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Headache
Stephen D. Silberstein, MD
Medscape

Headaches can be classified into 2 major categories: primary and secondary. Primary headache disorders include migraine, both episodic and chronic (a subtype of chronic daily headache); tension-type headache, both episodic and chronic (another subtype of chronic daily headache); and cluster headache. Secondary headaches result from other organic disturbances, such as infection, metabolic disorders, or other systemic illness. The number of investigations into the pathophysiology and treatment of these different types of headache continues to grow, and many findings were presented at the 54th Annual Meeting of the American Academy of Neurology.

Migraine Treatment
Clinical trials investigating the efficacy of triptans have traditionally assessed the treatment of patients with moderate or severe migraine. However, in clinical practice, patients do not want to wait until their migraine is moderate or severe in intensity before taking their medication. Preliminary evidence has suggested that treatment in the mild phase of a migraine provides higher pain-free rates.
Klapper and colleagues[1] investigated whether treatment of mild migraine with oral zolmitriptan 2.5 mg confers higher pain-free response rates compared with placebo in the acute treatment of patients who are highly disabled by migraine. This multinational, double-blind, placebo-controlled trial randomized patients to receive oral zolmitriptan 2.5 mg or placebo to treat a single migraine attack. Participants' migraine attacks typically started as mild but progressed to moderate/severe intensity, and they had moderate or severe migraine-related disability (MIDAS grade III/IV). Patients treated the attack while it was in the mild phase.

The intent-to-treat population comprised 280 patients (mean age, 42 years; 86% female). Two hours after treating mild migraine, 43.4% of the zolmitriptan group were pain free vs 18.4% of placebo patients (P < .0001). For patients who treated their migraine very early, the response was more pronounced: of zolmitriptan patients who treated a mild migraine within 15 minutes, 56.6% were pain free at 2 hours compared with 20.0% of placebo recipients. Furthermore, it took significantly less time for zolmitriptan vs placebo patients to achieve a pain-free response (P < .0001).

For patients with significant migraine-related disability, treating mild migraine with this dose of zolmitriptan produces high pain-free response rates and, compared with placebo, significantly reduces the time it takes to become pain free. In addition, the earlier the mild migraine is treated with zolmitriptan, the greater the pain-free response. This result is compatible with the experience of clinical practice. Early treatment of disabling headache produces better outcomes.


Migraine Prophylaxis and Weight Gain
Preventive migraine medications often are associated with weight gain, which has a negative effect on patient compliance, health, and social well being. Loewinger and Young[2] determined the relative effects on weight of various preventive medications used in the treatment of headache. They reviewed the medical records of patients who were seen in a headache clinic and treated with divalproex, fluoxetine, nortriptyline, riboflavin, or topiramate. Patients who received monotherapy, or polytherapy with a selective serotonin reuptake inhibitor (SSRI) other than fluoxetine, were included. Based on an assumption of straight-line weight change for 2 time-points surrounding the time of interest, the researchers calculated weight for 90, 180, and 270 days after the initiation of treatment. Initial average weight was 150.8 +/- 27.7 lb for those receiving divalproex, 150.0 +/- 30.4 lb for those on fluoxetine, 154.3 +/- 33.4 lb for nortriptyline, 152.3 +/- 28.8 lb for riboflavin, and 185.0 +/- 54.4 lb for topiramate. At 90 days, mean weight gain was 1.8 +/- 3.8 lb for divalproex, 1.5 +/- 3.0 lb for fluoxetine, 3.4 +/- 3.3 lb for nortriptyline, 0.3 +/- 2.5 lb for riboflavin, but a weight loss of 6.9 +/- 3.4 lb for those on topiramate. At 270 days, weight gain totaled 4.1 +/- 6.8 lb for divalproex, 6.2 +/- 5.7 lb for fluoxetine, 3.8 +/- 4.5 lb for nortriptyline, 0.5 +/- 5.4 lb for riboflavin, with a weight loss of 10.8 +/- 8.3 lb for topiramate.
Baseline weight, length of treatment, preventive medication, and drug dose all correlated significantly with final weight (P < .05 for all). Age and use of an SSRI (excluding fluoxetine) did not correlate with final weight (P = not significant [NS]), and gender was only marginally significant (P = .06). Using Dunnett's method for multiple comparisons, and controlling for baseline weight, gender, age, use of an SSRI, and dose, revealed significant differences in weight for patients receiving topiramate compared with all other treatment groups (P < .05 for all) except riboflavin (P = NS).

Thus, patients treated with topiramate lost weight, in contrast to those treated with divalproex, fluoxetine, or nortriptyline. Patients receiving riboflavin experienced minimal weight change.


Botulinum Toxin and Migraine
In 1992, Binder made the serendipitous discovery that migraine sufferers experienced fewer and less severe headaches following the cosmetic use of botulinum toxin type A (BTX-A). Since then, its potential use in headache prevention has been met with both enthusiasm and skepticism; several studies have examined the effect of BTX-A on different pain conditions, including migraine. Thus far, controlled studies of BTX-A for patients with migraine and tension-type headache have used severity and frequency of headaches as outcome measures and have yielded promising but mixed results. But no studies have examined whether BTX-A can reduce disability in patients who suffer from episodic or chronic migraine.
Eross and Dodick[3] conducted a prospective, open-label study to determine the effects of BTX-A for patients with episodic or chronic migraine. They included migraine patients in their clinic who received BTX-A for headache treatment during 2001. Each patient received a total of 25 units of BTX-A in divided doses injected into the frontalis, temporalis, procerus, and corrugator muscles. The clinician had the discretion to inject additional doses (25 to 75 units) into cervical paraspinal muscles depending on interictal tenderness to palpation. Patients completed a questionnaire before treatment and at follow-up (at least 3 months after treatment). From these, investigators determined the percent change in disability, number of headache days, and change in severity of headache for all patients, and for the subgroups of patients with episodic migraine and chronic migraine. Ultimately, those who experienced at least a 50% improvement in disability were teased out of the whole and the clinical characteristics separating responders from nonresponders were abstracted from patients' histories.

BTX-A reduced disability by more than 50% in the majority of the patients, and 40% achieved an excellent response (more than 75% improvement in disability). Response to BTX-A was independent of underlying muscle tenderness and the amount of BTX-A used. Furthermore, those with episodic migraine were more likely to respond to BTX-A than those with chronic migraine. Patients younger than 40 years of age were more likely to respond to BTX-A than those older than 60 years of age, which may relate to the duration of the illness. Analgesic overuse predicted a negative response to BTX-A for headache prevention.


Cluster Headache
Cluster headache is the most severe and debilitating of the primary headaches. It can have a chronic course and be unresponsive to medication. Positron emission tomography (PET) has shown that the inferior posterior hypothalamic gray matter homolateral to the pain is activated during cluster headache attacks.[4] A voxel-based morphometric magnetic resonance imaging (MRI) study also demonstrated changes in the same area in patients with cluster headache.[5] This suggests that the cluster headache generator is located in this region.
Leone and associates[6] reasoned that high-frequency electrical stimulation of this area might prevent activation during cluster headache and thus relieve intractable forms of the disorder. They previously reported success with 1 severely compromised patient.[7] At this meeting, they presented preliminary results and follow up of 4 patients with severe, intractable, chronic cluster headache. They implanted stereotactic electrodes into the hypothalami of 4 patient, for a total of 5 implants in 4 patients (3 men, 1 woman, mean age 51.2 years, range 39-63 years). All had International Headache Society (IHS) chronic cluster headache, with 1 being bilateral. MRI and angio-MRI ruled out secondary causes for their headaches. Mean illness duration was 7 years (range 3-9 years), with an average of 7 attacks per day.

All patients have been completely free of headache attacks after a mean of 7.8 months (range 1-16 months). Two patients (including 1 who received bilateral implants) required no add-on pharmacologic therapy; 1 patient required methysergide (3 mg/day); and the most recently operated patient is being tapered from dexamethasone.

The stimulator was switched off 3 times in 1 patient, and once in another patient. On 3 occasions, pain reappeared within 48 hours, but on the other, it reappeared after 23 days. When stimulation was restarted, the pain disappeared twice in less than 24 hours and twice after 10 days. All 4 patients have normal blood pressure, heart rate, electrolyte balance, hormone levels, and behavior. In this study, hypothalamic stimulation was well tolerated and may be a treatment option for intractable chronic cluster headache.


Menstrual Migraine Pathogenesis
Menstrual migraine attacks may be triggered by the fall in estrogen levels that are associated with menstruation. Cortical spreading depression (CSD) is considered the basis for the migraine aura. Welch and colleagues[8] examined estrogen effects on gene regulation in mice after CSD. Using adult male mice, adult ovariectomized female mice, and adult ovariectomized female mice with estrogen replacement, the investigators induced 4 episodes of CSD by application of 300 mM potassium chloride. They then analyzed differential gene expression of 1176 known mouse genes.
Genes regulated in both male and ovariectomized female mice relative to ovariectomized female with estrogen included: apolipoprotein E precursor and glutathione S-transferase 5 (protective against oxidative stress), and the vasoactive and pain-modulating peptides atrial natriuretic peptide (ANP) and neuropeptide Y (NPY). In male rats, ANP was upregulated and NPY was downregulated. By contrast, in ovariectomized female with estrogen CSD mice, NPY was upregulated whereas ANP was reduced. The genes downregulated by estrogen included: (1) the protein inhibitor of neuronal nitric oxide, which is involved in NO signaling; (2) a regulator of g-protein signaling 4 and calmodulin; (3) the heat shock protein 86; and (4) cytokines and receptors monocyte chemoattractant protein-1, granulocyte-macrophage colony-stimulating factor, and interleukin-11.

CSD regulates protective genes against potential pathologic consequences (oxidative stress) in both sexes. In this model, estrogen downregulates genes involved in signal transduction and NO signaling. The hormone differentially affects genes that may link CSD-initiated vascular responses and pain, diminishing the vasodilator (ANP) and increasing the vasoconstrictor (NPY) response to CSD. Estrogen also suppresses chemokine gene expression response to CSD. The drop in estrogen levels at menstruation, known to trigger migraine, might be favorable to vasodilation and inflammation, which could account for some aspects of the pathogenesis of headache. However, the relevance of this model is uncertain as menstrual migraine typically occurs without aura.


Chronic Daily Headache
The term chronic daily headache (CDH) refers to frequent headaches that occur 15 or more days a month, including those headaches that are associated with medication overuse. CDH is classified as primary or secondary. Primary CDH sufferers have headaches more than 15 days/month that are not related to a structural or systemic illness. Population-based studies in the United States, Europe, and Asia suggest that 4% to 5% of the general population have primary CDH. In population samples, chronic tension-type headache is the leading cause of primary CDH, whereas in clinic populations, the cause is chronic (transformed) migraine.
Primary CDH can be subclassified on the basis of average headache duration (>/= 4 hours, or < 4 hours). When headache duration is less than 4 hours, the differential diagnosis includes cluster headache, chronic paroxysmal hemicrania, idiopathic stabbing headache, hypnic headache, and other miscellaneous headache disorders. When the headache duration is 4 hours or longer, the major primary disorders to consider are chronic migraine, hemicrania continua, chronic tension-type headache, and new daily persistent headache.[9]

Patients with episodic migraine may develop more frequent headaches and have daily or near daily headaches known as chronic or transformed migraine. Using analysis of transverse relaxation rates, R2, R2*, and R2' (R2* value reflects blood oxygen level dependence; R2' is a measure of nonheme iron in tissues), Welch and associates[10] have studied transformed migraine patients radiographically during headache and demonstrated activation (hyperoxia) of the red nucleus (RN) and substantia nigra (SN), and dysfunction of periaqueductal gray (PAG) based on increased iron levels (elevated R2'). Now, this group[11] reports a patient with transformed migraine who reverted to episodic migraine after treatment.

For 6 months, a 48-year-old woman suffered transformed migraine that was associated with overuse of ergotamine and acetaminophen. Detoxification using repeated dosages of intravenous dihydroergotamine resulted in reversion from transformed migraine to episodic migraine.

During the CDH phase of her illness, respective R2* values were reduced in the RN and SN, and R2' in RN and SN were likewise abnormally low relative to normal. The indices also indicated prominent activation (increased flow and hyperoxia) of these structures during headache. Subsequent studies performed when she was headache-free demonstrated that R2* and R2' in the RN and in the SN returned to normal. The R2' in PAG during episodic migraine for this woman was increased at 6.88 ms-1 (mean for episodic migraine = 6.11 0.88, n = 17) but elevated compared with controls (4.33 0.97 ms-1, n = 17).

This patient's daily headache was associated with chronic activation of pain networks that included RN and SN. Headache resolution was associated with resolution of activation, although evidence showed persistent PAG dysfunction. This case offers the first objective correlation of the clinical features of transformed migraine and its response to treatment with functional changes in brainstem nociceptive networks.


Classification Systems for CDH
The IHS classification has been criticized for its approach to CDH. Some argue that many patients cannot be classified, and others find the system cumbersome, requiring multiple diagnoses. The Silberstein-Lipton (S-L) criteria provide an alternative to the IHS classification of CDH.
Bigal and colleagues[12] applied alternative diagnostic approaches to a sample of CDH patients seeking treatment at a headache clinic. These researchers reviewed clinical records from a headache specialty clinic, identifying 638 patients who fulfilled the following eligibility criteria: (1) headaches lasting more than 4 hours each day for more than 15 days each month; and (2) no evidence of organic disorder. Based on chart and diary reviews, patients were classified according to both the IHS and S-L criteria.

The S-L criteria classified patients as follows: chronic migraine (CM) (1.8): 558 patients (87.4%); CM with medication overuse (1.8.1): 399 patients (62.5%); CM without medication overuse (1.8.2): 158 patients (24.7%); chronic tension-type headache (CTTH) (2.2): 6 patients (0.9%); CTTH with overuse (2.2.1): 2 patients (0.3%); CTTH without overuse (2.2.2): 4 patients (0.6%); new daily and persistent headache (NDPH) (4.6): 69 patients (10.8%); NDPH with overuse (4.6.1): 21 patients (3.3%); NDPH without overuse (4.6.2): 48 patients (7.5%); hemicrania continua (HC) (4.8): 5 patients (0.8%); HC without overuse (4.8.2): 5 patients (0.8%).

The IHS criteria classified 631 (98.9%) patients with 14 different diagnoses (compared with 8 above). The most common diagnoses were migraine without aura (MO) + CTTH + analgesic overuse (AO): 320 (50.1%); and MO + CTTH (21.9%).

Both systems are capable of classifying most patients with CDH who also have daily headache diaries. However, the S-L system is more parsimonious and, thus, easier to apply. It is compatible with natural history, and thus useful both in prospective and retrospective research.


Snoring and Headache
Sleep-disordered breathing is often associated with snoring and can be associated with headache, perhaps secondary to hypoxia, hypercapnia, or altered sleep architecture. In clinic patients and in cross-sectional population surveys, snoring has been associated with episodic headache. Scher and coworkers[13] examined the risk of CDH associated with snoring.
Participants were identified from a community sample of adults. Cases were defined as those with 180+ headache days per year, and controls had 2 to 104 headache days per year. All participated in a telephone survey about their health. The investigators assessed snoring with the question: "How often do you snore: never/rarely, less than half the time, more than half the time, or always?" Those who answered "always" were considered habitual snorers; all others were deemed nonsnorers. Other relevant questions concerned sleep problems ("trouble falling or staying asleep or sleeping too much") and fatigue ("feeling tired or having little energy").

Cases were more likely to be habitual snorers than controls (odds ratio [OR] = 2.1 [1.3-3.3]). In addition, cases were also more likely than controls to report problems with sleeping (OR = 2.5[1.8-3.5]) or being tired (OR = 2.5[1.7-3.7]), independent of snoring status.

Compared with nonsnorers, habitual snorers were older (P < .001), more likely to have a history of hypertension (P < .001), and more likely to have a history of psychiatric illness (P < .05), for both cases and controls. For controls only, habitual snorers consumed more dietary caffeine (P < .01) and had higher body mass index (P < .01).

In this sample, CDH was independently associated with habitual snoring. The risk of CDH associated with snoring was found for women and men, and younger and older individuals. Sleep-disordered breathing may be an important cause of chronic daily headache in the community.


References
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Loewinger LE, Young WB. Headache preventives: effect on weight. Neurology. 2002;58:A286.
Eross EJ, Dodick DW. The effects of botulinum toxin type A on disability in episodic and chronic migraine. Neurology. 2002;58:A497.
May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet. 1998;352:275-278.
May A, Ashburner J, Buchel C, et al. Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nature Med. 1999;5:836-838.
Leone M, Franzini A, Amico DD, et al. Preliminary results and followup of stereotactic electrode implant in posterior hypothalamic gray matter to relieve intractable chronic cluster headache. Neurology. 2002;58:A89-A90.
Leone M, Franzini A, D'Amico D, et al. Stereotactic electrode implant in inferior posterior hypothalamic gray matter to relieve intractable chronic cluster headache: the first reported case. Neurology. 2001;56:218.
Welch KM, Choudri R, Cui L, et al. Estrogen regulation of gene expression in cortical spreading depression; relevance to menstrual migraine. Neurology. 2002;58:A91.
Silberstein SD, Lipton RB, Sliwinski M. Classification of daily and near-daily headaches: field trial of revised IHS criteria. Neurology. 1996;47:871-875.
Welch KM, Nagesh V, Aurora S, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache. 2001;41:629-637.
Aurora SK, Nagesh V, Norris LL, Welch KM. Functional imaging of subcortical nociceptive structures in response to treatment of chronic daily headache. Neurology. 2002;58:A91.
Bigal ME, Sheftell FD, Lipton RB, Rapoport AM, Tepper SJ. Evaluation of chronic daily headache: correlation between the International Headache Society and the proposed headache classification for chronic daily headache systems. Neurology. 2002;58:A172.
Scher AI, Stewart WF, Lipton RB. Snoring and chronic daily headache: results from the Frequent Headache Epidemiology Study. Neurology. 2002;58:A332-A333.




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