About 60% of women with migraines experience headaches during periods or menstrual migraines. If not treated optimally, migraines have the potential to interfere with the sufferer's quality of life. 

Menstrual Migraine
Illustration: A woman getting migraine during the period
Image source: http://www.eatingwell.com



What is Menstrual Migraine?

Menstrual migraine or catamenial migraine is one type of headache that is most often experienced and is often associated with the menstrual cycle (headaches during the period). Menstrual migraine is characterized by a longer attack duration and more intense pain than the common migraine.

The diagnosis criteria for menstrual migraines are the same as the common migraine diagnostic criteria. What distinguishes is the time in which menstrual migraine attacks occur concerning the menstrual cycle.

There are two types of menstrual migraines, namely:

1. Pure menstrual migraine:
headache attacks occur only 2–3 days after menstruation and do not occur at any other time
2.Migraine related to menstruation:
attacks of headaches mainly occur 2 to 3 days after menstruation (two out of three menstrual cycles) and occur at different periods.

The prevalence of pure menstrual migraines ranges from 1–14%, while the prevalence of menstrual migraines is 3–71%. Age most commonly occurs in the late 30s to early 40s and rarely occurs after menopause.



What are the causes, and how Menstrual Migraines occur?

Menstrual migraines are thought to occur due to decreased estrogen levels. Somerville first put forward this hypothesis in 1972. A decrease in estrogen levels can lead to an increase in prostaglandins. During menstruation, there is an increase in prostaglandin levels by more than three times. Prostaglandins cause neurogenic inflammation that triggers neuropeptides' release. Then, these neuropeptides trigger the trigeminovascular system and cause migraine attacks. 

Additionally, on research, hormones and estrogen receptors are widely expressed in the brain and trigeminovascular system. The density of these estrogen receptors in the brain and the trigeminovascular system is affected by estrogen levels changes during the menstrual cycle.

Estrogen receptors are mainly found in the periaqueductal area, thalamus, amygdala, and other brain areas that control pain perception. It is thought that estrogen levels fluctuations during the menstrual cycle are closely related to migraines and migraine-related behaviors such as allodynia and mood changes.



How to Manage Menstrual Migraines?

Menstrual migraine treatment can be divided into:
  1. acute therapy,
  2. short-term prophylactic therapy (mini-prophylaxis),
  3. long-term prophylactic therapy.

1. Acute Menstrual Migraine Therapy

In general, menstrual migraines' initial treatment is similar to nonmenstrual migraines (common migraines). Triptans or nonsteroidal anti-inflammatory drugs are effective enough to relieve migraine attacks. Based on various studies conducted in the United States, rizatriptan is the most effective treatment option for menstrual migraines' acute therapy.

Sumatriptan:
Various studies have been conducted to assess the efficacy of sumatriptan, both as monotherapy and in combination with naproxen. Sumatriptan at a dose of 50–100 mg orally, rectally, or subcutaneously has been reported to effectively relieve migraine intensity.

In their study, Martin et al. reported that acute therapy using sumatriptan was superior to placebo in alleviating the dysmenorrhoea, back pain, and irritability that often accompany migraine attacks. Two randomized controlled studies also reported that the combination of acute therapy sumatriptan and naproxen was more effective than the placebo in relieving migraine attacks.

Estrogen:
Based on research, estrogen levels correlate with migraine activity. Therefore, a hormonal therapy strategy was developed to prevent menstrual migraines. The goal of this treatment is to limit the drop in estrogen levels during menstruation. Clinical studies have shown that giving low doses of estrogen supplementation during menstruation effectively treats menstrual migraines.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Other Analgesics:
NSAIDs such as aspirin, ibuprofen, diclofenac, and naproxen are widely used to treat acute migraines, including menstrual migraines. Various studies have reported that NSAIDs are not inferior to triptans. However, NSAIDs have more side effects and contraindications than triptans, such as gastrointestinal bleeding, liver disorders, and kidney disease.

Several randomized controlled studies suggest that compared with placebo, combination therapy of paracetamol, aspirin, and caffeine effectively relieves acute pain in pure menstrual migraines and migraines related to menstruation.

Other Therapy:
There is currently research being developed on a new antimigraine drug—calcitonin gene-related peptide (CGRP) receptor antagonists.

2. Menstrual Migraine Miniprophylaxis Therapy

If acute therapy with both drugs is ineffective, short-term prevention (mini-prophylaxis) is the next step in therapy. Miniprophylaxis can be given to women with regular menstrual cycles. Therapy is given about 5–7 days, starting 2 days before the estimated start of menstruation until the end of menstruation. The treatment option for mini-prophylaxis is the triptan class of drugs. Alternatively, naproxen, mefenamic acid, and nonsteroidal anti-inflammatory drugs can also be used.

Sumatriptan:
Newman et al. conducted a study in women with menstrual-related migraines who were given sumatriptan 25 mg, 3 times daily as mini-prophylaxis. The time range for administration was 2-3 days before menstruation and was given for 5 days. This study reported that 52.4% of participants who took sumatriptan were free from migraine attacks.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Other Analgesics:
The use of NSAIDs as mini-prophylaxis for menstrual migraines has been evaluated in several studies. Sances et al. Conducted a double-blind randomized controlled trial by administering naproxen 550 mg twice daily. Naproxen is consumed 1 day before menstruation and for 7 days in 3 consecutive months. As a result, it was reported that there was a reduction in migraine intensity and duration in the intervention group.

Allais et al. examined the effectiveness of naproxen given for 14 days, starting 7 days before menstruation, and given for 3 consecutive months. After 3 months, naproxen was given for 10 days, starting 5 days before menstruation. This study also reported that the number and intensity of migraine attacks decreased in the naproxen group.

Another study examining the effectiveness of mefenamic acid 500 mg given 3 times daily during the menstrual cycle showed a reduction in pain intensity in 79.1% of cases. Another study using celecoxib 200 mg once daily for 7–10 days during menstrual periods reduced the number of attacks and the number of days menstrual-related migraine attacks occur.

Dihydroergotamine:
D'Alessandro et al. evaluated the use of 3.5 mg slow-release dihydroergotamine (DHE) in 20 women with menstrual migraines. Therapy is given 2 times a day for 2 days before the first day of menstruation for 5 days. After 5 months of therapy, the study results showed a reduction in migraine duration and attack severity.

Another study conducted research using 10 mg DHE for 6 days of menstrual periods in 3 consecutive cycles also showed a reduction in attack intensity.

Estrogen:
Estrogen supplementation during the perimenstrual period can minimize the risk of migraines. However, migraine attacks may occur upon discontinuation of therapy. The effective dose is 100 µg transdermal estradiol or 2 mg estradiol gel. In a randomized controlled study by Lignieres et al., the administration of 2.5 mg estradiol gel during the perimenstrual period (2 days before menstruation to 7th day of menstruation) was reported to reduce the severity and duration of attacks.

Another study by MacGregor reported that estradiol gel started 10 days after ovulation was also effective in reducing the number of days of migraine attacks. However, the incidence of migraine increased by 44% in the first 5 days after discontinuing therapy.


3. Long-term prophylactic therapy

Long-term menstrual migraine prophylactic therapy options include:
Topiramate:
Topiramate is frequently used as long-term prophylactic therapy for migraine. But, there is only one study evaluating topiramate's efficacy in menstrual migraine. The study included 198 patients with menstrual-related migraines who experienced at least four migraine attacks per month. Topiramate therapy is given at a dose of 50–200 mg per day for 6 months. During the therapy period, there was a reduction in the number of attacks outside the perimenstrual period. However, topiramate fails to reduce the duration and intensity of migraine attacks.

Combined Hormonal Contraception:
The aim of giving combined hormonal contraceptives is to minimize the decrease in hormone levels to prevent menstrual migraines.

One study examined the use of 3 mg drospirenone (DRSP) and 30 µg ethinylestradiol (EE. They were taken orally within the first 21 days of the menstrual cycle, followed by 7 days of placebo. Then, the contraceptive regimen was given again for 168 days. The result found a significant reduction in headache scores in menstrual migraines. Another study using a long-term vaginal ring regimen has also shown similar results.

A Cochrane review compared the effectiveness of long-term and cyclic KHK regimens. Headache improved in subjects on a long-term, uninterrupted regimen.

Progesterone:
Progesterone can reduce nociceptive activation of the trigeminovascular system and inhibit estrogen receptor regulation. Progesterone is also thought to reduce cortical excitability through its agonist effect on GABA receptors in the trigeminal ganglion. Multiple studies using progesterone have also been conducted and have shown a reduction in migraine duration and headache intensity.

Phytoestrogens:
Only 2 small studies investigated the use of phytoestrogens for the prophylaxis of menstrual migraines. Burke et al. evaluated 49 patients taking phytoestrogens daily for 24 weeks. Another small study conducted a study of 10 patients. Both of these studies reported phytoestrogens effectively reduce the frequency of attacks without any reported side effects.


Guidelines for Therapy in Menstrual Migraine

To date, there is no specific therapy for pure menstrual migraine or menstrual-related migraines that is approved by the United States Food and Drug Administration. However, the International Headache Society recommends the use of triptans for acute therapy and migraine prophylaxis.


Summary
Menstrual migraine is a type of migraine that often occurs in women, and if not treated optimally, it can greatly affect the patient's quality of life. The management of menstrual migraines includes acute therapy and prophylaxis. Several medicaments, especially triptans, are effective as acute therapy and prophylaxis for menstrual migraines.

In addition, NSAIDs and hormonal regimens are also effective in treating and preventing menstrual migraines.

According to the individual patient profile, patients and clinicians can decide how therapy is believed to provide greater effectiveness and safety. Patients also need to avoid exposure to things that can trigger migraines, such as lack of sleep, alcohol consumption, and stress.