The diagnosis and treatment of migraine as its own entity is a complicated and delicate balance between identification and management. The situation is more complex, however, when the patient with migraine presents with comorbid conditions (eg, mood, neurologic, or musculoskeletal pain disorders). These comorbid conditions have important clinical implications. In fact, the risk of these and other comorbid disorders is much higher for migraineurs than for persons without a history of migraine. Comorbid conditions can also complicate treatment in some patients because of the potential for drug interactions or exacerbation of one condition by therapy for the other. The onus is on the physician to consider migraine treatment regimens that include the potential to manage underlying comorbidities and, conversely, to consider treatment regimens when migraine itself may be secondary to other primary symptoms.
Acute migraine is a common and debilitating primary headache disorder. The American Migraine Study II, which investigated the prevalence, sociodemographic profile, and burden of migraine in persons 12 years or older in the United States in 1999, found that 18.2% of female respondents and 6.5% of male respondents reported a history of migraine. These statistics translate into almost 28 million migraineurs in this country.1 The Global Burden of Disease Study rated the disability associated with severe migraine on a par with that of quadriplegia.2 The clinical, pragmatic, and analytic ramifications of these data for the practicing physician cannot be denied.
Migraineurs are frequently affected by neurologic and mood disorders, as well as other pain syndromes. Complications with treatment arise when the patient with migraine has an associated comorbid disorder. While a particular medication might be medically indicated to alleviate one set of symptoms, it could easily exacerbate the symptoms of another coexisting condition.
My purpose here is to alert the physician to the potential existence of comorbid or coexistent disorders in the treatment of migraine and to provide suggestions for prescribing pharmacologic agents for the migraineur with comorbid disorders.
A comorbid condition is one that is found more often than would be expected if its occurrence were by random chance. One of the conditions may cause the other, or the 2 states may exist concurrently because they share some genetic or environmental risk factors.3
In migraineurs, comorbidity is a frequent phenomenon with important clinical implications: symptoms may be common to both conditions, thereby heightening the challenge of differential diagnosis4 and treatment. A matched case-control study by Joish and colleagues,5 for example, using data from 1998 Idaho Medicaid claims, found that the risk of diagnosis of other conditions was 5 times higher for migraineurs than for patients without a history of migraine. Prevalent comorbid disorders are summarized in Table 1.3,6-8
Depression. A number of studies have found that mood disorders are more common in migraineurs than in the general population.9-13 Among these was the Detroit Area Study of Headache, an epidemiologic study of 1696 adults; 683 participants met the International Headache Society (IHS) migraine criteria, 253 had severe nonmigraine headache, and 760 were without migraine or severe headache. The odds ratio (OR), adjusted for sex, for major depression was 3.51 for migraineurs (4.90 for those who experienced aura and 3.03 for those who did not experience aura) and was 3.18 for those who experienced severe headache.11 Migraine was associated with an elevated risk of the first onset of major depression, and major depression was similarly linked to an increased risk of the development of migraine.11
Hypotheses regarding the comorbidity of migraine and major depression include migraine as a trigger for depression and a psychological basis for the presence of both conditions. In addition, the findings of the Detroit Area Study of Headache-particularly the bidirectionality of influence between these 2 conditions-are consistent with a shared pathophysiology between migraine and depression.3,4
Bipolar disorder. Bipolar disorder is more common in migraineurs.14-17 A 1990 study of 457 adults found a significantly greater risk of bipolar disorder among migraineurs (OR, 2.9; 95% confidence interval [CI], 1.1 to 8.6) than non-migraineurs.18 A 2003 study that included 1167 patients with bipolar disorder and 1283 persons without bipolar disorder found that migraine was twice as common among those with bipolar disorder (24% vs 11%; P < .05).17
Panic disorder. Panic disorder is also more common among migraineurs.9,10,13,19 A population-based telephone interview study that assessed the frequency of panic disorder in approximately 10,000 persons aged 12 to 29 years found that the risk of migraine among males with panic disorder was 7 times greater than in those without a history of panic disorder.19
A study of patients at a psychiatric clinic showed that migraine without aura was the most common form of headache among patients with panic disorder. The authors also found that patients with headache of any type had a greater duration of panic disorder.20
Migraine occurring during a panic attack has been documented in a small number of patients.21 These particular persons had concomitant severe migraine associated with autonomic dysregulation, such as nausea and vomiting, during panic attacks. In addition, they exhibited significant emotional disturbances between migraine episodes, all resulting in a substantially reduced quality of life.
Epilepsy. Epilepsy has been associated with migraine. Ottman and Lipton22 studied 1948 adult patients with epilepsy and 1411 parents and siblings of those patients. They observed a strong association between migraine and epilepsy that was independent of the age at onset, type, and etiology of seizure, or of family history of epilepsy. The risk ratio for migraine among the patients with epilepsy was 2.4, compared with 1.0 for their non-epileptic relatives. Risk of migraine was highest among those with epilepsy caused by head trauma. For migraineurs with epilepsy, migraine risk was greater both before and after a seizure.6 A study of 126 patients with epilepsy found that 23 (18.2%) had experienced seizure-associated migraine or a migrainous disorder.23 Of these 23 patients, 21 (91.3%) had postictal headaches; the predominant epilepsy syndrome (52.2% of patients) was characterized by focal seizures.
Migraine and epilepsy are both chronic, episodic neurologic disorders that share a number of symptoms, including auras, mood alterations, and focal sensory disturbances.24 Neuronal hyperexcitability secondary to altered electrolyte or neurotransmitter levels has been hypothesized to increase the risk of both migraine and epilepsy, and genetic and environmental factors are believed to contribute to the comorbidity of migraine and epilepsy.4,6
Stroke. A number of studies have found stroke to be related to migraine.8 In women younger than 45 years, a significant association between migraine and ischemic stroke risk has been observed, particularly for those who use oral contraceptives and those who smoke more than 20 cigarettes a day.25,26 Stroke appears to be more common among migraineurs who experience aura than among those who do not.27
The interaction between migraine and stroke is not well understood, but Welch8 categorized 4 types of relationships between migraine and stroke:
Category I is coexisting stroke and migraine, in which migraine occurs independently of the stroke syndrome and does not contribute to a stroke syndrome.
Category II is stroke with clinical features of migraine, in which a structural lesion that is involved in the stroke syndrome causes symptoms similar to those of migraine but is not related to the pathogenesis of migraine.
Category III is migraine-induced stroke, which meets both of the following criteria:
1. The neurologic signs are identical to those seen in previous migraine attacks.
2. The stroke occurs during a typical migraine attack, and although risk factors for stroke may be present, all other causes of stroke can be ruled out.
Category IV is an indeterminate relationship between migraine and stroke.
Essential tremor. Essential tremor is yet another migraine neurologic comorbidity. A 1990 prospective study compared the incidence of essential tremor in a group of 58 migraineurs with that in a group of 85 controls without migraine, and contrasted those results with the incidence of migraine in a group of 74 patients with essential tremor and 102 controls without essential tremor. Approximately 15 times as many patients with migraine had essential tremor as controls without migraine, and about twice as many patients with essential tremor had migraine.28
MUSCULOSKELETAL PAIN DISORDERS
Migraineurs frequently exhibit musculoskeletal symptoms. A cross-sectional population-based study of more than 50,000 adults conducted in Norway found that musculoskeletal symptoms were approximately twice as common in persons with migraine as in those who were headache-free.29 The prevalence of chronic headache (migrainous and non-migrainous) was 4 times greater in persons with musculoskeletal symptoms than in those without those symptoms. Among study participants with musculoskeletal pain symptoms, migraine was most prevalent in those whose symptoms were widespread, followed by those with symptoms localized to the neck.
Fibromyalgia. Fibromyalgia has been linked to migraine. A study that included 51 women with fibromyalgia and 52 women without fibromyalgia or other pain syndrome observed that the incidence of migraine among patients with fibromyalgia was significantly greater than among the healthy controls (72.5% vs 13.5%; P < .001).30
A separate study of 101 patients with transformed migraine (chronic daily migraine) seen consecutively at a headache clinic reported an incidence of fibromyalgia of 35.6%.31 Those patients with comorbid fibromyalgia were significantly older (mean age of 37.3 vs 34.8 years; P = .009) and were more likely to report having incapacitating headaches (88.9% vs 66.1%; P = .0235).31
The pathophysiology of fibromyalgia is not understood, but the disorder is considered to be a hyperalgesic state stemming from defective central pain processing.32,33 Both migraine and fibromyalgia may be caused by abnormal central serotonergic functioning resulting in hyperalgesia.34
Myofascial pain syndromes. Myofascial pain syndromes, including temporomandibular disorder, have been linked to migraine. A study that included 72 migraineurs whose headaches tended to occur on awakening, and 37 non-migraineurs who were matched for age and sex found that the migraineurs had a significantly greater incidence of masticatory muscle tenderness (P < .001 for temporalis; P < .05 for masseter and pterygoid), a history of temporomandibular joint pain (P < .01), mandibular deviation (P < .05), and bruxism/clenching (P < .01) than the nonmigrainous controls.35
Primary Raynaud phenomenon. Migraine has been associated with primary Raynaud phenomenon and several conditions with which Raynaud phenomenon often overlaps, including systemic sclerosis (scleroderma), systemic lupus erythematosus (SLE), and Sjögren syndrome.36-43 Zahavi and colleagues37 reported that the incidence of Raynaud phenomenon was greater in a group of 111 migraineurs than in a group of 111 controls matched for age and sex.
A study by O'Keeffe and coworkers38 of 93 patients with primary Raynaud phenomenon and 93 age- and sex-matched healthy controls found a significantly higher incidence of migraine among the patients than among the controls (OR, 5.4; 95% CI, 2.8 to 10.3). The incidence of musculoskeletal chest pain was also significantly greater among the patients with Raynaud phenomenon and migraine than among the patients with Raynaud phenomenon without migraine (60% vs 28%; P = .003). Similarly, several studies of patients with scleroderma, SLE, and Sjögren syndrome have observed a higher incidence of migraine among those patients compared with healthy controls.40-43
The link between migraine and these conditions is not known. Vascular pathology is a key finding in Raynaud phenomenon, scleroderma, SLE, and Sjögren syndrome.36,44,45 Scleroderma, SLE, and Sjögren syndrome can also have CNS involvement,46-48 which may be related to vascular damage. For example, the most frequently documented CNS pathology in SLE is small-vessel cerebral vasculopathy and microinfarcts that may result from multiple attacks of acute inflammation in the small vessels.49
Asthma and eczema. Several atopic disorders, including asthma and eczema, have been associated with migraine. In a case-control study of more than 60,000 pairs, investigators calculated a relative risk of asthma among migraineurs of 1.59 (95% CI, 1.54 to 1.65) and a relative risk of eczema in those patients of 1.55 (95% CI, 1.41 to 1.71).50
Allergies. The association between allergies and migraine is not clear. A study comparing triggering factors for patients with migraine and patients with tension-type headache (TTH) found that of the 4 factors mentioned significantly more frequently by migraineurs than by patients with TTH, 3 involved the nose or sinus (ie, weather, smoke, and smell).51 An association between food allergy and migraine has been debated.52 The pathophysiologic factor that may be common to migraine and allergy may be histamine, which has been found to trigger migraine-like headache and which induces the release of nitric oxide by the vascular endothelium.53 Several vasodilating substances found in food, including tyramine, phenylethylamine, nitrates and nitrites, monosodium glutamate, and alcohol, have been implicated in triggering migraine.52
GI TRACT DISORDERS
Reflux. Triggering of migraine by GI tract disorders, particularly reflux, has been noted in case studies.54,55 Reflux-associated migraine often occurs in the morning and frequently includes pain radiating from the teeth or gums.
Irritable bowel syndrome. Irritable bowel syndrome (IBS) has been associated with migraine. An epidemiologic study in which 350 adults reported symptoms consistent with IBS found that 32% of these persons also had migraine, compared with 18% of those without IBS (P < .01).56 The pathophysiologic link between migraine and IBS is not known. However, some investigators have hypothesized that patients with IBS may also have central hyperalgesia,57 which might have relevance for migraine in these patients as well.
OTHER DISORDERS AND CONDITIONS
Chronic fatigue syndrome. Chronic migraine has been associated with chronic fatigue syndrome (CFS). A study of 63 patients with chronic migraine found that 84.1% had CFS (as defined by the CDC). This figure dropped to 50.8% when the CFS definition was modified to exclude headache.58 The pathophysiologic connection between CFS and migraine is not known, but altered central serotonergic function, noted in patients with CFS, may be relevant.59,60
Menstruation and dysmenorrhea. Menstruation has been reported as a trigger for migraine. Approximately 70% of all migraineurs are female, and about 70% of those female migraineurs describe a relationship between their headache and their menstrual periods.61 A study of the relationship between migraine and menstruation conducted in 55 women attending a headache clinic found that 7.2% had migraine exclusively during a particular part of their menstrual cycle (ie, 2 days before the onset of menstruation through the first 2 days of menstruation [day 1 ± 2 days]); 34.5% of the patients had migraine episodes throughout the menstrual cycle but had a greater frequency of attacks during day 1 ± 2 days of their cycle.62
MacGregor63 proposed that the term "menstrual migraine" be used to reference migraine in patients whose attacks occur only during day 1 ± 2 of the cycle. The term "menstrually related migraine" was proposed to describe migraine in patients who have episodes that occur anytime during the cycle but with increased incidence during day 1 ± 2 of the cycle.
Silberstein64 has suggested that migraine may be linked to late luteal phase dysphoric disorder and dysmenorrhea. Increased sensitivity to estrogen withdrawal and prostaglandins has been proposed to contribute to the triggering of menstrual migraine and menstrually related migraine.63 Estrogen itself does not directly cause migraine. Rather, a rapid decrease in estrogen levels, coupled with the fluctuation of other hormones, is most likely to be associated with migraine.65
Comorbidity can complicate treatment in some patients because of the potential for drug interactions or exacerbation of one condition by therapy for the other. However, it may also be possible to treat migraine and some of its comorbid conditions with a single agent. Recommendations for treating the patient with migraine and comorbid conditions, developed from a survey of headache specialists, appear in Table 2.66
Most drugs used in migraine prophylaxis are not specific for migraine and were developed for other indications. They are the agents with efficacy for both migraine and comorbid conditions (Table 3).67,68 Divalproex, gabapentin, or topiramate may be considered for the migraineur with epilepsy.4,6 Amitriptyline, a tricyclic antidepressant (TCA), and/or a selective serotonin reuptake inhibitor, such as fluoxetine, may be used in the migraineur with depression or fibromyalgia.69,70 Propranolol may benefit the migraineur with essential tremor.71,72 Calcium channel blockers may be used for migraineurs with Raynaud phenomenon.73
Recent data presented at the American Headache Society meeting suggest that naratriptan and frovatriptan may be effective as intermittent prophylaxis for menstrually associated migraine.74,75 In addition, other research demonstrates that because NSAIDs inhibit the formation of prostaglandins and decrease endometrial contractility,76 these agents are also indicated in the treatment of menstrual migraine, including premenstrual syndrome, and dysmenorrhea-associated headaches.61 If one NSAID is not effective, another may be.61
Finally, the weight loss associated with topiramate makes it useful as prophylaxis for migraineurs with comorbid conditions accompanied by weight gain (eg, fibromyalgia).
For the patient with comorbid epilepsy, agents that lower seizure threshold (eg, TCAs) should be avoided.3 β-Blockers, which may worsen depression, should not be used to treat migraine in patients who have comorbid depression.
Treatment for migraine, as for many other disorders, must take into account the entire patient. With migraine, especially, effectiveness is to be balanced with patient-preferred treatment attributes and his or her expectations and lifestyle. Other important treatment considerations when prescribing a medication include duration of action, onset of response, and tolerability. Failure to consider comorbidities in the recognition and treatment of the patient with migraine may ultimately lead to exacerbation of the comorbid conditions themselves or, at least, result in patient dissatisfaction.
Conversely, treatment of the comorbid symptoms may not satisfactorily resolve patient migraine complaints. The onus is therefore on the physician to consider a total management approach that includes the treatment of comorbid conditions when prescribing pharmacologic therapy for the patient who presents with migraine or migrainous symptoms. n
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