Menstrual-Related Headache

Gregory Moy; Vikas Gupta

Menstrual-Related Headache

Author: Gregory Moy Editor: Vikas Gupta Updated: 10/4/2022 9:51:20 AM

Introduction

Menstrual-related headaches are a common class of headaches that occur in women related to a decline in estrogen during the menstrual cycle. To treat this type of headache, it must be appropriately diagnosed regarding the menstrual cycle or aligned with exogenous hormones, usually 2 days before the onset of menses to the third day of menstrual bleeding. Triptans, nonsteroidal anti-inflammatory drugs (NSAIDs), and hormone therapy are just a few of the many pharmacological interventions used in the management and treatment of menstrual-related headaches.

Etiology

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Etiology

Menstrual-related headaches are related to several important factors, mainly estrogen, which has actions involved in the serotonergic and glutamatergic systems of the CNS. This accounts for its association with headaches, where serotonin and estrogen levels are directly related. During the late secretory phase of the menstrual cycle, when estrogen is low, the production of serotonin decreases, leading to increased calcitonin gene-related peptide (CGRP) and substance P from trigeminal nerves. These substances are involved in the pathophysiology of general migraines and cause vasodilation of intracerebral vessels and sensory sensitization of the trigeminal nerve. The permeability of the blood-brain barrier increases, releasing pro-inflammatory mediators in pain-sensitive meninges.[1] Around menstruation, cranial nociception is perceived as more intense due to a decrease in endogenous opioid activity, exacerbating the pain pathway.

Family history should be assessed when a patient presents to a provider with a general acute headache. Genetic differences include increased expression of membranous protein channels and receptors involved in the pathophysiology of migraines.[2] These individuals are more susceptible to acute migraine attacks. Other risk factors include those on certain medications, such as combined hormonal contraception. Those who are on higher doses of estrogen are more likely to suffer from MRH due to the acute falls in estrogen during the late luteal and early follicular stages of the menstrual cycle.

Epidemiology

Migraines affect around 12% of the general population and are more frequent in women than men. Peak migraine prevalence in women occurs between the early 30s and early 40s, and menstrual-related headaches are very common in the perimenopausal period, likely due to marked fluctuations in estrogen levels. Up to 41% of all women experience a migraine episode by their early 50s.[3]

Pathophysiology

Increases in sensitivity to pain responses to both central stimuli and peripheral appear to be influenced by estrogen. Estrogen affects the sensitivity of dopaminergic and serotonin receptors and cerebral vessels to serotonin.[4] Activation of central nociceptive pathways from the cortex and brain stem stimulates the trigeminal vascular system, which innervates cerebral blood vessels. This leads to the release of vascular inflammatory substances, including prostaglandins, CGRP, and cytokines.[5]

History and Physical

Menstrual-related headaches generally present similarly to nonestrogen-related migraines.[6] They frequently have a pulsatile quality, last for about 1 day, are unilateral, associated with nausea, and can be disabling. Many individuals also report photophobia during attacks, which is relieved by lying down in a dark, quiet room. Menstrual-related headaches should align with the late luteal and early follicular stages of the menstrual cycle, a headache between 2 days before the onset of menses and the third day of menstrual bleeding.

Most patients have a normal neurological exam, but some can experience cutaneous allodynia, which is the perception of pain produced by a small stimulus, such as brushing hair, touching the scalp, shaving, or wearing contact lenses, resulting in sensitization of central pain pathways, in migraine. Additionally, patients can have tenderness or difficulty resting on the allodynic side. Although rare, some studies suggest migraines can be potential risk factors for causing Bell palsy, sensorineural hearing loss, and oculomotor cranial nerve palsies.[7]

Evaluation

Menstrual-related headaches are mainly a clinical diagnosis. In general, radiographic images are relatively normal; however, magnetic resonance imaging findings can sometimes have white matter hyperintensities, which have been linked to brain hyperperfusion, breakdown of the blood-brain-barrier, and localized cerebral edema, rather than to primary ischemia. Diffuse non-lateralizing brain hyperperfusion generally prevails during migraine attacks for more than 48 hours in the cerebral cortex, thalamus, and basal ganglia.[8] Radiographic imaging is only warranted when the quality, location, and duration differ from previous headaches.

Migraines cause vasodilation of intracerebral vessels and sensory sensitization of the trigeminal nerve, causing inflammatory changes in the pain-sensitive meninges. This increases the blood-brain barrier's permeability, which releases proinflammatory mediators. Factors to consider when choosing the type of examination depend on the clinical indication, diagnostic performance, availability of computed tomography or magnetic resonance imaging, radiologist expertise, and patient contraindications. Any imaging of the vessels requires the use of IV contrast. Computed tomography angiogram and magnetic resonance angiogram examinations image the arteries and veins. MRH should have normal imaging and can sometimes be a diagnosis of exclusion in an emergency medicine setting.

Diagnostic criteria according to International Classification of Headache Disorders, 3rd edition:[9]

Pure menstrual migraine:

Attacks in a menstruating woman fulfilling the criteria for migraine without aura
Attacks occur on days 2 days before and last till the third day of menstruation
- Occur in at least 2 out of 3 menstrual cycles
- Do not occur at other times of the cycle

Menstrually related migraine:

Attacks in a menstruating woman fulfilling the criteria for migraine without aura
Attacks occur on days 2 days before and last till the third day of menstruation
- Occur in at least 2 out of 3 menstrual cycles
- Can also occur at other times of the cycle

Treatment / Management

Therapeutic lifestyle measures may be beneficial for controlling migraines, including proper sleep hygiene, healthy nutrition, routine meal schedules, regular exercise, and managing migraine triggers such as stress, alcohol, weather, and, most commonly, hormones.

Managing menstrual-related headaches starts with identifying where the headache aligns with the patient’s menstrual cycle. Suppose a patient is already on oral contraceptive pills. In that case, the headache may be prevented simply by altering her current hormone regimen by reducing the estrogen dose to limit the premenstrual decline in estrogen that precipitates the MRH.[10][11](A1)

If women are opposed to starting hormonal therapy, are noncompliant, or contraindications exist, common abortive therapy involves using triptans, which target the direct pathophysiologic mechanism of migraines. All triptans are serotonin 1b/1d receptor agonists that prevent pain by blocking trigeminal nerve activation, inhibiting the release of vasoactive peptides, and promoting vasoconstriction.[12][13](A1)

Most NSAIDs block COX 1/2 and can be an effective monotherapy in some women. Mefenamic acid has been extensively studied for treating acute MRH and can relieve general dysmenorrhea.[13][14](A1)

Metoclopramide given intravenously has been proven to be as efficacious as triptan therapy when treating acute migraines in an emergency room setting.[15] Akathisia is a potential side effect that can be prevented with diphenhydramine; however, adding diphenhydramine does not improve migraine severity.

Dihydroergotamine is an alpha-adrenergic blocker, vasoconstrictor, and potent serotonin 1b/1d receptor agonist usually reserved for severe cases of chronic intractable migraine headaches or status migrainosus.[16]

Pharmacologic modulation of CGRP activity appears to mediate trigeminovascular pain transmission in migraine. CGRP antagonists are novel options for acute migraine treatment in patients with either insufficient response or contraindications to first-line medications.[17][18][19](A1)

Other alternative nonpharmacological interventions to consider are nerve blocks. Patients opposed to taking oral or intravenous medications may be candidates for the sphenopalatine ganglion block.[20] This technique involves saturating a long cotton swab in a local anesthetic and inserting the swab into the naris of the unilateral side of the patient’s headache. In contrast, the patient is in the sniffing position. The swab should be inserted until resistance is met at the posterior wall of the nasopharynx and left in place for at least 10 minutes.

Neuromodulation, such as transcutaneous electrical nerve stimulation, single-pulse transcranial magnetic stimulation, and, in extreme circumstances, surgical deactivation of migraine trigger sites, has limited data but is a therapy directed at stimulating the nervous system with an electrical current or a magnetic field. These options are generally reserved for patients with poor response or contraindications to pharmacological interventions.

The use of opioids in treating MRH is generally avoided due to long-term changes in the CNS at the molecular level. Opioids lead to increased descending facilitation from the rostral ventromedial medulla and increased excitatory neurotransmission at the level of the dorsal horn, causing medication overuse headaches.[21] Other data suggests that chronic opioid administration increases CGRP expression in primary afferent neurons, upregulating pain afferents.

Differential Diagnosis

Menstrual-related headaches have a broad differential diagnosis, including other primary headaches such as tension and cluster headaches. Treatment of MRH and other primary headaches overlap so that diagnosis can be distinguished from the patient's history and physical exam features. Some can experience cutaneous allodynia, the perception of pain produced by a small stimulus, such as brushing hair, touching the scalp, shaving, or wearing contact lenses. This results in the sensitization of central pain pathways in migraines. These episodes typically last seconds to minutes, but when they increase in intensity and frequency over time, they indicate trigeminal neuralgia, which responds well to a different therapy.

Secondary headaches from trauma, vascular-related injury, metastasis, or infection can also be considered. Cerebral aneurysms, cerebral venous thrombosis, dissection syndromes, encephalitis, meningitis, intracranial hemorrhage, and temporal arteritis have different features that can usually be either ruled out or diagnosed with laboratory testing, additional head imaging, or CSF sampling. Since MRH is rarely associated with aura, it is less common to be mistaken for a transient ischemic attack. Useful features for distinguishing MRH include the duration, timing, quality, comparison to previous headaches, neurological exam, and other associated symptoms during and after the attacks.

Treatment Planning

Table 1. Acute therapy for migraine*Adverse effects in this section pertain to all triptans unless specified

Drug class/Drug	Drug	Dose range	Notes
Nonsteroidal anti-inflammatory drugs	Aspirin[22] Ibuprofen Naproxen Diclofenac Diclofenac epolamine Tolfemanic acid Celecoxib[23] Dexletoprofen	900-100 mg 400-600 mg 275-825 mg 50-100 mg 65 mg 200 mg 120 mg 50 mg	All NSAIDs have similar efficacy
Non-opioid analgesic	Acetaminophen[24]	1000-3000 g	Acute-life threatening hepatotoxicity at > 4 g/d
Serotonin 1b/1d agonists (triptans) (Sumatriptan)*[25]	Sumatriptan (oral) Sumatriptan (intranasal solution)[26] Sumatriptan (intranasal powder) Sumatriptan (spray) Sumatriptan (subcutaneous)	50-100 mg as a single dose, maximum dose: 200 mg/d 20 mg as a single dose in 1 nostril; if symptoms persist, may repeat dose after ≥2 hours, maximum dose: 40 mg/d 22 mg as a single dose, may repeat dose after ≥2 hours if symptoms persist or return, maximum dose: 44 mg/d 10 mg as a single dose in 1 nostril. Repeat dose after ≥1 hour if symptoms persist or return; maximum dose: 30 mg/d 6 mg as a single dose, may repeat dose (usually same as the first dose) after ≥1 hour if symptoms persist or return, or lesser dosage if 6 mg was not tolerated, maximum dose: 6 mg/dose; 12 mg/d	All formulations of triptans are contraindicated in severe hepatic impairment. Contraindicated in patients with cardiovascular illness as prolonged QT interval on ECG and subsequent ventricular arrhythmias, including torsades de pointes (TdP) and ventricular fibrillation, are reported. It may also cause dizziness, lethargy, tremors, vertigo, akathisia, dystonia, and pathological laughter. Other vasospasm-related events include peripheral ischemia, ischemic colitis, splenic infarction, and Raynaud disease. It should be avoided in patients with uncontrolled hypertension and pregnancy. Ocular side effects include transient and permanent blindness and significant partial vision loss. The use of concomitant serotonergic drugs may cause serotonin syndrome. Unpleasant taste is lower with intranasal zolmitriptan than with intranasal sumatriptan. Patients who do not respond to 1 triptan may respond to another. Naratriptan and frovatriptan have a slower onset and lower efficacy.
Serotonin 1b/1d agonists (triptans) (Naratriptan)	Naratriptan[27]	2.5 mg as a single dose; may repeat dose after ≥4 hours; maximum dose: 2.5 mg/dose; 5 mg/d.	Use within 24 hours of an ergotamine preparation or a different triptan is not advised. Contraindicated with severe renal impairment (CrCl <15 mL/minute).
Serotonin 1b/1d agonists (triptans) (Zolmitriptan)	Zolmitriptan (oral) Zolmitriptan (intranasal)	2.5 mg as a single dose; may repeat dose after ≥2 hours; maximum dose: 5 mg/dose; 10 mg/d[28] 2.5 to 5 mg as a single dose; may repeat dose after ≥2 hours; maximum: 5 mg/dose; 10 mg/d	Refer to the section on sumatriptan above for the side effects of triptans.
Serotonin 1b/1d agonists (triptans) (Frovatriptan)	Frovatriptan	2.5 mg as a single dose; may repeat dose after ≥2 hours if needed; maximum dose: 2.5 mg/dose; 5 mg/d	Slower onset
Serotonin 1b/1d agonists (triptans) (Almotriptan)	Almotriptan	12.5 mg as a single dose; may repeat dose after ≥2 hours when needed; maximum dose: 12.5 mg/dose; 25 mg/d[29]	Reduce dose to half with hepatic impairment
Serotonin 1b/1d agonists (triptans) (Rizatriptan)	Rizatriptan	5 to 10 mg as a single dose; may repeat dose after ≥2 hours if needed; maximum dose: 20-30 mg/d	Propranolol increases rizatriptan levels by 70%. So, the dose of rizatriptan must be adjusted downward for these patients.
Serotonin 1b/1d agonists (triptans) (Eletriptan)	Eletriptan[30]	40 mg as a single dose; may repeat dose after ≥2 hours if needed; maximum dose: 40 mg/dose; 80 mg/d	Primarily metabolized by cytochrome P-450 enzyme CYP3A4. Not advised within at least 72 hours of treatment with other drugs that are potent CYP3A4 inhibitors: itraconazole, ketoconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, and nelfinavir.
Antiemetics	Metoclopramide (IV, IM, oral)[31] Prochlorperazine (IV, IM)	10-20 mg as a single dose 10 mg as a single dose	IV route is preferred for metoclopramide. Pretreat with diphenhydramine to prevent akathisia and other acute dystonic reactions.
CGRP antagonists	Rimegepant[18] Ubrogepant[32]	75 mg every other day; maximum dose: 75 mg/d 50 to 100 mg as a single dose; may repeat dose after ≥2 hours if needed; maximum dose: 200 mg/d	Administration early in the course of a migraine attack may improve response to treatment. Second-line therapy when triptans are contraindicated, poorly tolerated, or ineffective. More studies are needed to establish efficacy and safety.
Serotonin 5-HT1F receptor agonist[33]	Lasmiditan[34]	50 to 100 mg as a single dose; may increase to 100 or 200 mg as a single dose if needed; repeat doses have not established efficacy.	Administration early in the course of a migraine attack may improve response to treatment. Second-line therapy when triptans are contraindicated, poorly tolerated, or ineffective. A significant side effect is dizziness (9% to 17%). Wait at least 8 hours between dosing and driving or operating heavy machinery. It may enhance the CNS depressant effect of alcohol.
Ergot derivative	Dihydroergotamine[35]	IM: 1 mg as a single dose; may repeat hourly as required; maximum dose: 3 mg/d, 6 mg/week IV: 1 mg as a single dose; may repeat hourly as required; maximum dose: 2 mg/d, 6 mg/week SUBQUT: 1 mg as a single dose; may repeat every 2 hours as required; maximum dose: 3 mg/d, 6 mg/week Intranasal: 0.5 mg per spray: 1 spray (0.5 mg) into each nostril; repeat after 15 minutes (total of 4 sprays per dose); maximum dose: 4 sprays (1 dose)/d	Use is contraindicated in severe hepatic or renal impairment as well as pregnancy or breastfeeding. Also contraindicated in patients with hypertension or ischemic heart disease. It should not be used within 24 hours of triptans or ergot-like agents. It is also avoided when combined with potent CYP3A4 inhibitors (including azole antifungals, protease inhibitors, and some macrolide antibiotics).

Table 2. Preventive therapy for migraine[36]

Drug Class	Drug	Dose Range	Adverse Effects/Contraindications
Beta-adrenoceptor blockers[37]	Propranolol Metoprolol Timolol	80-240 mg 50-150 mg 10-20 mg	Contraindicated in asthma, syncope, heart block
Antidepressants	Amitriptyline Nortriptyline Venlafaxine	10-150 mg 25-100 mg 37.5-150 mg	Somnolence Insomnia, hypertension
Calcium-channel blockers	Verapamil[38]	180-480 mg	Constipation, hypotension, edema
Antiepileptic drugs[37]	Divalproex sodium Topiramate Gabapentin	200-1500 mg 25-150 mg 300-1800 mg	Weight gain, thrombocytopenia, tremor Renal calculi, amnesia, glaucoma, dysequilibrium, weight loss
CGRP monoclonal antibodies	Erenumab Galcanezumab	70 to 140 mg every 4 weeks, subcutaneously 120 mg monthly subcut	Injection site reactions, muscle spasms, hypersensitivity reaction Injection site reactions, vertigo, pruritus, constipation

Prognosis

Women who suffer from menstrual-related headaches generally have a good prognosis, and headaches usually respond well to conventional first-line pharmacological therapy. However, success sometimes depends on the reliability of predicting the regularity of a woman’s menstrual cycle. Those with irregular cycles are usually not good candidates for hormone-directed therapy.

Complications

Although triptans are relatively safe drugs, some contraindications do exist. Cardiovascular disease should be screened for hypertension, hypercholesterolemia, smoking history, obesity, diabetes, strong family history of coronary artery disease, and menopause before initiation of therapy. Prinzmetal angina and coronary artery disease are absolute contraindications due to the risk of coronary vasospasm.[39] A complete history of other medications should be taken to avoid possible drug-drug interactions. Patients on antidepressants are at higher risk of developing serotonin syndrome. Chronic exposure to triptans could lead to the downregulation of serotonin receptors and changes in central inhibitory pathways that translate to an impairment of antinociceptive activity and a permanent feeling of head pain.

Oral contraceptive pills should not be given to patients who are older than 35 years and smoke cigarettes, have 2 or more risk factors for coronary artery disease or known ischemic heart valve disease, hypertension, history of venous thromboembolism, thrombogenic mutations such as antiphospholipid disease or systemic lupus erythematosus, history of stroke, breast cancer, or migraine with aura.[40] These are all risk factors for hypercoagulability and can ultimately lead to an embolism. Studies have shown that the use of combined hormonal contraceptives among women with migraines with aura is a higher risk of ischemic stroke.[40]

NSAIDs are contraindicated in patients with peptic ulcer disease or at risk for gastroduodenal disease due to blocking prostaglandin, which protects the gastric mucosa. Patients at increased risk of cardiovascular disease may be restricted to NSAID use due to reduced prostaglandin I2 production by vascular endothelium with limited inhibition of prothrombotic platelet thromboxane A2 production, putting patients at higher risk for embolism. Patients with renal disease should avoid NSAID use due to the blockage of prostaglandins, which promote renal vasodilation and maintain renal perfusion.[41]

Deterrence and Patient Education

Patients who experience frequent or severe headaches may benefit from a one-month headache diary in which they can record the duration, intensity, and location of each headache and whether it responds to therapy. Additionally, potential triggers such as food, alcohol, stressors, weather conditions, and what day of their menstrual cycle they are on can be logged. This data may provide information for avoidance and may help to determine what triggers their migraine headaches and what makes them better.

Enhancing Healthcare Team Outcomes

Coordinating care between healthcare professionals is essential to patient care, especially when modulating a patient's pharmacological therapy. Whether a woman's menstrual headaches are being managed by a neurologist or in the emergency setting, it is important to coordinate with all clinicians. Patients should see the same clinician or, at the very least, a provider in the same health network where other specialists can easily access the electronic medical record. Having old records is an invaluable tool to see if there are any medication regimen changes, history differences, or physical exam findings.

Whether a neurologist, an emergency clinician, or another specialist is currently treating the patient, improving care coordination with the primary care clinician would minimize the adverse effects of new interventions. For example, suppose a woman with an acute migraine presents and does not know that she has an underlying cardiac problem and is given triptan therapy. In that case, this can lead to fatal coronary vasospasm. Coordinating medication regimens with input from a pharmacist can be a very helpful interprofessional strategy.

Monitoring a patient's headache calendar and coordinating the dates with the patient's menstrual cycle is key to targeting treatment. If there are clear differences in the pattern of quality, location, and timing in the patient's previous recorded headaches, it can suggest an alternate diagnosis. Collaborating care can ultimately change patient management and help identify if the patient needs outpatient therapy versus emergent treatment. Nursing also provides crucial care, coordinating actions between various disciplines and providing necessary patient counseling.

The importance of communication between the interprofessional team cannot be undervalued as patients started on combined hormonal contraception can have serious adverse effects. Patients being treated for acute migraines that have worsened may need to change their long-term treatment regimen, but not before clinicians and other associated healthcare providers coordinate therapies.

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