggering migraine mechanisms.”
The influence of neurotransmitters such as calcitonin gene-related peptide (CGRP)14,15 may also play a role, as may nutritional deficiencies. At the very least, studies have identified nutritional deficiencies that significantly raise your risk of migraines. Among them is riboflavin (vitamin B2).
Riboflavin Deficiency Linked to Migraine
A paper,16 published in Frontiers in Neurology in 2017 looked at riboflavin’s influence on migraine and Parkinson’s disease, highlighting its neuroprotective potential.
According to this paper, “riboflavin ameliorates oxidative stress, mitochondrial dysfunction, neuroinflammation and glutamate excitotoxicity; all of which take part in the pathogenesis of PD, migraine headache and other neurological disorders.”
Here, the authors link migraine pain to neurovascular dysfunction, inflammation and “dysfunction in cranial vascular contractility,” and cite research showing people who have migraine with aura have lower levels of antioxidants and higher levels of oxidative stress than migraine-free controls.
They’ve also been shown to have higher levels of mitochondrial dysfunction, and at least two polymorphisms in mitochondrial DNA have been shown to heighten migraine susceptibility. The authors also note that:17
“[C]ommon triggers of migraine have the ability to generate oxidative stress; mechanisms include mitochondrial dysfunction, calcium excitotoxicity, activation of microglia, activation of NADPH oxidase, and as a byproduct of MAO (monoamine oxidase), cytochrome P450, or NO synthase. Collectively, it is indicated that oxidative stress is an important hallmark of migraine disease.”
Riboflavin may help by ameliorating many of the hallmarks of migraine, including oxidative stress, mitochondrial dysfunction, neuroinflammation, homocysteine neurotoxicity and glutamate excitotoxicity, as shown below.18
The paper goes into some detail, explaining the biochemical influence of riboflavin on all of these, so for a more comprehensive understanding, I’d suggest reading through the original paper.
In conclusion, the authors of this Frontiers in Neurology paper note that:19
“Riboflavin has demonstrated its ability to tackle significant pathogenesis-related mechanisms in neurological disorders, exemplified by the ones attributed to the pathogenesis of … migraine … In addition, riboflavin is required for pyridoxine activation.
Riboflavin and PLP, the active form of pyridoxine, play essential roles in homocysteine metabolism, and tryptophan-kynurenine pathway. Indeed, any accumulation of homocysteine or kynurenines due to vitamin insufficiency can lead to significant neurological consequences.
Taking into consideration the limited riboflavin absorption and utilization in 10–15% of global population, long term riboflavin insufficiency could participate in the development of multiple neurological disorders, emphasizing the importance of long-term riboflavin-sufficient diet especially in vulnerable populations.”
Since riboflavin is a water-soluble B vitamin, you need to get a consistent supply from your diet. Foods rich in riboflavin include:20
Identifying Riboflavin Deficiency, and Dosing Suggestions
While riboflavin deficiency is thought to be rare in the U.S., older adults, women on birth control pills, alcoholics, pregnant and lactating women, vegans and those with liver disorders are at increased risk for deficiency.21 Common signs and symptoms of deficiency include:22
Fatigue
Swollen throat
Blurred vision
Depression
Itchy or cracking skin
Dermatitis around the mouth
Liver degeneration
Hair loss
Reproductive problems
Urine analysis can identify a riboflavin deficiency. As a general rule, deficiency is said to be present if your urinary riboflavin is below 40 micrograms per day.23 The recommended daily intake is 1.3 milligrams for adult men, 1.1 mg for adult women, 1.3 mg for male adolescents (14 to 18 years of age) and 1.0 mg for female adolescents.24
If you struggle with migraines, however, you may need far higher doses. As noted in a study published in the European Journal of Neurology in 2004, researchers found 400 mg of riboflavin per day reduced migraine frequency by 50%, from four days a month to two days a month, after three months of use. The duration and intensity remained largely unaffected, however.25
Other Vitamin Deficiencies Implicated in Migraines
Aside from riboflavin, other nutrients deficiencies that have been implicated in migraines include:
• Vitamins B6, B12 and folic acid — One 2009 study26 evaluated the effect of 2 mg of folic acid, 25 mg vitamin B6 and 400 mcg of vitamin B12 in 52 patients diagnosed with migraine with aura. Compared to the placebo group, those receiving these supplements experienced a 50% reduction in the prevalence of migraine disability (from 60% to 30%) over a six-month period.
• Magnesium — Magnesium has also been shown to play an important role in the prevention and treatment of migraines, and migraine sufferers are more likely to suffer from magnesium deficiency than non-migraineurs.27
Since magnesium administration is both easy and safe, researchers have noted that empiric treatment with a magnesium supplement is justified for all migraine sufferers.28 As a prophylactic, be prepared to boost your magnesium intake for at least three months to experience results, ideally in combination with CoQ10.
In many cases, receiving a high dose of magnesium can also abort an attack in progress. The most effective way to administer magnesium for migraine would be to get an intravenous (IV) infusion. I used to regularly administer magnesium IVs for those with acute migraines and it seemed to work for most patients to abort the headache.
Barring that option, magnesium threonate may be your best option for an oral supplement. It has superior absorbability compared to other forms of magnesium, and since its ability to cross the blood-brain barrier makes it more likely to have a beneficial effect on your brain.
Foods rich in magnesium29 include: almonds and cashews, boiled spinach, peanut butter, avocado, potato, brown rice, banana, wild Alaskan salmon and yogurt made from organic grass fed milk with no added sugars, just to name a few.
• Coenzyme Q10 (CoQ10) — A migraine study30,31,32 presented at the annual American Headache Society meeting in 2016, which involved 7,420 children, teens and young adults, found 51% had low levels of CoQ10, 31% had low vitamin D status and 16% had low levels of riboflavin.
Those suffering from chronic migraines were overall more likely to have CoQ10 and riboflavin deficiency compared to those with episodic migraines. While the final study results do not appear to have been published yet, other research have found similar links.
For example, a 2015 study33 in The Journal of Headache and Pain found supplementation with a proprietary combination of magnesium, riboflavin and CoQ10 for three months lowered migraine frequency from 6.2 days at baseline to 4.4 days at three months. Pain intensity was also significantly reduced. Foods rich in CoQ1034 include: grass fed beef, herring, organic pastured chicken, sesame seeds, broccoli and cauliflower.
• Vitamin D — While many studies appear to refute a link between low vitamin D and migraine, there have been some showing vitamin D may play a role. For example, migraine research using vitamin D supplementation has demonstrated a reduction in C-reactive protein (a marker for inflammation) and a statistically significant reduction in migraine frequency.35
Another study36 by Finnish researchers, while not focused on migraines specifically, found men with the lowest vitamin D levels had 113% higher odds for frequent headaches than those with the highest levels. Overall, the lower the men’s blood level of vitamin D, the more frequent their headaches.
A 2013 study37 looking at the relationship between vitamin D levels and migraine found a weak but positive relationship in terms of frequency, but not in terms of severity. The best way to optimize your vitamin D level is through regular sun exposure. If taking an oral supplement, be sure to use vitamin D3 (not D2), along with magnesium, vitamin K2 and calcium.
Migraine Prevention 101
When it comes to migraines, your best bet is to take preventive action, as treating migraines acutely is very difficult. Migraine medications often do not work, and can have serious side effects.38
Your first step would be to identify and avoid potential triggers. While there are many (and what triggers a migraine for one might not trigger it in another), the list below includes some of the most common culprits. Keeping a journal where you record and track suspected triggers can help you determine any correlations.
Food and drink — Especially wheat and gluten, dairy, cane sugar, yeast, corn, citrus, eggs, artificial preservatives or chemical additives, cured or processed meats, alcohol (especially red wine and beer), aspartame, caffeine and MSG.39
Allergies — Including food allergies,40 food sensitivities and chemical sensitivities. Research41 published in the journal Lancet back in 1979 showed migraineurs with food antigen immunoreactivity experienced profound relief when put on an elimination diet. Another randomized, double-blind crossover study42 published in 2010 found that a six-week-long diet restriction produced a statistically significant reduction in migraines in those diagnosed with migraine without aura. If you suspect you might have a food allergy, I suggest doing a diet elimination challenge to see if your symptoms improve. Keep in mind that depending on your typical migraine frequency, you may need to avoid the suspected food for a few weeks in order to evaluate whether it had an effect or not. To confirm the results, reintroduce the food or drink on an empty stomach. If the suspected food is the culprit, you will generally be able to feel the symptoms return within an hour, although migraines can sometimes have a longer lag time than, say, bloating or drowsiness.
Hormones — Some women experience migraines before or during their periods, during pregnancy or during menopause. Others may get migraines from hormonal medications like birth control pills or hormone replacement therapy.
Light, noise and smells — Bright lights, fluorescent lights, loud noises and strong smells (even pleasant ones) can trigger and/or exacerbate a migraine. A study43,44 from Harvard Medical School found even blind migraine sufferers who still had melanopsin receptors were sensitive to light. Blue light in particular can be problematic. Many digital devices and LED light sources emit mostly blue light. Research has found that this light increases migraine pain and activates your trigeminal nerve, associated with the pain of migraines.45 Meanwhile, green light may help ease migraine pain and photosensitivity.46,47 At this time there are no lightbulbs or sunglasses that increase your exposure to pure wavelength green light that are cost effective. However, there are orange or red-tinted glasses that will block blue light, which may be helpful. You may also consider eliminating your exposure to your digital devices while you’re in the middle of a migraine.
Changes in sleep cycle — This includes both missing sleep and oversleeping.
Stress — Any kind of stress or emotional trauma can trigger a migraine, even after the stress has passed.
Dehydration and/or hunger — Skipping meals or fasting are also common triggers.
Physical overexertion — Extremely intense exercise, and even sex, has been known to bring on migraines.
“If I can cure your migraine, I’m going to get the Nobel Prize—that is how big that is”, says Allan Purdy, Professor of Neurology at Dalhousie University (Halifax, NS, Canada). Purdy is one of many headache experts who feature in the documentary Out of my Head, written and directed by Susanna Styron, who was compelled to make a film about migraine for and with her daughter Emma. “Who I am when I am having a migraine is different”, Emma says, feeling “betrayed by [her] body” as her migraine manifests as partial blindness. Reading from her treatise on migraine, In Bed, journalist and author Joan Didion’s explains how she becomes insensible to the world around her: this is “not just a headache [but] something that would totally brutalise you”. Joining Didion in the film, a group of individuals talk openly about stigma, misconception, isolation, and intense pain that can accompany migraine.
This film couldn’t be any more personal, articulate, and informative, but can it hit its target of changing cultural and social attitudes so that migraine is taken more seriously? Ultimately, without experiencing a migraine oneself, can one really get inside the head of someone who is?
“Migraine is a neurological disorder, not a terrible, disabling headache”, David Dodick from the Mayo Clinic (Arizona, USA) tells the viewer. In fact, headache, or the accompanying pain, is just one clinical manifestation deriving from a sensory processing disturbance affecting the nervous system. Migraine will often start with a sensory warning—the feeling is unique to each person, perhaps hypersensitivity to smell, sound, or light. Didion says she feels a flush of blood into the cerebral arteries.
“There are days I don’t see anything except for shapes”, says Billie who lost her health insurance when she lost her job because of migraine. Auras of this type are experienced by almost a third of people with migraine (and can be experienced without pain); aphasia, or a dysphasic language dysfunction, is also a common example of migraine aura, and a clip of newsreader Serene Branson’s incoherent, and infamous, live broadcast in 2011 as she has an on-air migraine attack is unwittingly a perfect demonstration of the phenomenon.
To explore the burden of migraine, Out of my Head uses production techniques to weave a visual tapestry of narrative to complement personal and professional testimonies. Some scenes are played out in animation or explained in infographics, a collection of drawings evoke a language of pain, and conventional but uniformly understood film clips of storm-filled skies and lightning bolts all work together to illustrate the debilitating effects of migraine. At times, distortions and contortions of the film’s images and sounds act as visual and sonic metaphors for the turmoil—for example, vision impaired by a “spinning kaleidoscope”—that a migraine wreaks on everyday life.
These production effects add to the tension in the film, reflecting and articulating a struggle to vocalise pain, something so subjective that it can reinforce a stigma, accompanied by a lack of empathy, and even ridicule from family, peers, employers, and teachers.
Out of my Head is ambitious. It wants to help the viewer to understand this complex disorder. Stigmatisation is an ongoing challenge for those whose lives are seriously impeded by migraine and for the future of migraine research. To emphasise this point, the documentary features a raft of people, some well known public figures, who are different demographically—the disorder does not discriminate, but they face discrimination because migraine is so misunderstood. Cultural representations in television or advertising reveal an ingrained stereotype of migraine misery: white middle-class women lying down with their arm raised across their face, hand pressed against their head, indicating nervous temperament rather than pathophysiological illness, and suggesting that migraine is more of a so-called lifestyle disorder than a neurological one.
The documentary also explores a rarely talked about creative, spiritual element of migraine: “Athena is born out of Zeus’s head…[suggesting] the idea of knowledge being born from pain”, Emma explains. The viewer learns of Hildegard of Bingen’s visions, her spiritual epiphany now speculated to be a migraine state. The viewer is also reminded of Lewis Carroll’s Alice in Wonderland; the many hallucinations, moments of aphasia, and falling down a hole possibly inspired by his migraine aura.
It is speculated that migraines might have influenced many a masterpiece, including artist Georgia O’Keeffe’s paintings of her headaches and the Declaration of Independence, written by Thomas Jefferson after six weeks of headaches. Highly revered Indian choreographer Shiamak Davar says that migraine has made his work better, although he does acknowledge that this hasn’t happened for everyone: “I don’t want to glamorise it”, he says. And indeed, there is nothing glamorous about wanting to bang your head against a wall, or being barely able to stand inhabiting in your own body, or to have what is known as “compassion fatigue” because your partner has gone into a dark room for days again. The whole family is affected by migraine. Styron knows that. So does Isiah Lineberry, who turned to activism to help people like his wife Sheila who was overwhelmed by a fear of dying from her migraine attacks.
A study for the first time has revealed a possible association between migraines and carpal tunnel syndrome (CTS), with migraines more than twice as prevalent in patients with CTS as in those without.
“The association of these two distinct disease processes is a fascinating connection that needs to be explored further,” study investigator Douglas M. Sammer, MD, chief of the Hand and Upper Extremities Division, Department of Plastic Surgery, University of Texas Southwestern Medical Center at Dallas, said in a statement.
“This association suggests the possibility, although not demonstrated in this study, of a common systemic or neurologic risk factor,” the authors write. In addition, migraine headache may be an early warning sign of increased risk for future CTS, they say.
The study was published online in Plastic and Reconstructive Surgery.
In a cross-sectional analysis of 25,880 adults who responded to the 2010 National Health Interview Survey, 952 (3.7%) had CTS and 4212 (16.3%) had migraine headache.
A case of CTS was defined as a respondent who answered “yes” to two questions: “Have you ever been told by a doctor or other health professional that you have a condition affecting the wrist and hand called carpal tunnel syndrome?” and “During the past 12 months have you had carpal tunnel syndrome?”
A case of migraine was defined as a respondent who answered “yes” to the question, “During the past 3 months, did you have severe headache or migraine?”
The study team found that migraine prevalence was higher in those with than without CTS (34% vs 16%; adjusted odds ratio [aOR], 2.60; 95% confidence interval [CI], 2.16 – 3.13).
CTS prevalence was also higher in persons with than without migraine headache (8% vs 3%; aOR, 2.67; 95% CI, 2.22 – 3.22).
CTS was associated with older age, female sex, obesity, diabetes, and smoking. Migraine headache was associated with younger age, female sex, obesity, diabetes, and smoking.
“Although we have theories, at this time we simply don’t know why people with carpal tunnel syndrome are more likely to have migraines, and vice versa,” Dr Sammer said. “A deeper understanding of how and why this connection exists may lead to earlier diagnosis or even the ability to implement preventive measures,” he added.
Unlike CTS, migraine has not historically been considered a compression neuropathy, the researchers note in their article. However, some recent evidence suggests that some migraine headaches may be associated with nerve compression around the head and neck and that some migraines may be successfully treated by targeted peripheral nerve decompression, they note.
“Based on the findings of this study and prior studies, it may be worthwhile in patients with migraine to perform an examination for peripheral nerve compression in the head and neck,” the authors suggest.
A key limitation of the study, say the researchers, is that the survey question for migraine headache was worded “migraine or severe headache.” This lack of specificity may have led to a number of false-positive respondents without true migraine headaches, they point out.
Another limitation is the fact that this was a survey-based study and did not consist of patients with CTS or migraine headache diagnoses confirmed by a medical professional.
Experts Weigh In, Urge Caution
Reached for comment, Matthew S. Robbins, MD, director, Inpatient Services, Montefiore Headache Center, chief of neurology, Einstein Division, Montefiore Medical Center, Bronx, New York, told Medscape Medical News that the study is “interesting and does address this connection for the first time.”
“From my own clinical practice, I do believe in the study results reported,” Dr Robbins said. “However, the emphasis on peripheral nerve compression as a cause or major factor for migraine is highly disputed, and most of us who diagnose, treat, and study patients with migraine regularly know that migraine is a problem of the brain.”
He added, “The labeling of the disorder as ‘migraine headache’ rather than ‘migraine’ also reflects a lack of emphasis on this point, as migraine features so many other symptoms aside from headache, as any patient would describe. Migraine is a disorder where there is an inherited sensitivity of the nervous system, and with time there is sensitization of broader pain pathways that elevate the risk of experiencing other pain conditions. That is why migraine is associated not just with carpal tunnel syndrome but low back pain, fibromyalgia, temporomandibular dysfunction, and other pain conditions — the list is long.”
Dr Robbins agrees that the methods for defining migraine in this study were “not ideal, [but] the authors took advantage of a large, established national database with immense power, so within the study mechanism this is a limitation to concede. However, it is likely that the question does capture many of those with active migraine.”
But Stephen Silberstein, MD, director of the Headache Center at Thomas Jefferson University, Philadelphia, Pennsylvania, has major concerns about the methods. The “crucial fundamental flaw” is defining migraine as having severe headache or migraine in the last 3 months.
“The only way to show an association is lifetime prevalence of migraine as opposed to any headache in the last 3 months, so the criteria questions they used are not adequate,” he told Medscape Medical News.
Levels of the inflammatory marker C-reactive protein (CRP) are significantly elevated in young adults with migraine, which may not only offer insights into the pathogenesis of the condition but also point to novel therapeutic avenues, researchers say.
Delegates here at the American Headache Society (AHS) 58th Annual Scientific Meeting heard that levels of the protein, as measured on high-sensitivity CRP (hsCRP) assay, were higher by 11% in people with migraine compared with those in unaffected individuals, rising to 17% among women.
Gretchen Tietjen, MD, professor and chair of neurology and director of UTMC Headache Treatment and Research Program, University of Toledo, Ohio, and colleagues say the study findings show “a positive association between migraine diagnosis and elevated hsCRP, with a significant effect size,” particularly in young women.
Conflicting Results
Although there has been a great deal of interest in potential association between markers of inflammation and migraine, the evidence linking increased CRP levels with the condition is limited, and there have been conflicting results from population-based studies. However, it is notable that those studies were conducted in different age groups from that in the current analysis.
The researchers therefore examined data on 9269 adults aged 24 to 32 years taking part in Wave 4 of the Add Health Study, as part of which participants discussed diagnoses of migraine, depression, and anxiety with their healthcare provider. In addition, dried capillary whole blood spots were obtained from the individuals during in-home visits, on which blood hsCRP assay was performed.
The team found that 1049 (11.3%) participants reported migraine.
Linear regression analysis, taking into account sociodemographic factors, body mass index, infections, current pregnancies, subclinical symptoms, anxiety, and depression, indicated that mean hsCRP levels were significantly higher in individuals with migraine than in those without.
Specifically, participants with migraine had an hsCRP level of 5.54 ± 9.04 mg/L vs 4.40 ± 7.47 mg/L in those without migraine (P < .001).
Although women had higher mean hsCRP levels than men, the difference in levels between those with and without migraine was significantly different only in men, at 3.63 ± 6.32 mg/L vs 3.05 ± 5.25 mg/L in men (P = .03) and 6.26 ± 9.78 mg/L vs 5.75 ± 8.97 mg/L in women (P = .08).
Interestingly, when all potential confounding factors were taken into account, migraine was significantly associated with log hsCRP levels across the whole sample, at an r value of 0.11 (P = .04), and in women, at an r value of 0.17 (P = .01), but not in men (r = 0.01; P = .94).
Dr Tietjen believes that the relationship between CRP levels and migraine could be direct. “I think that it is possible that it is a consequence of having migraine, in that, when there’s changes within the brain in the endothelium, that can increase levels of things like [CRP] and inflammation,” she said.
Noting that the relationship was more pronounced in women, she added: “Whether it has something to do with endothelial activation being more easily triggered in women than in men I think is interesting, but I don’t think we can say for sure why we would see it more frequently in women than men.”
Nevertheless, Dr Tietjen said the current findings may point to therapies that target inflammation in general, and CRP levels in particular, potentially being beneficial in migraine.
She highlighted the JUPITER trial, in which the statin rosuvastatin was shown to reduce the incidence of major cardiovascular events in individuals with high CRP levels, although she acknowledged that concerns have been raised about the study’s methodology.
In addition, Catherine Buettner MD, MPH, and colleagues conducted a randomized, double-blind, placebo-controlled trial of simvastatin plus vitamin D, finding that the combination is effective for prevention of headache in adults with episodic migraine.
“Why would it be an effective migraine treatment unless something tied into the migraine pathogenesis had either something to do with cholesterol or inflammation or something that statins actually work on?” Dr Tietjen commented.
“I did think that that was very intriguing, as [CRP] might be something that would guide us as to which patients would be most likely to respond to which therapies,” she added.
Dr Tietjen concluded: “I think it’s an area ripe for more study, but I do believe that it makes sense in what we’re learning both about the importance of the endothelium potentially in migraine and the fact that we are seeing that some therapies that actually have an effect on [CRP] may be effective in migraine in a relatively young, healthy population of people.”
Commenting on these findings, Stephen Silberstein, MD, professor, Department of Neurology, Thomas Jefferson University and Jefferson Health, and director, Jefferson Headache Center, Department of Neurology, Jefferson Hospital for Neuroscience, Philadelphia, Pennsylvania, said the results “look interesting.”
However, he told Medscape Medical News that the wide overlap in the confidence intervals were “of concern” and limited the degree to which the study could be interpreted.
Women who seek treatment for acute migraine during pregnancy go on to have rates of preeclampsia, preterm delivery, and low-birthweight babies that far exceed national averages, a new study suggests.
And being an older mother seems to be an independent predictor of these adverse delivery outcomes, the study showed.
“Over half the patients experienced some type of adverse birth outcome, which suggests that pregnancies in such patients should be considered high risk, especially in older women,” said lead author Matthew S. Robbins, MD, associate professor, clinical neurology, Albert Einstein College of Medicine, chief of neurology, Jack D. Weiler Hospital, Montefiore Medical Center, and director of inpatient services, Montefiore Headache Center, Bronx, New York.
Dr Robbins presented his study here at the American Academy of Neurology (AAN) 2016 Annual Meeting.
Although migraine is fairly common among women of childbearing age, most women with migraine don’t experience attacks during pregnancy. However, some do, possibly from lack of sleep, additional stresses, or other headache triggers, said Dr Robbins.
The new study included 90 pregnant women (mean age, 29.3 years) who presented to a Bronx hospital with acute migraine and received a neurologic consultation during the study: July 1, 2009, to June 30, 2014.
Many of the women (38.8%) were African American, which, according to Dr Robbins, is typical for the Bronx. Most were overweight or obese, with 76.7% having a body mass index of 30 kg/m2 or more. Almost a third of the group (30%) was nulliparous.
Aura “Over-Represented”
Migraine with aura “was very over-represented in the sample,” at 40.7% of patients, commented Dr Robbins. Almost 13% of the group had a diagnosis of chronic migraine, and almost a third (31.4%) presented in status migrainosus.
Various intravenous and other therapies and interventions were used to treat these women, said Dr Robbins.
Researchers had delivery data on 79 of the 90 women (87.8%). They found that the rate of preeclampsia was 19.5% for the migraine sample compared with a national rate of 3% to 4%, said Dr Robbins.
The preterm delivery rate was 28.2%, or more than double the rate nationally (11.4%) or locally in the Bronx (11.7%), said Dr Robbins.
Also higher among the migraine group was the rate of low-birthweight babies: 19.2% compared with 8.0% for the national rate and 9.5% for the local rate.
Why these women have more negative pregnancy outcomes is unclear. “It’s not yet known what makes such women with migraine more susceptible to such complications,” commented Dr Robbins.
Contributing factors could include more “migraine comorbidity” and cardiovascular issues in women with these headaches. “Women with migraine have a higher rate of cardiovascular complications which may in part be genetic,” said Dr Robbins.
Migraine may be associated with changes to the endothelium that could also play a role in preeclampsia, added Dr Robbins.
Active migraine may affect maternal and fetal well-being, which could be yet another factor contributing to adverse outcomes, he said.
On the other hand, the rate of cesarean deliveries was slightly lower (30.8%) in the migraine group than the local (33.1%) or national (32.7%) rates. This is likely explained by preterm deliveries almost always being vaginal births, said Dr Robbins.
When the researchers pooled data, they found that being age 35 years or older predicted adverse delivery outcomes (odds ratio, 7.737; 95% confidence interval, 1.971 – 30.379; P = .003).
Having chronic migraine or status migrainous did not predict adverse delivery outcomes.
“It’s hard to know if we should generalize this to other populations; this was done in an inner-city population who were overweight and had a history of pre-eclampsia,” said Dr Robbins.
“Even so, this does suggest that if women have active migraine in pregnancy, maybe they should be followed quite closely during the pregnancy for complications later on.”
Dr Robbins suggested that clinicians counsel women who are prone to migraine that the condition typically improves as the pregnancy advances.
Doctors might want to emphasize nonmedication approaches, such as relaxation techniques, biofeedback, and trigger avoidance, said Dr Robbins.
Also, they may want to recommend therapies that are safe in pregnancy, including nerve blocks with local anesthesia and devices recently approved by the US Food and Drug Administration, he said.
As well, Dr Robbins pointed out that acetaminophen and some antinausea medicines “have a long track record of safety and I’m fairly comfortable using them.”
Although triptans are generally not used in pregnancy, a registry study from the company behind sumatriptan (GlaxoSmithKline) showed that the rate of birth defects is “quite similar” to that in the general population, noted Dr Robbins.
A limitation of the study was lack of a control group of women who had migraine but didn’t present to acute care. Also, said Dr Robbins “we cannot attribute causality” to the medications or the therapies that the women had received earlier in their pregnancy.
Asked to comment on these findings was David J. Dickoff, MD, a general community neurologist in Yonkers, New York.
“The importance of the migraine study is to alert all doctors, especially obstetricians, that history of migraine headaches is a risk factor for pre-eclampsia,” Dr Dickoff said. “These patients may need to be considered high risk and followed more closely for BP [blood pressure] elevations and proteinuria.”
Jennifer Graves, MD, PhD, assistant professor, neurology, University of California at San Francisco, was one of the session coordinators.
The study, said Dr Graves, “highlights migraine as a potential risk factor for adverse events in pregnancy” and suggests that in these women, additional screening at routine visits may improve care.
“It is of interest for neurologists to help create migraine screening questions for our obstetric colleagues that may carry import for predicting these adverse events in pregnancy,” said Dr Graves. “More prospective study of the value of these associations will be needed.”
Rarely and tragically, migraineurs commit suicide or overdose on medications we prescribe.
CASE HISTORIES
Case 1
This 40-year-old man had an 11-year history of migraine without aura initially several times per month but daily for the last 6 years. The headaches were fairly constant of moderate to severe intensity with nausea, light and noise sensitivity, and vomiting several times monthly. Over the years, he was evaluated and treated for the headaches by a family physician, internist, allergist, ENT physician, dentist (temporomandibular joint [TMJ] specialist), an ophthalmologist, chiropractor, two pain specialists, a neurosurgeon, physiatrist, three psychologists, four neurologists, and three headache specialists. He was minimally responsive or unresponsive to all of the usual preventive and symptomatic migraine medications. Chronic opiates would dull the pain. Other treatments were not effective including two prolonged hospital stays for intravenous medications, physical therapy, TMJD treatment, three cervical epidural steroid injections for bulging discs, biofeedback, psychotherapy, a septoplasty, and allergy shots.
He was working as a business executive until 6 months previously when he went on disability. He tried to stay busy with his supportive wife and two teenage children but felt increasingly depressed despite treatment. His wife found him dead in bed with a suicide note from an overdose of opiates and antidepressants.
Case 2
This 31-year-old woman had a history of migraine without aura since the age of 13 initially one or two times per month triggered by stress or her menses. During the prior 4 years, the headaches increased in frequency to every other day or daily with moderate to severe intensity associated with nausea and vomiting. Numerous preventive medications either were not effective or had side effects. She was tried on all of the triptans and dihydroergotamine, which were either not effective or caused side effects. She began receiving opiates from multiple primary care physicians. She had numerous visits to urgent care clinics and emergency departments for acute treatments and would often receive opiate injections. She reported some pain relief with opiates (acetaminophen combinations with codeine or oxycodone) taken alone or with oral promethazine. She also had chronic complaints of anxiety and depression being treated with alprazolam and paroxetine and zolpidem for insomnia. She saw several neurologists who warned her about the risks of medication rebound and discussed other treatment options.
Two weeks previously, her last neurologist advised her to taper off of opiates and referred her to a headache specialist. She reported being depressed with some suicidal ideation a couple of months previously but no specific plan. She stated that she would not hurt herself because of her three young children. Her husband, who was at the visit, was very supportive.
Two weeks later, the husband called the last neurologist saying that he found his wife dead in bed in the morning. Before going to sleep that evening, she had complained of a bad headache. Later that day, the neurologist also received a phone call from the coroner’s office asking about her history. An autopsy was normal except for a drug screen which revealed high therapeutic doses of promethazine, alprazolam, zolpidem, a therapeutic dose of paroxetine, and a twice therapeutic range level of oxycodone. The forensic pathologist deemed the death an accident due to an acute combined drug intoxication.
QUESTIONS
Are migraineurs at an increased risk of suicide?
Which patients with migraine and depression require psychiatric referral?
If opiates are to be used in migraineurs, how might physicians protect the patients from misuse and even death and themselves from potential medical malpractice claims?
Tricyclics such as amitriptyline and venlafaxine are preferred migraine preventives but can also be used to overdose. Is there anything the clinician can do to prevent an overdose?
In case 2, how do you distinguish an overdose from a suicide?
EXPERT OPINION
Migraines are a common entity the world over with a 1-year prevalence of 11.7–13.2% in the United States. Migraine is one of the top 20 causes of disability worldwide and, only in the US and Europe, accounts for an estimated 250 million lost days from work or school every year.[1] Headaches, and particularly migraines, should be a public health priority given that they are prevalent worldwide, are usually lifelong conditions and cause disability both in terms of the disease and lifestyle restrictions they impose on the individual. Despite this, migraine is the least publicly funded of all neurological illnesses relative to its economic impact.[2] Migraine and depression are common comorbid conditions and so suicides could be extrapolated to have a high occurrence in migraineurs; however, recent literature alludes to migraines being an independent risk factor for suicides. Therefore, it is important to carefully screen such patients and identify red flags for potential referral to psychiatry. Unfortunately many of the drugs used to treat migraines carry black box warnings for suicides and some have high abuse potential, which could knowingly or unknowingly assist in suicide attempts. It is often difficult to differentiate between accidental drug overdose and suicides. This makes it all the more important for physicians to screen for comorbid psychiatric conditions and identify the risk of abuse and suicide in migraineurs.
Are migraineurs at an increased risk of suicide?
Both episodic and chronic migraines have been associated with comorbid psychiatric conditions. Most recently the CaMEO study revealed that chronic migraineurs were 205% more likely to have depression and 140% more likely to have anxiety than episodic migraineurs. The presence of these psychiatric comorbidities in themselves could lead to a higher rate of suicides in migraineurs.[3] Although the bidirectional association between migraine and depression has been well documented,[4, 5] awareness of the increased risk of suicide in migraineurs is a recently developing phenomenon. Ever since the first epidemiological study showing evidence of increased risk of suicide attempt among migraineurs was published in 1991,[6] there have been several studies corroborating the association.[7-11] Two large epidemiological studies have alluded to the fact that there is a direct risk of increased suicidality associated with migraineurs, even after adjusting for the effect of co-occurring psychiatric disorders.[12, 13] In a recent, large population based Canadian study, suicidal ideation was significantly more common for those with migraines.[14] However, one recent Australian population based nationwide study of chronic pain and suicide found that those with neck or back problems had the highest levels of suicidality while migraineurs were not associated with lifetime suicidality after controlling for mental health and substance abuse.[15]
Much of the research done in this area has been conducted on adolescents. The first epidemiological study showing evidence of increased risk of suicide attempt among migraineurs was published in 1991 among adolescents.[6] Ever since then, several studies, including a Taiwanese study involving 7900 students, it was found that subjects with migraines were more likely to have high suicidal risk than those without (odds ratio [OR] = 4.3).[16]
Whether this increase in the suicide risk for migraineurs is intrinsic or due to some other confounding factors is still up for debate. In December 2008, the US Food and Drug Administration issued a warning suggesting that the use of all anti-epileptic drugs (AEDs) is associated with an increased risk of suicidal ideation and behavior which is relevant since a number of AEDs are used to treat migraines.[17] Similarly, many of the antidepressants carry a black box warning since a meta-analysis of 372 randomized clinical trials showed that there was an increased rate (4 vs 2%) of suicidal thinking or behavior among patients who took antidepressants as compared with those who took placebo.[18] It is interesting to note that none of the suicide attempts documented in the trials were fatal.
Which patients with migraine and depression require psychiatric referral?
The data discussed prior illustrate the need for physicians dealing with migraineurs to be adept in screening for the risk of suicide. Routine screening for suicidality in migraineurs has been suggested previously; however, further research is needed before we can say that this would be effective.[14] When Sheehan et al evaluated the risk of suicides in a group of people with chronic daily headache (CDH), they found that subjects in the high suicidal risk group were more likely to be females (OR = 10.3).[16] In another population based study, although the prevalence of suicidal ideations in women was greater than that in men (10.4 vs 8.4%), this difference was not statistically significant.[14] This study also looked at the risk factor profiles of migraineurs. It showed that for female migraineurs, being unmarried, younger age, having a greater limitation in activity, and being poor were linked to suicidal ideation whereas only the first three were linked to suicidal ideations in males. White male migraineurs had a higher association with suicidality, consistent with the previously reported higher incidence in white males.[19] Classically, suicide rates are reportedly higher (by up to seven times) in those aged 75 and older than in adolescents in the general population.[20] Interestingly, in one study it was noted that migraineurs under the age of 30 had at least four times the odds of lifetime suicidal ideation than those over 65 years of age.[14] It was postulated that their increased vulnerability could be due to lack of coping mechanisms, which would reduce the perceived burden of their illness. Prior history of suicidal attempts increases the chance of a completed suicide by 15-fold,[21] and therefore should also always prompt a psychiatric referral. Since the risk of suicidal inclinations are only further compounded by the presence of other psychiatric comorbidities,[22] it would stand to reason that migraineurs with other psychiatric diagnoses would also need closer monitoring by a psychiatrist. Other factors like chronic pain, which increase the risk of suicidality in the general population, should be screened for in migraineurs since they will only increase the risk of suicidality. Chronic pain in general is a source of great distress that decreases quality of life, resulting in hopelessness and despair, and emergence of suicidal wishes.[23] Individuals suffering from chronic pain may be particularly appropriate for suicide screening and intervention efforts. Two large studies, one of which studied risk of suicide in the 21–30 year age group with episodic headache and the other in 12–14 year olds with chronic daily headaches, found that the there was a significantly higher risk of suicidality in patients who experienced migraines with auras.[6, 23-25] This may be due to the fact that auras make the patients more aware of their impending headache, thereby creating more distress.
Genetics are at least partially responsible for the risk of suicide as shown by twin, adoption and family based studies, but studies examining the association between specific gene variants and suicide in migraineurs have yielded inconsistent results. Reduced serotonergic activity and dysfunctions in monoamine neurotransmission has been linked with histories of suicidal behavior.[26, 27] A recent study that recruited females with chronic migraines failed to show any association between MAO-A3 gene variants and suicidal risk.[28] Presumably this could be due to the small sample size employed, and further studies are required for a more comprehensive analysis.
If opiates are to be used in migraineurs, how might physicians protect the patients from misuse and even death and themselves from potential medical malpractice claims?
It is reported that 11.7–30% of all migraine patients use opioids.[29] Data from pain clinics estimate opioid dependence to be as high as 19%.[30] In 2010 alone, opiates were responsible for 75% of the approximately 38,000 drug overdose deaths in the United States.[31] Although not many studies elaborate on the issue of opioid misuse in migraineurs, there are studies which correctly identify that individuals with chronic pain are at a higher risk of misuse of prescribed opioids.[32-34] Many studies have observed various factors associated with opioid misuse and death, which include long acting opioids, additional psychoactive medications, additional substance use disorders, younger age, pain severity (more subjective pain, multiple pain complaints, greater pain related limitations), risk factors in three or more categories (ie, psychosocial factors, drug related factors, and genetic factors).[35-39]
Screening for opioid misuse is the cornerstone of protecting patients from drug related complications including death. Several effective screening tools exist like the Revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R) or Opioid Risk Tool (ORT), but there is a dearth of validated tests or tools to reliably predict patients who are not suitable for opioid therapy or those who need increased vigilance during therapy.[35, 40, 41] Some self-reported questionnaires run the risk of false responses given by misusers, while some instruments are lengthy and impractical in clinical scenarios. In any case, screening should not be limited to single questionnaires and must include collateral information in the shape of testing of biologic material such as blood and urine, opioid treatment agreements, prescriptions of smaller quantities of opioids and frequent follow-ups, providing different pharmacological agents for breakthrough pain, and input from prescription monitoring programs like the Internet System for Tracking Over-Prescribing (I-STOP). New York State’s I-STOP law, which was recently enforced in August 2013, is useful to ensure no multisourcing of medications and to streamline the screening process for identifying those at higher risk of opioid-associated death.[42] Opioid naïve pain patients who are at risk to abuse prescriptions might be identified by evaluating for pre and comorbid substance abuse and psychopathology.[43] Patients on opiates, who require higher doses of medications, should undergo a more thorough psychiatric evaluation at every consultation. All of the above resources should guide us with risk factor stratification and in identifying patients needing increased vigilance rather than being used to deny necessary pain treatment.
In spite of all of the above resources, opioid misuse continues to be a major public health hazard. Another valuable resource that we feel has gone largely untapped is the role of the caregiver. High risk patients should be encouraged to bring along their loved ones to physician encounters, where both might receive information and resources to help them gain insight into the patient’s condition, as is more relevant with our cases. They should be made aware of the risk of psychiatric comorbidities, opioid misuse, under-treatment and suicides, and advised about the red flags that should prompt them to seek urgent help. Contracting for safety should be encouraged to an extent that patients should be required to reach out to the physician as soon as any thoughts about suicide emerge. The implementation of directly observed treatment strategies could be employed to ensure patients adhere to a specific medication regimen and do not overdose. Establishing a therapeutic alliance similar to the 12-step Alcoholics Anonymous program could pay off huge dividends in terms of better outcomes. Pharmacological management should always be augmented by other treatment options, such as relaxation training, thermal biofeedback with relaxation training, electromyographic feedback, and cognitive behavioral therapy, which have shown to be effective in decreasing disease burden.[44, 45]
Malpractice claims from chronic pain management have been on the rise. In a review by the American Society of Anesthesiologists, data collected between 2005 and 2008 revealed that 17% of 295 chronic non-cancer pain claims were related to medication management problems and death was the most common outcome in medication management claims.[46] In another study, addiction from prescribed opioids was suspected in 24% of the deaths.[47] In actuality, physicians can start by protecting themselves from malpractice claims by using the same strategies that they use to protect their patients from opioid misuse.
In an article by Rich et al that attempted to find similarities among malpractice lawsuits involving patients who overdosed on opioids, methadone, followed by hydrocodone, was found to be the leading cause of death.[48] It also pointed out that error in prescribing doses, presence of comorbid mental disorders, toxicological presence of benzodiazepines, and unrelieved pain were the most common factors in the medical records of the decedents. In some cases, opiates were started at too high a dose, titrated too rapidly, converted to other opioids incorrectly and failing to effectively screen for comorbid conditions, which could compromise therapy. Therefore, the first important strategy to protect against malpractice suits would be to make the prescriber aware of the current practices. Physicians should also be aware of potential combined adverse effects of polypharmacy and educate their patients since failure to do so has also been cited in malpractice claims.[49] Rarely P-450 “slow metabolizers” have also been known to be at a higher risk for opiate toxicity so clinicians should consider the effects of the drug utilized on the ability of the P-450 enzyme system to clear opioids. Another article stressed the importance of obtaining informed consent for the risk of iatrogenic addiction or re-addiction with chronic opioid analgesic therapy.[50] Other severe risks, such as death, should also be disclosed even when probability of occurrence is negligible. Failing to appropriately monitor patients with a past medical history significant for aberrant drug-related behaviors and substance abuse were also reasons on which malpractice claims were commonly based and so special emphasis should be placed on this aspect to protect the physician from any potential malpractice claims.
Tricyclics such as amitriptyline and venlafaxine are preferred migraine preventives but can also be used to overdose. Is there anything the clinician can do to prevent an overdose?
Certain antidepressants are used frequently in migraine prophylaxis, not as primary antidepressants but due to their evidence based use for the prevention of migraine. According to the recent guidelines of episodic migraine, both drugs have level B evidence for their usage. However, all medications have risks in association with them. All antidepressants (and antiepileptic medications for that matter) are labeled with increased risk of suicidality. According to several small studies,[51, 52] the use of venlafaxine may be associated with a greater risk of suicide than SSRIs. One of the studies suggests that the use of amitriptyline shows no greater risk than the use of other antidepressants in a group of people being treated for suicidality.[52] It is worth noting that tricyclics have a fairly narrow therapeutic index and overdose with these medications may be easier than with other medications. It does suggest that the use of these medications should be closely monitored. The practitioner should monitor for worsening mood, suicidality, inappropriate usage or dosing of these medications and use of concurrent medications or illicit substances. If necessary, shorter follow-up times, pill counts, or having a family member or caregiver dispense medications could also be considered.
In case 2, how do you distinguish an overdose from a suicide?
Opioids have become one of the more common class of drugs associated with accidental fatal poisoning. However, the true numbers of deaths due to an accidental overdose and suicide are unknown largely due to misclassification or lack of classification of intent.[51-54] Due to the same reason, studies conducted in this regard have been difficult to interpret. One method was to question overdose survivors with substance abuse disorders about their intentions at the time of overdose. A review of studies which employed that method indicated that only a minority of overdoses were reported to be intentional.[55] Having said that, a number of qualitative studies indicate that “intentional overdose” may not be equivalent to “suicide,”[56] further complicating the interpretation of such studies. There is some evidence that individuals intending to commit suicide via overdose are unlikely to use their usual drug of choice or use a much higher dose than that which they usually take.[57, 58] With the publication of the fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM), many of the numerous opioid abuse disorders have been simplified and condensed under the term opioid use disorders. This may change the way we perceive or analyze data since previous studies used DSM-4 or earlier diagnostic criteria.
Determining whether an overdose was suicidal or accidental often depends on the circumstances surrounding the death. Indicators of suicide include previous suicide attempts, sudden negative life events, saving pills so as to have a lethal dose on hand, or “preparing” for one’s death by writing a will, etc.
Individuals contemplating suicide usually display signs of needing help largely by threatening to commit suicide or if all else fails could leave a suicide note. If there are no red flags such as the one described above, authorities will usually assume that death occurred as a result of overdose, like in our case. On a biological level, overdose can be particularly confusing since organisms learn to make responses that attenuate the effect of the drug in the presence of cues previously paired with the drug. This would explain the “failures” of tolerance that occur when a drug-experienced individual suffers an “overdose.”[59-61] Pavlovian conditioning resulting in situation-specific tolerance is capable of leading to overdose in a non-familiar setting and accidental overdose. It is important to keep in mind that not all overdoses are intentional and not all intentional overdoses are necessarily suicide attempts.
Women with migraine face increased risk for cardiovascular events and CV mortality, according to a large prospective study in The BMJ.
In the Nurses’ Health Study II, over 115,000 women aged 25 to 42 without angina or CV disease reported whether they’d ever been diagnosed with migraine and then were followed for roughly 20 years. Some 15% reported migraine at baseline.
During follow-up, roughly 1300 major CV events and 220 CV deaths occurred. Compared with women without migraine, those with migraine had significantly increased risks for myocardial infarction (adjusted hazard ratio, 1.4), stroke (HR, 1.6), angina/revascularization (HR, 1.7), and cardiovascular mortality (HR, 1.4). Findings were similar regardless of age, hormone therapy use, oral contraceptive use, smoking status, or hypertension.
Information about migraine aura was not available — an important limitation, the authors and editorialists note, given that prior research suggested that a migraine-stroke association was largely limited to a subgroup with aura.
Dr. Eleanor Bimla Schwarz of NEJM Journal Watch Women’s Healthweighed in: “We have known for years that women with migraines have increased risk of stroke. The question that remains unanswered is at what age women with migraines should start daily aspirin to lower their risk of cardiovascular disease.”
Abstract
Objective To evaluate the association between migraine and incident cardiovascular disease and cardiovascular mortality in women.
Design Prospective cohort study among Nurses’ Health Study II participants, with follow-up from 1989 and through June 2011.
Setting Cohort of female nurses in United States.
Participants 115 541 women aged 25-42 years at baseline and free of angina and cardiovascular disease. Cumulative follow-up rates were more than 90%.
Main outcome measures The primary outcome of the study was major cardiovascular disease, a combined endpoint of myocardial infarction, stroke, or fatal cardiovascular disease. Secondary outcome measures included individual endpoints of myocardial infarction, stroke, angina/coronary revascularization procedures, and cardiovascular mortality.
Results 17 531 (15.2%) women reported a physician’s diagnosis of migraine. Over 20 years of follow-up, 1329 major cardiovascular disease events occurred and 223 women died from cardiovascular disease. After adjustment for potential confounding factors, migraine was associated with an increased risk for major cardiovascular disease (hazard ratio 1.50, 95% confidence interval 1.33 to 1.69), myocardial infarction (1.39, 1.18 to 1.64), stroke (1.62, 1.37 to 1.92), and angina/coronary revascularization procedures (1.73, 1.29 to 2.32), compared with women without migraine. Furthermore, migraine was associated with a significantly increased risk for cardiovascular disease mortality (hazard ratio 1.37, 1.02 to 1.83). Associations were similar across subgroups of women, including by age (<50/≥50), smoking status (current/past/never), hypertension (yes/no), postmenopausal hormone therapy (current/not current), and oral contraceptive use (current/not current).
Conclusions Results of this large, prospective cohort study in women with more than 20 years of follow-up indicate a consistent link between migraine and cardiovascular disease events, including cardiovascular mortality. Women with migraine should be evaluated for their vascular risk. Future targeted research is warranted to identify preventive strategies to reduce the risk of future cardiovascular disease among patients with migraine.
Introduction
Migraine is a primary headache disorder that affects approximately one fifth of the general US population for at least part of their lives, and women are affected three to four times more often than men.123 Migraine, specifically migraine with aura, has been consistently associated with increased risk of stroke, including both ischemic and hemorrhagic subtypes.45 Although the pathophysiology of migraine has close links to the vascular system, the mechanisms by which migraine increases risk of stroke remain unclear.67 Potential mechanisms for an association between migraine and stroke include endovascular dysfunction,89 increased thrombogenic susceptibility,10increased prevalence of vascular risk factors,11 shared genetic markers,1213 cortical spreading depolarization,1415and inflammation.1617
As most of these mechanisms also increase the risk of other cardiovascular disease events, migraine may be viewed as a marker of increased risk for any vascular disease event. However, as the one year prevalence of migraine peaks in midlife whereas the incidence of cardiovascular events increases exponentially with age, links between migraine and any cardiovascular disease are not easily identifiable. Long follow-up, particularly of younger populations, is needed to study this association. Few prospective studies have reported an association between migraine and any cardiovascular disease events,18192021 including ischemic heart disease and cardiovascular death.182021
Because of the high prevalence of migraine, any association between migraine and cardiovascular disease would have a substantial effect on public health. We thus aimed to evaluate the association of migraine with total and specific cardiovascular disease events as well as cardiovascular disease specific mortality in the Nurses’ Health Study II, one of the largest prospective cohort studies on health in younger women, aged 25 to 42 at baseline.
Methods
Study population
Established in 1989, the Nurses’ Health Study II is an ongoing prospective cohort study of 116 430 female registered nurses in the United States who were 25-42 years old at baseline. Information on reproductive factors, lifestyle factors, and medical history was collected through a self administered questionnaire at baseline and has been updated every two years through follow-up questionnaires. The cumulative response rate based on person time is more than 90%. For the purpose of this analysis, we included follow-up from baseline through June 2011. We excluded 889 women who reported cardiovascular disease at baseline (angina, a coronary revascularization procedure, myocardial infarction, or stroke) from our analyses, leaving 115 541 women free of angina or any symptomatic cardiovascular disease for our analyses.
Patient involvement
No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for recruitment, design, or implementation of the study. No patients were asked to advise on interpretation or writing up of results. Results of the study will be disseminated to patients’ organizations and via the webpage of the Nurses’ Health Study (http://www.nurseshealthstudy.org).
Assessment of migraine
On the baseline (1989) and two follow-up questionnaires (1993 and 1995), women were asked to indicate whether a physician had diagnosed them as having migraine. Person time status for having a migraine started whenever migraine was first reported. Agreement between self reported migraine and 2004 International Headache Society criteria was high in another comparable cohort of female health professionals.22 Information on migraine aura, migraine frequency, or migraine specific drugs was not available.
Ascertainment of cardiovascular disease events
Every two years, women reported any incident cardiovascular disease event on the follow-up questionnaires and then completed a supplemental questionnaire confirming the event. Self reported information on cardiovascular disease was confirmed through review of medical record or supporting information by a physician who was blinded to the exposure status and the specific research question under study. Deaths were identified by reports from next of kin, from postal authorities, or by searching the National Death Index. At least 98% of deaths among the Nurses’ Health Study II participants were identified using these approaches.23 Causes of death were confirmed by review of autopsy reports, medical records, and death certificates.
The occurrence of non-fatal myocardial infarction was confirmed if symptoms met World Health Organization criteria, which require typical symptoms plus either diagnostic electrocardiographic findings or elevated cardiac enzyme concentrations.24 If medical records were unavailable, we considered myocardial infarctions probable when additional confirmatory information was provided by the participant. Information on angina and coronary revascularization procedures (percutaneous transluminal coronary angioplasty or coronary artery bypass grafting surgery) was self reported, and we included only events that occurred before a manifest cardiovascular disease event.
A non-fatal stroke diagnosis was confirmed, according to National Survey of Stroke criteria, if the participant had a new focal neurologic deficit with sudden or rapid onset that persisted for more than 24 hours.25 We excluded cerebrovascular pathology due to infection, trauma, or malignancy, as well as “silent” strokes discovered only by radiologic imaging. Radiology reports of brain imaging (computed tomography or magnetic resonance imaging) were available in 89% of those with medical records. We classified strokes as ischemic stroke (thrombotic or embolic occlusion of a cerebral artery), hemorrhagic stroke (subarachnoid and intraparenchymal hemorrhage), or stroke of probable/unknown subtype (a stroke was documented but the subtype could not be ascertained owing to medical records being unobtainable).
Fatal cardiovascular disease was defined as fatal coronary heart disease, fatal stroke, or fatal cardiovascular disease. Fatal coronary heart disease was defined as ICD-9 (international classification of diseases, ninth revision) codes 410-412 and was considered confirmed if fatal coronary heart disease was confirmed via medical records or autopsy reports or if coronary heart disease was listed as the cause of death on the death certificate and there was prior evidence of coronary heart disease in the medical records. We designated as probable those cases in which coronary heart disease was the underlying cause on the death certificates but no prior knowledge of coronary heart disease was indicated and medical records concerning the death were unavailable. Similarly, we used ICD-9 codes 430-434 to define fatal stroke and followed the same procedures to classify cases of confirmed or probable fatal stroke. Lastly, fatal cardiovascular disease was defined by ICD-9 codes 390-458.
Our primary outcome measure was major cardiovascular disease, a combined endpoint of myocardial infarction, stroke, or fatal cardiovascular disease (fatal stroke, fatal myocardial infarction, and fatal coronary heart disease). We chose this composite outcome as it has been used as outcome in previous studies,1826 and it follows guidelines on prevention of all cardiovascular disease to capture the full impact of risk factors and cardiovascular health.27 We further assessed the following secondary outcome measures: total myocardial infarction, which was defined as fatal or non-fatal myocardial infarction; total stroke, which included all fatal and non-fatal stroke cases (ischemic, hemorrhagic, and undetermined subtypes); angina/coronary revascularization procedure; and cardiovascular disease mortality.
Statistical analyses
We calculated person time from the return date of the 1989 questionnaire until the date of diagnosis of cardiovascular disease, date of death, or end of follow-up (June 2011), whichever occurred first. We used Cox proportional hazards models with age and two year follow-up cycle as timescale to evaluate the association between migraine and the various outcomes. We calculated age adjusted and multivariable adjusted hazard ratios and corresponding 95% confidence intervals. The multivariable adjusted models controlled for age (continuous), elevated cholesterol (yes/no), diabetes (yes/no), hypertension (yes/no), body mass index (<25, 25-<30, ≥30), smoking status (never, past, current), alcohol consumption (0, 0-14.9, ≥15 g/day), physical activity (metabolic equivalent of tasks (METs) in fifths) (continuous), postmenopausal hormone use (never, past, current), menopausal status (premenopausal, postmenopausal, dubious), ever used oral contraceptive (never, past, current), aspirin use (<2 days/week, ≥2 days/week), acetaminophen (paracetamol) use (<2 days/week, ≥2 days/week), non-steroidal anti-inflammatory drug use (<2 days/week, ≥2 days/week), and family history of myocardial infarction before the age of 60 (yes/no). We adjusted for all the covariates in the models in a time varying fashion on the basis of information available on each of the biennial questionnaires (1991 to 2009).
We evaluated effect modification by age (<50/≥50), smoking status (current/past/never), hypertension (yes/no), postmenopausal hormone therapy (current/not current), and oral contraceptive use (current/not current). We tested effect modification by including an interaction term for migraine and the potential effect modifier in the outcome models.
We tested the proportional hazards assumption by including an interaction term for migraine status and the logarithm of follow-up time for the primary outcomes in age adjusted models. We found no statistically significant violation. In sensitivity analyses, we repeated the analyses on the basis of migraine information provided at baseline only.
We had 3.1% missing information on all covariates and used a missing variable indicator to account for this lack of information in our multivariable models. In sensitivity analyses, we used multiple imputation (proc mi) to account for missing information and also ran a model excluding all missing information.
We used SAS 9.3 for all analyses. All P values were two sided, and we considered a P value of less than 0.05 to be statistically significant.
Results
Of the 115 541 women in this study, 17 531 (15.2%) reported a physician’s diagnosis of migraine at baseline in 1989. An additional 6389 women newly reported a physician’s diagnosis on subsequent questionnaires and were classified having migraine during follow-up. Women with migraine were more likely to have an unfavorable cardiovascular risk factor profile, including hypertension, hypercholesterolemia, family history of myocardial infarction, body mass index of 30 or above, and current smoking status. They were also more likely to use aspirin, acetaminophen, and non-steroidal anti-inflammatory drugs (table 1⇓).
Table 2⇓ summarizes the associations between migraine and various cardiovascular outcomes. During follow-up, 1329 major cardiovascular disease events (678 total myocardial infarctions, 651 total strokes, and 203 angina/coronary revascularization procedures) occurred. A total of 223 deaths due to cardiovascular disease occurred. Compared with women without migraine, those with a self reported physician’s diagnosis of migraine had a multivariable adjusted hazard ratio of 1.50 (95% confidence interval 1.33 to 1.69) for developing major cardiovascular disease. Findings were significant for all evaluated individual outcomes, and the highest estimates were seen for stroke (hazard ratio 1.62, 1.37 to 1.92) and angina/coronary revascularizations (1.73, 1.29 to 2.32)
The associations between migraine and cardiovascular disease outcomes (major cardiovascular disease, total myocardial infarction, and total stroke) were not modified by age (<50/≥50) (P for interaction all≥0.34), current postmenopausal hormone use (P for interaction all≥0.57), current oral contraceptive use (P for interaction all≥0.84), current smoking status (P for interaction all≥0.26), or hypertension (P for interaction all≥0.37). In sensitivity analyses, we restricted analysis to women with a report of migraine at baseline. The multivariable adjusted hazard ratios were 1.57 (1.38 to 1.77) for major cardiovascular disease, 1.77 (1.49 to 2.11) for total stroke, and 1.39 (1.17 to 1.66) for total myocardial infarction. The results of the association between migraine and major cardiovascular disease were very similar when we used multiple imputation (hazard ratio 1.50, 1.33 to 1.71) or when we excluded missing information (1.53, 1.35 to 1.74).
Discussion
In this large, prospective cohort study of female nurses aged 25 to 42 at inclusion who were free of cardiovascular disease at the start of follow-up and with more than 20 years of follow-up, we found consistent associations between migraine and cardiovascular disease events. We found an approximately 50% increased risk for major cardiovascular disease. This association persisted after adjustment for traditional vascular risk factor and was apparent for myocardial infarction, stroke, and coronary artery procedures as well as for angina. We also found an increased risk of cardiovascular disease mortality.
Comparison with other studies
Most studies evaluating the association between migraine and vascular events have been limited to ischemic stroke.428 Some studies have reported an association between migraine and cardiovascular disease.18192021Results of our study are in line with findings from the Women’s Health Study,18 another large prospective cohort study among female health professionals aged 45 or older at inclusion. In the Women’s Health Study, migraine was associated with an increased risk of major cardiovascular disease events (hazard ratio 1.42, 95% confidence interval 1.16 to 1.074), including cardiovascular disease mortality (1.63, 1.07 to 2.50). In the Women’s Health Study, the increased risk was apparent only for women who reported migraine with aura. In our study, information on aura was not available.
In a matched cohort study of 11 541 patients with migraine who were aged 18 to 45 years and an equal number of controls from the Taiwan National Health Insurance database, Wang and colleagues reported an increased risk of ischemic heart disease for people with migraine (hazard ratio 2.50, 1.78 to 3.52).20 The Reykjavik Study, which included 18 725 men and women, showed very similar results for the association between overall migraine and cardiovascular disease mortality.21 After adjustment for potential confounders, participants with any indication of migraine had a 16% increased risk of dying from any cause (hazard ratio 1.16, 1.04 to 1.29). This risk was stronger for people with migraine with aura (hazard ratio 1.21, 1.12 to 1.30) and was higher for mortality from cardiovascular disease (1.27, 1.13 to 1.43) compared with people without headache. Results from the American Migraine Prevalence and Prevention study also indicate an increased risk of cardiovascular disease events. In this population based case-control study of 6102 patients with migraine and 5243 controls, migraine overall was associated with a relative risk for myocardial infarction of 2.16 (1.70 to 2.76) and for total stroke of 1.54 (1.16 to 2.05).19
Two studies have found an association between migraine with aura and angina but not myocardial infarction.2930The lack of association with myocardial infarction may be related to shorter follow-up time. In our data, women with migraine had an increased risk for myocardial infarction, as well as for angina and coronary revascularization procedures.
Many studies have focused on the evaluation of potential modifying factors and on the identification of a subgroup of patients with migraine who are at high risk for developing a subsequent stroke. Studies have consistently found that the association between migraine and stroke was observable only among younger people and was stronger among women.28 Among women, several studies have focused on the role of smoking and oral contraceptive use.283132 In particular, the combination of smoking and oral contraceptive use among young women with migraine with aura markedly increased the risk of ischemic stroke, reaching a 10-fold increase for current cigarette smokers and oral contraceptives users.33 However, for overall vascular risk status, several studies indicate that the association between migraine and ischemic stroke is apparent only among those with a low cardiovascular risk profile.3334
Studies on modifying effects of other cardiovascular disease events are sparse. Findings of the Women’s Health Study indicate that migraine with aura and an increased vascular risk profile resulted in a higher risk of incident myocardial infarction.34 However, the event rate among women with migraine with aura was still too small to robustly evaluate the role of individual vascular risk factors, including postmenopausal hormone use.
Potential biological mechanisms
Several mechanisms that have been implied for migraine have also been linked with increased risk of cardiovascular disease, such as increased thrombogenic susceptibility,10 shared genetic markers,1213 and inflammation processes.1617 Our findings confirm results of other studies that women with migraine have a higher prevalence of vascular risk factors, such as hypertension, higher body mass index, and hypercholesterolemia.1119 However, as all studies evaluating the association between migraine and cardiovascular disease have controlled for these factors, the association between migraine and cardiovascular disease is unlikely to be explained by this. Evidence suggests that the pathophysiology of migraine can also be viewed in part as a systemic disorder affecting the endovascular system.93536373839
Strengths and limitations of study
Our study has several strengths, including the prospective design, large number of participants and outcome events, long follow-up, high participation rate, standardized evaluation of migraine and cardiovascular disease risk factors, confirmation of outcomes by physician’s review, and the homogeneous nature of the cohort (all were nurses), which may reduce confounding by factors such as access to medical care.
Several limitations should be considered when interpreting our results. Firstly, physician diagnosed migraine status was self reported, leading to potential misclassification. In addition, people with mild migraines may not have reported symptoms to a clinician and thus not received a diagnosis. Because of the prospective design, however, such misclassification would probably result in underestimation of relative risks and would be unlikely to explain the observed association pattern. Furthermore, a previous report in a comparable study of female health professionals showed that self reported migraine had good agreement with the second edition of the International Classification of Headache Disorders,22 and our prevalence of migraine is close to that reported in other population based studies.184041 Secondly, we had no information on the presence or absence of migraine aura, and migraine with aura has been suggested to be the subgroup carrying most of the risk of cardiovascular disease.418 Furthermore, no information on frequency of migraine or migraine specific information was available. Thirdly, residual confounding—for example, by markers of inflammation or genetic factors101213 —remains a potential alternative explanation, as our data are observational. Finally, participants in this study were all nurses aged 25 to 42 at baseline and mostly white, so generalizability to other populations might be limited. However, we have no reason to believe that that the biological mechanisms by which migraine might be associated with vascular events and mortality would be different in other populations of women.
Implications of findings
The results of our study support the findings of other population based studies linking migraine with increased risk of cardiovascular disease.181920 Although most studies link migraine with aura with increased risk of ischemic stroke,428 emerging evidence indicates that this risk extends to other cardiovascular disease as well. Our data support consideration of a history of migraine as a marker for increased risk of any cardiovascular disease event.
To date, no clear mechanisms have been identified that could explain the increased risk of cardiovascular disease and mortality among patients with migraine, and no data exist on whether prevention of migraine attacks reduces these risks. Data from the National Health and Nutrition Examination Survey and results of a randomized clinical trial provide initial evidence that the combination of a statin and vitamin D may reduce the burden of migraine,4243which may be explained by the anti-inflammatory effects of these drugs. Future targeted research, such as on whether statins and vitamin D reduce the burden of migraine and cardiovascular disease, is urgently warranted to provide answers to patients and their treating physicians.
Conclusions
Results of this large, prospective cohort study among women support the hypothesis that migraine is a marker for increased risk of any cardiovascular events. Given the high prevalence of migraine in the general population, an urgent need exists to understand the biological processes involved and to provide preventive solutions for patients.
What is already known on this topic
Migraine has been consistently linked with increased risk of ischemic stroke
Few studies have shown an association of migraine with coronary events and cardiovascular mortality
What this study adds
Analysis of data from a large prospective cohort study in women show that migraine is associated with any cardiovascular disease, including coronary events and cardiovascular mortality
These results further add to the evidence that migraine should be considered an important risk marker for cardiovascular disease, at least in women
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