Migraine ICYMI

Key clinical point: Poor sleep quality significantly increased the risk of developing migraine and migraine-related burden.

Major finding: Poor sleep quality was more prevalent in patients with migraine vs healthy controls (66.9% vs 24.3%; P < .001), with the risk for migraine being 3.981-times higher in those with poor vs good sleep quality (P  =  .001). Poor sleep quality in patients with migraine was significantly associated with increases in total pain burden, decreased quality of life, and increased anxiety and depression (all P_trend < .05).

Study details: Findings are from a case-control and cross-sectional analysis including 134 patients with migraine with or without aura and 70 sex- and age-matched healthy controls.

Disclosures: This study was supported by the Elite Medical Professionals project of China-Japan Friendship Hospital. The authors declared no conflicts of interest.

Source: Duan S et al. Association between sleep quality, migraine and migraine burden. Front Neurol. 2022 (Aug 26). Doi: 10.3389/fneur.2022.955298

Key clinical point: Poor sleep quality significantly increased the risk of developing migraine and migraine-related burden.

Major finding: Poor sleep quality was more prevalent in patients with migraine vs healthy controls (66.9% vs 24.3%; P < .001), with the risk for migraine being 3.981-times higher in those with poor vs good sleep quality (P  =  .001). Poor sleep quality in patients with migraine was significantly associated with increases in total pain burden, decreased quality of life, and increased anxiety and depression (all P_trend < .05).

Study details: Findings are from a case-control and cross-sectional analysis including 134 patients with migraine with or without aura and 70 sex- and age-matched healthy controls.

Disclosures: This study was supported by the Elite Medical Professionals project of China-Japan Friendship Hospital. The authors declared no conflicts of interest.

Source: Duan S et al. Association between sleep quality, migraine and migraine burden. Front Neurol. 2022 (Aug 26). Doi: 10.3389/fneur.2022.955298

Key clinical point: Poor sleep quality significantly increased the risk of developing migraine and migraine-related burden.

Major finding: Poor sleep quality was more prevalent in patients with migraine vs healthy controls (66.9% vs 24.3%; P < .001), with the risk for migraine being 3.981-times higher in those with poor vs good sleep quality (P  =  .001). Poor sleep quality in patients with migraine was significantly associated with increases in total pain burden, decreased quality of life, and increased anxiety and depression (all P_trend < .05).

Study details: Findings are from a case-control and cross-sectional analysis including 134 patients with migraine with or without aura and 70 sex- and age-matched healthy controls.

Disclosures: This study was supported by the Elite Medical Professionals project of China-Japan Friendship Hospital. The authors declared no conflicts of interest.

Source: Duan S et al. Association between sleep quality, migraine and migraine burden. Front Neurol. 2022 (Aug 26). Doi: 10.3389/fneur.2022.955298

Key clinical point: Participants, especially women and those aged 50-85 years, who had a high intake of dietary thiamine were less likely to develop severe headache or migraine.

Major finding: Dietary thiamine intake was associated with a reduced risk for migraine or headache (adjusted odds ratio [aOR] 0.93; P  =  .046), particularly among women (aOR 0.90; P  =  .022) and those aged 50-85 years (aOR 0.86; P  =  .023).

Study details: Findings are from a cross-sectional study including 13,439 American adults, of which 2745 experienced migraine or severe headache in the past 3 months.

Disclosures: This study did not declare any source of funding. The authors declared no conflicts of interest.

Source: Li D et al. Dietary intake of thiamine and riboflavin in relation to severe headache or migraine: A cross-sectional survey. Headache. 2022 (Sep 1). Doi: 10.1111/head.14384

Key clinical point: Participants, especially women and those aged 50-85 years, who had a high intake of dietary thiamine were less likely to develop severe headache or migraine.

Major finding: Dietary thiamine intake was associated with a reduced risk for migraine or headache (adjusted odds ratio [aOR] 0.93; P  =  .046), particularly among women (aOR 0.90; P  =  .022) and those aged 50-85 years (aOR 0.86; P  =  .023).

Study details: Findings are from a cross-sectional study including 13,439 American adults, of which 2745 experienced migraine or severe headache in the past 3 months.

Disclosures: This study did not declare any source of funding. The authors declared no conflicts of interest.

Source: Li D et al. Dietary intake of thiamine and riboflavin in relation to severe headache or migraine: A cross-sectional survey. Headache. 2022 (Sep 1). Doi: 10.1111/head.14384

Key clinical point: Participants, especially women and those aged 50-85 years, who had a high intake of dietary thiamine were less likely to develop severe headache or migraine.

Major finding: Dietary thiamine intake was associated with a reduced risk for migraine or headache (adjusted odds ratio [aOR] 0.93; P  =  .046), particularly among women (aOR 0.90; P  =  .022) and those aged 50-85 years (aOR 0.86; P  =  .023).

Study details: Findings are from a cross-sectional study including 13,439 American adults, of which 2745 experienced migraine or severe headache in the past 3 months.

Disclosures: This study did not declare any source of funding. The authors declared no conflicts of interest.

Source: Li D et al. Dietary intake of thiamine and riboflavin in relation to severe headache or migraine: A cross-sectional survey. Headache. 2022 (Sep 1). Doi: 10.1111/head.14384

Key clinical point: Fremanezumab vs placebo demonstrated significant and clinically meaningful improvements in migraine- and headache-related disability in patients with chronic and episodic migraine, including those with difficult-to-treat migraine.

Major finding: At 12 weeks of treatment, a significantly higher proportion of patients receiving quarterly and monthly fremanezumab vs placebo reported ≥5-point reduction in 6-item Headache Impact Test scores (53% and 55% vs 39%, respectively; both P < .0001) and ≥30% reduction in Migraine Disability Assessment scores among patients with severe disability (69% and 79% vs 58%, respectively; both P < .001).

Study details: Findings are from a pooled analysis of three phase 3 trials including 3660 patients with episodic or chronic migraine with or without aura who were randomly assigned to receive quarterly or monthly fremanezumab or placebo.

Disclosures: This study was funded by Teva Pharmaceuticals. Five authors declared being current or former employees of Teva Pharmaceuticals. P McAllister reported receiving research support and serving as a consultant for Teva Pharmaceuticals and other sources.

Source: McAllister P et al. Impact of fremanezumab on disability outcomes in patients with episodic and chronic migraine: A pooled analysis of phase 3 studies. J Headache Pain. 2022;23:112 (Aug 29). Doi: 10.1186/s10194-022-01438-4

Key clinical point: Fremanezumab vs placebo demonstrated significant and clinically meaningful improvements in migraine- and headache-related disability in patients with chronic and episodic migraine, including those with difficult-to-treat migraine.

Major finding: At 12 weeks of treatment, a significantly higher proportion of patients receiving quarterly and monthly fremanezumab vs placebo reported ≥5-point reduction in 6-item Headache Impact Test scores (53% and 55% vs 39%, respectively; both P < .0001) and ≥30% reduction in Migraine Disability Assessment scores among patients with severe disability (69% and 79% vs 58%, respectively; both P < .001).

Study details: Findings are from a pooled analysis of three phase 3 trials including 3660 patients with episodic or chronic migraine with or without aura who were randomly assigned to receive quarterly or monthly fremanezumab or placebo.

Disclosures: This study was funded by Teva Pharmaceuticals. Five authors declared being current or former employees of Teva Pharmaceuticals. P McAllister reported receiving research support and serving as a consultant for Teva Pharmaceuticals and other sources.

Source: McAllister P et al. Impact of fremanezumab on disability outcomes in patients with episodic and chronic migraine: A pooled analysis of phase 3 studies. J Headache Pain. 2022;23:112 (Aug 29). Doi: 10.1186/s10194-022-01438-4

Key clinical point: Fremanezumab vs placebo demonstrated significant and clinically meaningful improvements in migraine- and headache-related disability in patients with chronic and episodic migraine, including those with difficult-to-treat migraine.

Major finding: At 12 weeks of treatment, a significantly higher proportion of patients receiving quarterly and monthly fremanezumab vs placebo reported ≥5-point reduction in 6-item Headache Impact Test scores (53% and 55% vs 39%, respectively; both P < .0001) and ≥30% reduction in Migraine Disability Assessment scores among patients with severe disability (69% and 79% vs 58%, respectively; both P < .001).

Study details: Findings are from a pooled analysis of three phase 3 trials including 3660 patients with episodic or chronic migraine with or without aura who were randomly assigned to receive quarterly or monthly fremanezumab or placebo.

Disclosures: This study was funded by Teva Pharmaceuticals. Five authors declared being current or former employees of Teva Pharmaceuticals. P McAllister reported receiving research support and serving as a consultant for Teva Pharmaceuticals and other sources.

Source: McAllister P et al. Impact of fremanezumab on disability outcomes in patients with episodic and chronic migraine: A pooled analysis of phase 3 studies. J Headache Pain. 2022;23:112 (Aug 29). Doi: 10.1186/s10194-022-01438-4

Key clinical point: Treatment of a migraine attack with 50 or 100 mg ubrogepant leads to more favorable treatment outcomes when pain is mild vs moderate or severe.

Major finding: At 2 hours after ubrogepant treatment, the rates of freedom from pain (50 mg: odds ratio [OR] 2.89; 100 mg: OR 3.50; both P < .0001) and migraine symptoms (all P < .001) were higher when pain was mild vs moderate or severe.

Study details: Findings are from a post hoc analysis of a phase 3, long-term extension trial including patients with migraine with or without aura who were randomly assigned to receive 50 mg ubrogepant (n = 401), 100 mg ubrogepant (n = 407), or usual care (n = 417).

Disclosures: This study was sponsored by AbbVie Six authors reported being current or former employees or stockholders of AbbVie. Several authors including the lead author reported serving as consultants or advisory board members or receiving honoraria or research support from various sources.

Source: Lipton RB et al. Efficacy of ubrogepant in the acute treatment of migraine with mild pain versus moderate or severe pain. Neurology. 2022 (Aug 17). Doi:  10.1212/WNL.0000000000201031

Key clinical point: Treatment of a migraine attack with 50 or 100 mg ubrogepant leads to more favorable treatment outcomes when pain is mild vs moderate or severe.

Major finding: At 2 hours after ubrogepant treatment, the rates of freedom from pain (50 mg: odds ratio [OR] 2.89; 100 mg: OR 3.50; both P < .0001) and migraine symptoms (all P < .001) were higher when pain was mild vs moderate or severe.

Study details: Findings are from a post hoc analysis of a phase 3, long-term extension trial including patients with migraine with or without aura who were randomly assigned to receive 50 mg ubrogepant (n = 401), 100 mg ubrogepant (n = 407), or usual care (n = 417).

Disclosures: This study was sponsored by AbbVie Six authors reported being current or former employees or stockholders of AbbVie. Several authors including the lead author reported serving as consultants or advisory board members or receiving honoraria or research support from various sources.

Source: Lipton RB et al. Efficacy of ubrogepant in the acute treatment of migraine with mild pain versus moderate or severe pain. Neurology. 2022 (Aug 17). Doi:  10.1212/WNL.0000000000201031

Key clinical point: Treatment of a migraine attack with 50 or 100 mg ubrogepant leads to more favorable treatment outcomes when pain is mild vs moderate or severe.

Major finding: At 2 hours after ubrogepant treatment, the rates of freedom from pain (50 mg: odds ratio [OR] 2.89; 100 mg: OR 3.50; both P < .0001) and migraine symptoms (all P < .001) were higher when pain was mild vs moderate or severe.

Study details: Findings are from a post hoc analysis of a phase 3, long-term extension trial including patients with migraine with or without aura who were randomly assigned to receive 50 mg ubrogepant (n = 401), 100 mg ubrogepant (n = 407), or usual care (n = 417).

Disclosures: This study was sponsored by AbbVie Six authors reported being current or former employees or stockholders of AbbVie. Several authors including the lead author reported serving as consultants or advisory board members or receiving honoraria or research support from various sources.

Source: Lipton RB et al. Efficacy of ubrogepant in the acute treatment of migraine with mild pain versus moderate or severe pain. Neurology. 2022 (Aug 17). Doi:  10.1212/WNL.0000000000201031

Key clinical point: A combined manual therapeutic approach that included soft-tissue and articulatory manual therapy techniques was more effective in reducing migraine impact than either technique alone.

Major finding: After 4 weeks of intervention, the improvement in pain intensity was greater with combined soft-tissue and articulatory manual therapy vs only soft-tissue (P < .001) or articulatory (P = .014) manual therapy. Reduction in migraine duration was significant with combined vs soft-tissue therapy (P  =  .02), with improvements maintained through a  4-week follow-up. No serious side-effects were reported.

Study details: Findings are from a randomized controlled trial including 75 patients with chronic or episodic migraine who were randomly assigned to receive soft-tissue therapy, articulatory therapy, or combination of both manual therapies.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interest.

Source: Muñoz-Gómez E et al. Potential add-on effects of manual therapy techniques in migraine patients: A randomised controlled trial. J Clin Med. 2022;11(16):4686 (Aug 11). Doi: 10.3390/jcm11164686

Key clinical point: A combined manual therapeutic approach that included soft-tissue and articulatory manual therapy techniques was more effective in reducing migraine impact than either technique alone.

Major finding: After 4 weeks of intervention, the improvement in pain intensity was greater with combined soft-tissue and articulatory manual therapy vs only soft-tissue (P < .001) or articulatory (P = .014) manual therapy. Reduction in migraine duration was significant with combined vs soft-tissue therapy (P  =  .02), with improvements maintained through a  4-week follow-up. No serious side-effects were reported.

Study details: Findings are from a randomized controlled trial including 75 patients with chronic or episodic migraine who were randomly assigned to receive soft-tissue therapy, articulatory therapy, or combination of both manual therapies.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interest.

Source: Muñoz-Gómez E et al. Potential add-on effects of manual therapy techniques in migraine patients: A randomised controlled trial. J Clin Med. 2022;11(16):4686 (Aug 11). Doi: 10.3390/jcm11164686

Key clinical point: A combined manual therapeutic approach that included soft-tissue and articulatory manual therapy techniques was more effective in reducing migraine impact than either technique alone.

Major finding: After 4 weeks of intervention, the improvement in pain intensity was greater with combined soft-tissue and articulatory manual therapy vs only soft-tissue (P < .001) or articulatory (P = .014) manual therapy. Reduction in migraine duration was significant with combined vs soft-tissue therapy (P  =  .02), with improvements maintained through a  4-week follow-up. No serious side-effects were reported.

Study details: Findings are from a randomized controlled trial including 75 patients with chronic or episodic migraine who were randomly assigned to receive soft-tissue therapy, articulatory therapy, or combination of both manual therapies.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interest.

Source: Muñoz-Gómez E et al. Potential add-on effects of manual therapy techniques in migraine patients: A randomised controlled trial. J Clin Med. 2022;11(16):4686 (Aug 11). Doi: 10.3390/jcm11164686

Key clinical point: Treatment of perimenstrual migraine attacks with lasmiditan was associated with early and sustained freedom from migraine-related pain.

Major finding: Women who received 200 mg lasmiditan vs placebo during perimenstrual migraine attacks were more likely to report freedom from migraine-related pain (odds ratio [OR] 6.04; P < .001) and pain relief (OR 2.29; P  =  .007) at 2 hours and sustained freedom from pain at 24 hours (OR 11.67; P  =  .001).

Study details: Findings are from a post hoc analysis of the phase 2 MONONOFU and phase 3 CENTURION trials including 303 women with migraine with or without aura who had ≥1 perimenstrual migraine attacks and were randomly assigned to receive lasmiditan (50, 100, or 200 mg) or placebo.

Disclosures: This study was funded by Eli Lilly and Company. Four authors declared being employees and minor stockholders of Eli Lilly and Company. The other authors reported ties with various sources, including Eli Lilly and Company.

Source: MacGregor EA et al. Efficacy of lasmiditan for the acute treatment of perimenstrual migraine. Cephalalgia. 2022 (Aug 18). Doi: 10.1177/03331024221118929

Key clinical point: Treatment of perimenstrual migraine attacks with lasmiditan was associated with early and sustained freedom from migraine-related pain.

Major finding: Women who received 200 mg lasmiditan vs placebo during perimenstrual migraine attacks were more likely to report freedom from migraine-related pain (odds ratio [OR] 6.04; P < .001) and pain relief (OR 2.29; P  =  .007) at 2 hours and sustained freedom from pain at 24 hours (OR 11.67; P  =  .001).

Study details: Findings are from a post hoc analysis of the phase 2 MONONOFU and phase 3 CENTURION trials including 303 women with migraine with or without aura who had ≥1 perimenstrual migraine attacks and were randomly assigned to receive lasmiditan (50, 100, or 200 mg) or placebo.

Disclosures: This study was funded by Eli Lilly and Company. Four authors declared being employees and minor stockholders of Eli Lilly and Company. The other authors reported ties with various sources, including Eli Lilly and Company.

Source: MacGregor EA et al. Efficacy of lasmiditan for the acute treatment of perimenstrual migraine. Cephalalgia. 2022 (Aug 18). Doi: 10.1177/03331024221118929

Key clinical point: Treatment of perimenstrual migraine attacks with lasmiditan was associated with early and sustained freedom from migraine-related pain.

Major finding: Women who received 200 mg lasmiditan vs placebo during perimenstrual migraine attacks were more likely to report freedom from migraine-related pain (odds ratio [OR] 6.04; P < .001) and pain relief (OR 2.29; P  =  .007) at 2 hours and sustained freedom from pain at 24 hours (OR 11.67; P  =  .001).

Study details: Findings are from a post hoc analysis of the phase 2 MONONOFU and phase 3 CENTURION trials including 303 women with migraine with or without aura who had ≥1 perimenstrual migraine attacks and were randomly assigned to receive lasmiditan (50, 100, or 200 mg) or placebo.

Disclosures: This study was funded by Eli Lilly and Company. Four authors declared being employees and minor stockholders of Eli Lilly and Company. The other authors reported ties with various sources, including Eli Lilly and Company.

Source: MacGregor EA et al. Efficacy of lasmiditan for the acute treatment of perimenstrual migraine. Cephalalgia. 2022 (Aug 18). Doi: 10.1177/03331024221118929

Migraine affects more than 1 in 6 US adults. This figure masks the fact that migraine is a predominantly female disorder; compared with men, 3-month migraine prevalence is more than 2-fold higher (21% vs. 10%) in women. Research by the World Health Organization has established migraine as second among the world’s causes of disability, and first among women of reproductive age.  

Despite this burden of illness, migraine is often not diagnosed or treated effectively. General lifestyle advice such as maintaining a healthy weight, sleep hygiene, regular meals, regular exercise and hydration, and management of identified predisposing or triggering factors—together with optimization of symptomatic migraine treatment—can benefit all women with migraine. However, specific hormonal events such as menstruation, hormonal contraception, pregnancy, menopause, and hormone replacement therapy have variable, but often predictable, effects on the frequency and severity of migraine. At each of these life stages, there are specific opportunities to intervene and relieve migraine burden.

Menstrual migraine

Menstruation is one of the most significant risk factors for migraine, notably migraine without aura, with increased prevalence during a 5-day perimenstrual window that starts 2 days before the onset of menses and continues through the first 3 days of menstruation.

The International Headache Society (IHS) recognizes 2 types of menstrual migraine. There is menstrually related migraine, which is migraine without aura that regularly occurs on or between day −2 to +3 of menstruation (there is no day 0), with additional attacks of migraine with or without aura at other times of the cycle. There is also pure menstrual migraine, which is migraine without aura that occurs only on or between day −2 to +3, with no attacks at any other time of the cycle.

In women with menstrually related migraine, the diagnosis should only be made if the relationship between migraine and menstruation is greater than a chance association. To confirm this diagnosis, migraine attacks during the day −2 to +3 window must occur in at least 2 of 3 menstrual cycles. Relying on history to confirm the diagnosis can be misleading. Use of a 3-month diary can reveal the predictable patterns associated with menstrual migraine, aiding diagnosis and management. 

Menstrual migraine affects 20% to 25% of women with migraine in the general population, and 22% to 70% of women seen in headache clinics. In women diagnosed with menstrual migraine, their perimenstrual attacks have distinctive clinical features which include more associated symptoms, longer duration, greater severity, greater susceptibility to relapse, greater resistance to treatment, and greater disability than migraines occurring at other times during the menstrual cycle.

Symptomatic treatment of perimenstrual attacks of migraine is the same as for treatment of non-menstrual attacks, but due to the longer duration of perimenstrual attacks, treatment usually needs to be repeated on several consecutive days. With respect to prevention, specific consideration should be given to the presence of menstrual disorders, contraceptive requirements, pregnancy wishes, and symptoms of perimenopause.

The 2 established triggers for perimenstrual migraine attacks are prostaglandin release, which also results in dysmenorrhea, and late luteal phase estrogen "withdrawal". There are no investigations to identify the relevant mechanism(s). However, a history of dysmenorrhea is suggestive of a prostaglandin trigger and both migraine and dysmenorrhea can benefit from treatment with prostaglandin inhibitors.

Contraceptive methods can effectively manage both perimenstrual triggers. The European Headache Federation and the European Society of Contraception and Reproductive Health recommend combined hormonal contraception (CHC) in women with menstrual migraine who require contraception or who have additional menstrual disorders that use of CHC would benefit. The desogestrel progestogen-only pill is an alternative option, particularly for women with aura, but bleeding side effects are a common reason for discontinuation.

The principal barriers to effective management of menstrual migraine are lack of awareness and under-diagnosis. Although the IHS criteria facilitate research diagnosis, there continues to be important unmet needs in the clinical management of women with menstrual migraine. Improved awareness by healthcare professionals is critical; women visiting their primary care physician or who are referred to a gynecologist seldom mention migraine unless specifically asked.

Contraception

Most women use contraception at some stage in their lives. Hormonal contraception, particularly CHC, is popular and effective, with additional non-contraceptive benefits.

As with the natural menstrual cycle, estrogen “withdrawal” (in this case the consequence of stopping contraceptive hormones during the hormone-free interval) can trigger migraine without aura. Eliminating the hormone-free interval by taking CHCs continuously, without a break, eliminates the risk of estrogen withdrawal migraine. Further, continuous use of CHC increases contraceptive efficacy and there are no differential safety concerns.

Contraceptive use of CHC is contraindicated in women with migraine aura, since migraine aura and use of ethinylestradiol are independent risk factors for ischemic stroke. Effective contraception need not be compromised since progestogen-only and non-hormonal methods—

several of which are more effective than CHC—are not associated with increased risk.

Despite there being little concern regarding use of CHCs in women with migraine without aura, clinical experience suggests that many women with migraine are denied CHCs. In some cases, this stems from misdiagnosing premonitory migraine symptoms as aura. In other cases, even a clear diagnosis of menstrual migraine without aura can result in CHCs being withheld due to the misconception of risk. To ensure that women receive optimum contraceptive options, contraceptive providers need a better understanding of the Medical Eligibility Criteria for Contraceptive Use as well as simple tools to aid migraine diagnosis.

Pregnancy and breastfeeding

Around 60-70% of pregnant women with migraine experience fewer attacks compared to pre-pregnancy, with improvement more likely in women with a history of menstrual migraine. In contrast, migraine with aura tends to continue to occur throughout pregnancy and postpartum and may start for the first time during this period. Women can be reassured that migraine, both with or without aura, does not have any adverse effect on the outcome of pregnancy. However, women with aura should be monitored during pregnancy since there is an increased risk of comorbid conditions, such as arterial and venous thrombosis, pre-eclampsia, and gestational hypertension.

Healthcare professionals need to be aware of their female patients with migraine who may be planning to conceive so that strategies for treating migraine can be discussed. Most drugs and other teratogens exert their greatest effects on the fetus in the first trimester, often before pregnancy is confirmed. Symptomatic treatment with acetaminophen and metoclopramide is safe. If this is ineffective, sumatriptan is an option. Ergot derivatives are contraindicated. If prophylaxis is considered necessary, propranolol is the safest and most effective option. Valproate is contraindicated for migraine prophylaxis in women of reproductive capacity who are not using adequate contraception due to the increased risk of neural tube defects, cardiac defects, and other developmental effects associated with use of this medication.

Fertility treatment is frequently associated with increased headache and migraine. It is also important to consider that headache can be symptomatic of emotional stress, which would benefit from supportive management.

Breastfeeding generally maintains the benefits of pregnancy on migraine and should be encouraged, where possible. Recent studies suggest that the number of women choosing to breastfeed is rising, but there is also evidence that women with migraine do not initiate breastfeeding or discontinue because of their concerns about taking medication.

Unfortunately, many women and healthcare professionals rely on information in the package inserts, which may not tell the full story. Milk supply can reduce within 48 hours without full and repeated emptying of the breast, so advising a woman to interrupt breastfeeding for even a few days while treating a migraine attack can destroy her milk production. Hence, maintaining breastfeeding during drug treatment is increasingly recommended. Healthcare professionals should be informed about which treatments can safely be used at this time. For acute treatment, acetaminophen and NSAIDS are first-line options and can be combined with metoclopramide. Sumatriptan is a second-line option that allows breastfeeding to continue without the need to ‘pump and dump’.

Menopause and hormone replacement therapy

Despite increased prevalence of menstrual migraine during perimenopause, headache and migraine are under-reported by women with perimenopausal migraine. Management should be directed to treating the menopausal symptoms, which may include hormone replacement therapy (HRT). Studies suggest a significant association between migraine and current use of HRT.

Understanding the effects of different types of HRT is important, as some studies suggest that a history of worsening migraine at menopause is a factor in predicting worsening migraine with HRT. However, the regimen of HRT, route of estrogen, and type of progestogen all have differing effects on migraine. Non-oral routes of continuous estrogen/progestogen are less likely to have a negative effect on migraine than oral formulations, and continuous estrogen/progestogen appears to be better tolerated than cyclical combined HRT. Oral micronized progesterone may directly benefit migraine due to GABAergic effects. Disturbed sleep is both a common migraine trigger and the action of progesterone to restore normal sleep will also benefit migraine.   

In contrast to CHCs, physiologic doses of transdermal estradiol and progesterone used in HRT are not associated with increased risk of ischemic stroke and can be used by women with migraine aura.

Conclusion

Many questions related to these topics don't have ready answers—questions like increased prevalence of hormone-related migraine, age of onset of menstrual migraines, and multispecialty treatment of these patients. Research is either limited or yet to be done, and we may not get the answers until healthcare professionals and women are more aware of the hormonal effects of migraine.

The effects of hormonal changes on migraine provide physicians with specific opportunities to identify and manage migraine in women. Under-treatment – in addition to causing unnecessary disability and suffering – is not economically cost-effective in terms of time lost from work and burden placed on the families of these patients. More effective health care would alleviate much of the suffering and therefore reduce both the personal and financial costs of migraine. Ineffective management of migraine in women has significant implications for women, their families, and their employers.

Migraine affects more than 1 in 6 US adults. This figure masks the fact that migraine is a predominantly female disorder; compared with men, 3-month migraine prevalence is more than 2-fold higher (21% vs. 10%) in women. Research by the World Health Organization has established migraine as second among the world’s causes of disability, and first among women of reproductive age.  

Despite this burden of illness, migraine is often not diagnosed or treated effectively. General lifestyle advice such as maintaining a healthy weight, sleep hygiene, regular meals, regular exercise and hydration, and management of identified predisposing or triggering factors—together with optimization of symptomatic migraine treatment—can benefit all women with migraine. However, specific hormonal events such as menstruation, hormonal contraception, pregnancy, menopause, and hormone replacement therapy have variable, but often predictable, effects on the frequency and severity of migraine. At each of these life stages, there are specific opportunities to intervene and relieve migraine burden.

Menstrual migraine

Menstruation is one of the most significant risk factors for migraine, notably migraine without aura, with increased prevalence during a 5-day perimenstrual window that starts 2 days before the onset of menses and continues through the first 3 days of menstruation.

The International Headache Society (IHS) recognizes 2 types of menstrual migraine. There is menstrually related migraine, which is migraine without aura that regularly occurs on or between day −2 to +3 of menstruation (there is no day 0), with additional attacks of migraine with or without aura at other times of the cycle. There is also pure menstrual migraine, which is migraine without aura that occurs only on or between day −2 to +3, with no attacks at any other time of the cycle.

In women with menstrually related migraine, the diagnosis should only be made if the relationship between migraine and menstruation is greater than a chance association. To confirm this diagnosis, migraine attacks during the day −2 to +3 window must occur in at least 2 of 3 menstrual cycles. Relying on history to confirm the diagnosis can be misleading. Use of a 3-month diary can reveal the predictable patterns associated with menstrual migraine, aiding diagnosis and management. 

Menstrual migraine affects 20% to 25% of women with migraine in the general population, and 22% to 70% of women seen in headache clinics. In women diagnosed with menstrual migraine, their perimenstrual attacks have distinctive clinical features which include more associated symptoms, longer duration, greater severity, greater susceptibility to relapse, greater resistance to treatment, and greater disability than migraines occurring at other times during the menstrual cycle.

Symptomatic treatment of perimenstrual attacks of migraine is the same as for treatment of non-menstrual attacks, but due to the longer duration of perimenstrual attacks, treatment usually needs to be repeated on several consecutive days. With respect to prevention, specific consideration should be given to the presence of menstrual disorders, contraceptive requirements, pregnancy wishes, and symptoms of perimenopause.

The 2 established triggers for perimenstrual migraine attacks are prostaglandin release, which also results in dysmenorrhea, and late luteal phase estrogen "withdrawal". There are no investigations to identify the relevant mechanism(s). However, a history of dysmenorrhea is suggestive of a prostaglandin trigger and both migraine and dysmenorrhea can benefit from treatment with prostaglandin inhibitors.

Contraceptive methods can effectively manage both perimenstrual triggers. The European Headache Federation and the European Society of Contraception and Reproductive Health recommend combined hormonal contraception (CHC) in women with menstrual migraine who require contraception or who have additional menstrual disorders that use of CHC would benefit. The desogestrel progestogen-only pill is an alternative option, particularly for women with aura, but bleeding side effects are a common reason for discontinuation.

The principal barriers to effective management of menstrual migraine are lack of awareness and under-diagnosis. Although the IHS criteria facilitate research diagnosis, there continues to be important unmet needs in the clinical management of women with menstrual migraine. Improved awareness by healthcare professionals is critical; women visiting their primary care physician or who are referred to a gynecologist seldom mention migraine unless specifically asked.

Contraception

Most women use contraception at some stage in their lives. Hormonal contraception, particularly CHC, is popular and effective, with additional non-contraceptive benefits.

As with the natural menstrual cycle, estrogen “withdrawal” (in this case the consequence of stopping contraceptive hormones during the hormone-free interval) can trigger migraine without aura. Eliminating the hormone-free interval by taking CHCs continuously, without a break, eliminates the risk of estrogen withdrawal migraine. Further, continuous use of CHC increases contraceptive efficacy and there are no differential safety concerns.

Contraceptive use of CHC is contraindicated in women with migraine aura, since migraine aura and use of ethinylestradiol are independent risk factors for ischemic stroke. Effective contraception need not be compromised since progestogen-only and non-hormonal methods—

several of which are more effective than CHC—are not associated with increased risk.

Despite there being little concern regarding use of CHCs in women with migraine without aura, clinical experience suggests that many women with migraine are denied CHCs. In some cases, this stems from misdiagnosing premonitory migraine symptoms as aura. In other cases, even a clear diagnosis of menstrual migraine without aura can result in CHCs being withheld due to the misconception of risk. To ensure that women receive optimum contraceptive options, contraceptive providers need a better understanding of the Medical Eligibility Criteria for Contraceptive Use as well as simple tools to aid migraine diagnosis.

Pregnancy and breastfeeding

Around 60-70% of pregnant women with migraine experience fewer attacks compared to pre-pregnancy, with improvement more likely in women with a history of menstrual migraine. In contrast, migraine with aura tends to continue to occur throughout pregnancy and postpartum and may start for the first time during this period. Women can be reassured that migraine, both with or without aura, does not have any adverse effect on the outcome of pregnancy. However, women with aura should be monitored during pregnancy since there is an increased risk of comorbid conditions, such as arterial and venous thrombosis, pre-eclampsia, and gestational hypertension.

Healthcare professionals need to be aware of their female patients with migraine who may be planning to conceive so that strategies for treating migraine can be discussed. Most drugs and other teratogens exert their greatest effects on the fetus in the first trimester, often before pregnancy is confirmed. Symptomatic treatment with acetaminophen and metoclopramide is safe. If this is ineffective, sumatriptan is an option. Ergot derivatives are contraindicated. If prophylaxis is considered necessary, propranolol is the safest and most effective option. Valproate is contraindicated for migraine prophylaxis in women of reproductive capacity who are not using adequate contraception due to the increased risk of neural tube defects, cardiac defects, and other developmental effects associated with use of this medication.

Fertility treatment is frequently associated with increased headache and migraine. It is also important to consider that headache can be symptomatic of emotional stress, which would benefit from supportive management.

Breastfeeding generally maintains the benefits of pregnancy on migraine and should be encouraged, where possible. Recent studies suggest that the number of women choosing to breastfeed is rising, but there is also evidence that women with migraine do not initiate breastfeeding or discontinue because of their concerns about taking medication.

Unfortunately, many women and healthcare professionals rely on information in the package inserts, which may not tell the full story. Milk supply can reduce within 48 hours without full and repeated emptying of the breast, so advising a woman to interrupt breastfeeding for even a few days while treating a migraine attack can destroy her milk production. Hence, maintaining breastfeeding during drug treatment is increasingly recommended. Healthcare professionals should be informed about which treatments can safely be used at this time. For acute treatment, acetaminophen and NSAIDS are first-line options and can be combined with metoclopramide. Sumatriptan is a second-line option that allows breastfeeding to continue without the need to ‘pump and dump’.

Menopause and hormone replacement therapy

Despite increased prevalence of menstrual migraine during perimenopause, headache and migraine are under-reported by women with perimenopausal migraine. Management should be directed to treating the menopausal symptoms, which may include hormone replacement therapy (HRT). Studies suggest a significant association between migraine and current use of HRT.

Understanding the effects of different types of HRT is important, as some studies suggest that a history of worsening migraine at menopause is a factor in predicting worsening migraine with HRT. However, the regimen of HRT, route of estrogen, and type of progestogen all have differing effects on migraine. Non-oral routes of continuous estrogen/progestogen are less likely to have a negative effect on migraine than oral formulations, and continuous estrogen/progestogen appears to be better tolerated than cyclical combined HRT. Oral micronized progesterone may directly benefit migraine due to GABAergic effects. Disturbed sleep is both a common migraine trigger and the action of progesterone to restore normal sleep will also benefit migraine.   

In contrast to CHCs, physiologic doses of transdermal estradiol and progesterone used in HRT are not associated with increased risk of ischemic stroke and can be used by women with migraine aura.

Conclusion

Many questions related to these topics don't have ready answers—questions like increased prevalence of hormone-related migraine, age of onset of menstrual migraines, and multispecialty treatment of these patients. Research is either limited or yet to be done, and we may not get the answers until healthcare professionals and women are more aware of the hormonal effects of migraine.

The effects of hormonal changes on migraine provide physicians with specific opportunities to identify and manage migraine in women. Under-treatment – in addition to causing unnecessary disability and suffering – is not economically cost-effective in terms of time lost from work and burden placed on the families of these patients. More effective health care would alleviate much of the suffering and therefore reduce both the personal and financial costs of migraine. Ineffective management of migraine in women has significant implications for women, their families, and their employers.

Migraine affects more than 1 in 6 US adults. This figure masks the fact that migraine is a predominantly female disorder; compared with men, 3-month migraine prevalence is more than 2-fold higher (21% vs. 10%) in women. Research by the World Health Organization has established migraine as second among the world’s causes of disability, and first among women of reproductive age.  

Despite this burden of illness, migraine is often not diagnosed or treated effectively. General lifestyle advice such as maintaining a healthy weight, sleep hygiene, regular meals, regular exercise and hydration, and management of identified predisposing or triggering factors—together with optimization of symptomatic migraine treatment—can benefit all women with migraine. However, specific hormonal events such as menstruation, hormonal contraception, pregnancy, menopause, and hormone replacement therapy have variable, but often predictable, effects on the frequency and severity of migraine. At each of these life stages, there are specific opportunities to intervene and relieve migraine burden.

Menstrual migraine

Menstruation is one of the most significant risk factors for migraine, notably migraine without aura, with increased prevalence during a 5-day perimenstrual window that starts 2 days before the onset of menses and continues through the first 3 days of menstruation.

The International Headache Society (IHS) recognizes 2 types of menstrual migraine. There is menstrually related migraine, which is migraine without aura that regularly occurs on or between day −2 to +3 of menstruation (there is no day 0), with additional attacks of migraine with or without aura at other times of the cycle. There is also pure menstrual migraine, which is migraine without aura that occurs only on or between day −2 to +3, with no attacks at any other time of the cycle.

In women with menstrually related migraine, the diagnosis should only be made if the relationship between migraine and menstruation is greater than a chance association. To confirm this diagnosis, migraine attacks during the day −2 to +3 window must occur in at least 2 of 3 menstrual cycles. Relying on history to confirm the diagnosis can be misleading. Use of a 3-month diary can reveal the predictable patterns associated with menstrual migraine, aiding diagnosis and management. 

Menstrual migraine affects 20% to 25% of women with migraine in the general population, and 22% to 70% of women seen in headache clinics. In women diagnosed with menstrual migraine, their perimenstrual attacks have distinctive clinical features which include more associated symptoms, longer duration, greater severity, greater susceptibility to relapse, greater resistance to treatment, and greater disability than migraines occurring at other times during the menstrual cycle.

Symptomatic treatment of perimenstrual attacks of migraine is the same as for treatment of non-menstrual attacks, but due to the longer duration of perimenstrual attacks, treatment usually needs to be repeated on several consecutive days. With respect to prevention, specific consideration should be given to the presence of menstrual disorders, contraceptive requirements, pregnancy wishes, and symptoms of perimenopause.

The 2 established triggers for perimenstrual migraine attacks are prostaglandin release, which also results in dysmenorrhea, and late luteal phase estrogen "withdrawal". There are no investigations to identify the relevant mechanism(s). However, a history of dysmenorrhea is suggestive of a prostaglandin trigger and both migraine and dysmenorrhea can benefit from treatment with prostaglandin inhibitors.

Contraceptive methods can effectively manage both perimenstrual triggers. The European Headache Federation and the European Society of Contraception and Reproductive Health recommend combined hormonal contraception (CHC) in women with menstrual migraine who require contraception or who have additional menstrual disorders that use of CHC would benefit. The desogestrel progestogen-only pill is an alternative option, particularly for women with aura, but bleeding side effects are a common reason for discontinuation.

The principal barriers to effective management of menstrual migraine are lack of awareness and under-diagnosis. Although the IHS criteria facilitate research diagnosis, there continues to be important unmet needs in the clinical management of women with menstrual migraine. Improved awareness by healthcare professionals is critical; women visiting their primary care physician or who are referred to a gynecologist seldom mention migraine unless specifically asked.

Contraception

Most women use contraception at some stage in their lives. Hormonal contraception, particularly CHC, is popular and effective, with additional non-contraceptive benefits.

As with the natural menstrual cycle, estrogen “withdrawal” (in this case the consequence of stopping contraceptive hormones during the hormone-free interval) can trigger migraine without aura. Eliminating the hormone-free interval by taking CHCs continuously, without a break, eliminates the risk of estrogen withdrawal migraine. Further, continuous use of CHC increases contraceptive efficacy and there are no differential safety concerns.

Contraceptive use of CHC is contraindicated in women with migraine aura, since migraine aura and use of ethinylestradiol are independent risk factors for ischemic stroke. Effective contraception need not be compromised since progestogen-only and non-hormonal methods—

several of which are more effective than CHC—are not associated with increased risk.

Despite there being little concern regarding use of CHCs in women with migraine without aura, clinical experience suggests that many women with migraine are denied CHCs. In some cases, this stems from misdiagnosing premonitory migraine symptoms as aura. In other cases, even a clear diagnosis of menstrual migraine without aura can result in CHCs being withheld due to the misconception of risk. To ensure that women receive optimum contraceptive options, contraceptive providers need a better understanding of the Medical Eligibility Criteria for Contraceptive Use as well as simple tools to aid migraine diagnosis.

Pregnancy and breastfeeding

Around 60-70% of pregnant women with migraine experience fewer attacks compared to pre-pregnancy, with improvement more likely in women with a history of menstrual migraine. In contrast, migraine with aura tends to continue to occur throughout pregnancy and postpartum and may start for the first time during this period. Women can be reassured that migraine, both with or without aura, does not have any adverse effect on the outcome of pregnancy. However, women with aura should be monitored during pregnancy since there is an increased risk of comorbid conditions, such as arterial and venous thrombosis, pre-eclampsia, and gestational hypertension.

Healthcare professionals need to be aware of their female patients with migraine who may be planning to conceive so that strategies for treating migraine can be discussed. Most drugs and other teratogens exert their greatest effects on the fetus in the first trimester, often before pregnancy is confirmed. Symptomatic treatment with acetaminophen and metoclopramide is safe. If this is ineffective, sumatriptan is an option. Ergot derivatives are contraindicated. If prophylaxis is considered necessary, propranolol is the safest and most effective option. Valproate is contraindicated for migraine prophylaxis in women of reproductive capacity who are not using adequate contraception due to the increased risk of neural tube defects, cardiac defects, and other developmental effects associated with use of this medication.

Fertility treatment is frequently associated with increased headache and migraine. It is also important to consider that headache can be symptomatic of emotional stress, which would benefit from supportive management.

Breastfeeding generally maintains the benefits of pregnancy on migraine and should be encouraged, where possible. Recent studies suggest that the number of women choosing to breastfeed is rising, but there is also evidence that women with migraine do not initiate breastfeeding or discontinue because of their concerns about taking medication.

Unfortunately, many women and healthcare professionals rely on information in the package inserts, which may not tell the full story. Milk supply can reduce within 48 hours without full and repeated emptying of the breast, so advising a woman to interrupt breastfeeding for even a few days while treating a migraine attack can destroy her milk production. Hence, maintaining breastfeeding during drug treatment is increasingly recommended. Healthcare professionals should be informed about which treatments can safely be used at this time. For acute treatment, acetaminophen and NSAIDS are first-line options and can be combined with metoclopramide. Sumatriptan is a second-line option that allows breastfeeding to continue without the need to ‘pump and dump’.

Menopause and hormone replacement therapy

Despite increased prevalence of menstrual migraine during perimenopause, headache and migraine are under-reported by women with perimenopausal migraine. Management should be directed to treating the menopausal symptoms, which may include hormone replacement therapy (HRT). Studies suggest a significant association between migraine and current use of HRT.

Understanding the effects of different types of HRT is important, as some studies suggest that a history of worsening migraine at menopause is a factor in predicting worsening migraine with HRT. However, the regimen of HRT, route of estrogen, and type of progestogen all have differing effects on migraine. Non-oral routes of continuous estrogen/progestogen are less likely to have a negative effect on migraine than oral formulations, and continuous estrogen/progestogen appears to be better tolerated than cyclical combined HRT. Oral micronized progesterone may directly benefit migraine due to GABAergic effects. Disturbed sleep is both a common migraine trigger and the action of progesterone to restore normal sleep will also benefit migraine.   

In contrast to CHCs, physiologic doses of transdermal estradiol and progesterone used in HRT are not associated with increased risk of ischemic stroke and can be used by women with migraine aura.

Conclusion

Many questions related to these topics don't have ready answers—questions like increased prevalence of hormone-related migraine, age of onset of menstrual migraines, and multispecialty treatment of these patients. Research is either limited or yet to be done, and we may not get the answers until healthcare professionals and women are more aware of the hormonal effects of migraine.

The effects of hormonal changes on migraine provide physicians with specific opportunities to identify and manage migraine in women. Under-treatment – in addition to causing unnecessary disability and suffering – is not economically cost-effective in terms of time lost from work and burden placed on the families of these patients. More effective health care would alleviate much of the suffering and therefore reduce both the personal and financial costs of migraine. Ineffective management of migraine in women has significant implications for women, their families, and their employers.

The theme of this month's commentary is alternative outcomes measures for future migraine studies. The traditional outcomes measures, such as headache frequency measured in headache days, have long been considered gold standards when evaluating the efficacy of preventive interventions. When headache conditions are complicated by interictal pain or other symptoms, or when medication overuse adds a higher frequency or greater severity, those traditional measures are somewhat less exact and specific. Meaningful change for patients with higher frequency of attacks, near-continuous pain, or other migraine symptoms is quite different from that for those without these complications.

Ailani and colleagues reviewed post hoc data from the CONQUER trial, a prior study evaluating the safety and efficacy of galcanezumab vs placebo in patients who had previously not benefited from two to four categories of migraine preventive medication. This refractory population was initially noted to have 4.1 fewer headache days per month than patients taking placebo, but the authors now attempted to review these data with a focus on a different measure: total pain burden (TPB). They defined daily TPB as a single composite measure assessing the frequency, duration, and severity of migraine, calculated by multiplying the number of hours of migraine by the maximum daily migraine pain severity score. The monthly TPB was calculated by adding the daily pain burden over the entire month. The Migraine Disability Assessment questionnaire (MIDAS) and Migraine-Specific Quality of Life Questionnaire (MSQ) scores were also included to compare migraine-related disability and quality of life.

The patients who received galcanezumab were noted to have a significantly lower TPB, both in episodic and chronic migraine. Significantly greater reductions in monthly TPB relative to placebo were observed at each individual month as well. The change from baseline TPB was also noted to be significantly improved in the galcanezumab group compared with the placebo group. The reduction in TPB was noted even when migraine-day reductions were accounted for as part of a sensitivity analysis.

Preventive trials for migraine treatment focus primarily on migraine-day reduction, and for many patients with higher-frequency migraine, this measure does not adequately account for their disease-related disability. This unique way of looking at pain as part of a bigger picture is much more significant and meaningful for this patient population. Migraine frequency is still a very important outcomes measure, but it would be wise to add TBP or another measure that looks more globally at disease-related disability, especially when investigating preventive options in patients with chronic migraine.

When considering whether an intervention is helpful, most patients and clinicians follow the headache frequency, severity, or quality-of-life factors. As most patients will readily report, not all "headache-free days" are created equal. Although most people with migraine will experience days with absolutely no headache pain or other migraine-associated symptoms, on many days they will still have some symptoms of migraine. Lee and colleagues attempted to quantify the difference between headache-free days and crystal-clear days.

Most headache studies use the frequency of headache days as a primary or secondary outcome. This study collected data on both headache days and crystal-clear days, using data from a questionnaire-based large South Korean nationwide population study that evaluated headache and sleep. The study questions were validated for migraine and aura, and included: "How many days have you had a headache during the previous 30 days?" and "How many days have you had crystal-clear days without headache during the previous 30 days?" The data were then analyzed and compared with the widespread pain index (criteria for fibromyalgia) as well as sleep duration, sleep quality, depression and anxiety scales, and an allodynia checklist.

A little over 3000 respondents completed the surveys; 1938 had experienced headache over the past year, 170 were classified as having a diagnosis of migraine, and 50 of those were diagnosed with aura as well. Out of the patients with migraine, 97% had "unclear days." This was higher than the rate of those with non-migraine headaches (91%). Nearly all people surveyed had some crystal-clear days (99.4%).

The number of crystal-clear days per 30 days was significantly lower in participants with migraine than in those with non-migraine headache. Participants with migraine also had higher frequencies of cutaneous allodynia, anxiety, and depression. The weekly average sleep duration in participants with migraine did not significantly differ from that in participants with non-migraine headaches. The widespread pain index rate was much higher in those with migraine as well.

Most patients will definitely understand the difference between crystal-clear and unclear headache days. Many of the newer outcomes studies in migraine have started focusing on the most bothersome symptom, as headache pain is far from the only significant or disabling symptom associated with migraine. This study makes clear that further outcomes changes are necessary, and that a potentially more meaningful result in migraine studies may actually be crystal-clear days rather than simply headache-free days.

Although there are more acute options available for headache treatment, medication overuse headache remains a major complicating factor for most clinicians who treat headache. When educating patients, there is always a strong emphasis on guidelines for acute medication use. Many patients struggle with knowing when to use an acute treatment and when to alternate with a different treatment, and often they will withhold treatment completely due to fear of medication overuse. The new class of calcitonin gene-related peptide (CGRP) antagonist medications has shown some potential benefit as a preventive option for both medication overuse headache and migraine.

The prospective study by Curone and colleagues enrolled 300 patients with confirmed medication overuse headache who did not undergo withdrawal of the overused acute medication. Patients who are already taking preventive medications were excluded, as were patients with diagnoses other than chronic migraine or medication overuse. Patients were given one of the three injectable CGRP antagonist medications for prevention and were followed up at 3, 6, 9, and 12 months. The primary outcome was MIDAS score as well as monthly headache days and analgesic consumption.

Out of 303 patients, 242 (80%) showed both a ≥50% reduction of monthly headache days and ≥50% reduction in analgesic intake at 3-month follow-up visit. At 9 months, 198 (65%) were still responders. Monthly analgesic intake decreased ≥50% in 268 of 303 patients (88%) at 3 months and in 241 of 303 patients (79%) at the 6-month follow-up.

For years there has been a debate regarding whether withdrawal of an overused medication is necessary for effective treatment of medication overuse headache. Many preventive treatments are less effective when medication overuse is ongoing. The CGRP class of medications does appear to be effective even with ongoing acute medication overuse. This class of medications should definitely be considered when withdrawing an overused medication is complicated, or when a patient needs to continue to take analgesic medications for another condition.

The theme of this month's commentary is alternative outcomes measures for future migraine studies. The traditional outcomes measures, such as headache frequency measured in headache days, have long been considered gold standards when evaluating the efficacy of preventive interventions. When headache conditions are complicated by interictal pain or other symptoms, or when medication overuse adds a higher frequency or greater severity, those traditional measures are somewhat less exact and specific. Meaningful change for patients with higher frequency of attacks, near-continuous pain, or other migraine symptoms is quite different from that for those without these complications.

Ailani and colleagues reviewed post hoc data from the CONQUER trial, a prior study evaluating the safety and efficacy of galcanezumab vs placebo in patients who had previously not benefited from two to four categories of migraine preventive medication. This refractory population was initially noted to have 4.1 fewer headache days per month than patients taking placebo, but the authors now attempted to review these data with a focus on a different measure: total pain burden (TPB). They defined daily TPB as a single composite measure assessing the frequency, duration, and severity of migraine, calculated by multiplying the number of hours of migraine by the maximum daily migraine pain severity score. The monthly TPB was calculated by adding the daily pain burden over the entire month. The Migraine Disability Assessment questionnaire (MIDAS) and Migraine-Specific Quality of Life Questionnaire (MSQ) scores were also included to compare migraine-related disability and quality of life.

The patients who received galcanezumab were noted to have a significantly lower TPB, both in episodic and chronic migraine. Significantly greater reductions in monthly TPB relative to placebo were observed at each individual month as well. The change from baseline TPB was also noted to be significantly improved in the galcanezumab group compared with the placebo group. The reduction in TPB was noted even when migraine-day reductions were accounted for as part of a sensitivity analysis.

Preventive trials for migraine treatment focus primarily on migraine-day reduction, and for many patients with higher-frequency migraine, this measure does not adequately account for their disease-related disability. This unique way of looking at pain as part of a bigger picture is much more significant and meaningful for this patient population. Migraine frequency is still a very important outcomes measure, but it would be wise to add TBP or another measure that looks more globally at disease-related disability, especially when investigating preventive options in patients with chronic migraine.

When considering whether an intervention is helpful, most patients and clinicians follow the headache frequency, severity, or quality-of-life factors. As most patients will readily report, not all "headache-free days" are created equal. Although most people with migraine will experience days with absolutely no headache pain or other migraine-associated symptoms, on many days they will still have some symptoms of migraine. Lee and colleagues attempted to quantify the difference between headache-free days and crystal-clear days.

Most headache studies use the frequency of headache days as a primary or secondary outcome. This study collected data on both headache days and crystal-clear days, using data from a questionnaire-based large South Korean nationwide population study that evaluated headache and sleep. The study questions were validated for migraine and aura, and included: "How many days have you had a headache during the previous 30 days?" and "How many days have you had crystal-clear days without headache during the previous 30 days?" The data were then analyzed and compared with the widespread pain index (criteria for fibromyalgia) as well as sleep duration, sleep quality, depression and anxiety scales, and an allodynia checklist.

A little over 3000 respondents completed the surveys; 1938 had experienced headache over the past year, 170 were classified as having a diagnosis of migraine, and 50 of those were diagnosed with aura as well. Out of the patients with migraine, 97% had "unclear days." This was higher than the rate of those with non-migraine headaches (91%). Nearly all people surveyed had some crystal-clear days (99.4%).

The number of crystal-clear days per 30 days was significantly lower in participants with migraine than in those with non-migraine headache. Participants with migraine also had higher frequencies of cutaneous allodynia, anxiety, and depression. The weekly average sleep duration in participants with migraine did not significantly differ from that in participants with non-migraine headaches. The widespread pain index rate was much higher in those with migraine as well.

Most patients will definitely understand the difference between crystal-clear and unclear headache days. Many of the newer outcomes studies in migraine have started focusing on the most bothersome symptom, as headache pain is far from the only significant or disabling symptom associated with migraine. This study makes clear that further outcomes changes are necessary, and that a potentially more meaningful result in migraine studies may actually be crystal-clear days rather than simply headache-free days.

Although there are more acute options available for headache treatment, medication overuse headache remains a major complicating factor for most clinicians who treat headache. When educating patients, there is always a strong emphasis on guidelines for acute medication use. Many patients struggle with knowing when to use an acute treatment and when to alternate with a different treatment, and often they will withhold treatment completely due to fear of medication overuse. The new class of calcitonin gene-related peptide (CGRP) antagonist medications has shown some potential benefit as a preventive option for both medication overuse headache and migraine.

The prospective study by Curone and colleagues enrolled 300 patients with confirmed medication overuse headache who did not undergo withdrawal of the overused acute medication. Patients who are already taking preventive medications were excluded, as were patients with diagnoses other than chronic migraine or medication overuse. Patients were given one of the three injectable CGRP antagonist medications for prevention and were followed up at 3, 6, 9, and 12 months. The primary outcome was MIDAS score as well as monthly headache days and analgesic consumption.

Out of 303 patients, 242 (80%) showed both a ≥50% reduction of monthly headache days and ≥50% reduction in analgesic intake at 3-month follow-up visit. At 9 months, 198 (65%) were still responders. Monthly analgesic intake decreased ≥50% in 268 of 303 patients (88%) at 3 months and in 241 of 303 patients (79%) at the 6-month follow-up.

For years there has been a debate regarding whether withdrawal of an overused medication is necessary for effective treatment of medication overuse headache. Many preventive treatments are less effective when medication overuse is ongoing. The CGRP class of medications does appear to be effective even with ongoing acute medication overuse. This class of medications should definitely be considered when withdrawing an overused medication is complicated, or when a patient needs to continue to take analgesic medications for another condition.

The theme of this month's commentary is alternative outcomes measures for future migraine studies. The traditional outcomes measures, such as headache frequency measured in headache days, have long been considered gold standards when evaluating the efficacy of preventive interventions. When headache conditions are complicated by interictal pain or other symptoms, or when medication overuse adds a higher frequency or greater severity, those traditional measures are somewhat less exact and specific. Meaningful change for patients with higher frequency of attacks, near-continuous pain, or other migraine symptoms is quite different from that for those without these complications.

Ailani and colleagues reviewed post hoc data from the CONQUER trial, a prior study evaluating the safety and efficacy of galcanezumab vs placebo in patients who had previously not benefited from two to four categories of migraine preventive medication. This refractory population was initially noted to have 4.1 fewer headache days per month than patients taking placebo, but the authors now attempted to review these data with a focus on a different measure: total pain burden (TPB). They defined daily TPB as a single composite measure assessing the frequency, duration, and severity of migraine, calculated by multiplying the number of hours of migraine by the maximum daily migraine pain severity score. The monthly TPB was calculated by adding the daily pain burden over the entire month. The Migraine Disability Assessment questionnaire (MIDAS) and Migraine-Specific Quality of Life Questionnaire (MSQ) scores were also included to compare migraine-related disability and quality of life.

The patients who received galcanezumab were noted to have a significantly lower TPB, both in episodic and chronic migraine. Significantly greater reductions in monthly TPB relative to placebo were observed at each individual month as well. The change from baseline TPB was also noted to be significantly improved in the galcanezumab group compared with the placebo group. The reduction in TPB was noted even when migraine-day reductions were accounted for as part of a sensitivity analysis.

Preventive trials for migraine treatment focus primarily on migraine-day reduction, and for many patients with higher-frequency migraine, this measure does not adequately account for their disease-related disability. This unique way of looking at pain as part of a bigger picture is much more significant and meaningful for this patient population. Migraine frequency is still a very important outcomes measure, but it would be wise to add TBP or another measure that looks more globally at disease-related disability, especially when investigating preventive options in patients with chronic migraine.

When considering whether an intervention is helpful, most patients and clinicians follow the headache frequency, severity, or quality-of-life factors. As most patients will readily report, not all "headache-free days" are created equal. Although most people with migraine will experience days with absolutely no headache pain or other migraine-associated symptoms, on many days they will still have some symptoms of migraine. Lee and colleagues attempted to quantify the difference between headache-free days and crystal-clear days.

Most headache studies use the frequency of headache days as a primary or secondary outcome. This study collected data on both headache days and crystal-clear days, using data from a questionnaire-based large South Korean nationwide population study that evaluated headache and sleep. The study questions were validated for migraine and aura, and included: "How many days have you had a headache during the previous 30 days?" and "How many days have you had crystal-clear days without headache during the previous 30 days?" The data were then analyzed and compared with the widespread pain index (criteria for fibromyalgia) as well as sleep duration, sleep quality, depression and anxiety scales, and an allodynia checklist.

A little over 3000 respondents completed the surveys; 1938 had experienced headache over the past year, 170 were classified as having a diagnosis of migraine, and 50 of those were diagnosed with aura as well. Out of the patients with migraine, 97% had "unclear days." This was higher than the rate of those with non-migraine headaches (91%). Nearly all people surveyed had some crystal-clear days (99.4%).

The number of crystal-clear days per 30 days was significantly lower in participants with migraine than in those with non-migraine headache. Participants with migraine also had higher frequencies of cutaneous allodynia, anxiety, and depression. The weekly average sleep duration in participants with migraine did not significantly differ from that in participants with non-migraine headaches. The widespread pain index rate was much higher in those with migraine as well.

Most patients will definitely understand the difference between crystal-clear and unclear headache days. Many of the newer outcomes studies in migraine have started focusing on the most bothersome symptom, as headache pain is far from the only significant or disabling symptom associated with migraine. This study makes clear that further outcomes changes are necessary, and that a potentially more meaningful result in migraine studies may actually be crystal-clear days rather than simply headache-free days.

Although there are more acute options available for headache treatment, medication overuse headache remains a major complicating factor for most clinicians who treat headache. When educating patients, there is always a strong emphasis on guidelines for acute medication use. Many patients struggle with knowing when to use an acute treatment and when to alternate with a different treatment, and often they will withhold treatment completely due to fear of medication overuse. The new class of calcitonin gene-related peptide (CGRP) antagonist medications has shown some potential benefit as a preventive option for both medication overuse headache and migraine.

The prospective study by Curone and colleagues enrolled 300 patients with confirmed medication overuse headache who did not undergo withdrawal of the overused acute medication. Patients who are already taking preventive medications were excluded, as were patients with diagnoses other than chronic migraine or medication overuse. Patients were given one of the three injectable CGRP antagonist medications for prevention and were followed up at 3, 6, 9, and 12 months. The primary outcome was MIDAS score as well as monthly headache days and analgesic consumption.

Out of 303 patients, 242 (80%) showed both a ≥50% reduction of monthly headache days and ≥50% reduction in analgesic intake at 3-month follow-up visit. At 9 months, 198 (65%) were still responders. Monthly analgesic intake decreased ≥50% in 268 of 303 patients (88%) at 3 months and in 241 of 303 patients (79%) at the 6-month follow-up.

For years there has been a debate regarding whether withdrawal of an overused medication is necessary for effective treatment of medication overuse headache. Many preventive treatments are less effective when medication overuse is ongoing. The CGRP class of medications does appear to be effective even with ongoing acute medication overuse. This class of medications should definitely be considered when withdrawing an overused medication is complicated, or when a patient needs to continue to take analgesic medications for another condition.

Key clinical point: Monoclonal antibodies inhibiting calcitonin gene-related peptide (CGRP) effectively reduced monthly headache days, symptomatic drug consumption, and headache severity consistently over 12 months in patients with chronic migraine complicated by medication overuse headache (MOH).

Major finding: Overall, 80% of patients showed both ≥50% reduction in monthly headache days and ≥50% reduction in analgesics intake at the 3-month follow-up visit and 78.8% continued to show the improvements at the 6-month follow-up visit. The mean Migraine Impact and Disability Assessment Scale score decreased from 56.5 (range 27-63) at baseline to 13.1 (range 11-37) at 9 months, with 71% of patients being responders even at 1 year.

Study details: The data come from a prospective study of 303 patients with chronic migraine complicated by MOH who received CGRP antagonists for at least 6 months up to 1 year.

Disclosures: No source of funding was declared. The authors declared no competing interests.

Source: Curone M et al. Overview on effectiveness of erenumab, fremanezumab, and galcanezumab in reducing medication overuse headache in chronic migraine patients. Neurol Sci. 2022 (Jul 14). Doi: 10.1007/s10072-022-06265-8

Key clinical point: Monoclonal antibodies inhibiting calcitonin gene-related peptide (CGRP) effectively reduced monthly headache days, symptomatic drug consumption, and headache severity consistently over 12 months in patients with chronic migraine complicated by medication overuse headache (MOH).

Major finding: Overall, 80% of patients showed both ≥50% reduction in monthly headache days and ≥50% reduction in analgesics intake at the 3-month follow-up visit and 78.8% continued to show the improvements at the 6-month follow-up visit. The mean Migraine Impact and Disability Assessment Scale score decreased from 56.5 (range 27-63) at baseline to 13.1 (range 11-37) at 9 months, with 71% of patients being responders even at 1 year.

Study details: The data come from a prospective study of 303 patients with chronic migraine complicated by MOH who received CGRP antagonists for at least 6 months up to 1 year.

Disclosures: No source of funding was declared. The authors declared no competing interests.

Source: Curone M et al. Overview on effectiveness of erenumab, fremanezumab, and galcanezumab in reducing medication overuse headache in chronic migraine patients. Neurol Sci. 2022 (Jul 14). Doi: 10.1007/s10072-022-06265-8

Key clinical point: Monoclonal antibodies inhibiting calcitonin gene-related peptide (CGRP) effectively reduced monthly headache days, symptomatic drug consumption, and headache severity consistently over 12 months in patients with chronic migraine complicated by medication overuse headache (MOH).

Major finding: Overall, 80% of patients showed both ≥50% reduction in monthly headache days and ≥50% reduction in analgesics intake at the 3-month follow-up visit and 78.8% continued to show the improvements at the 6-month follow-up visit. The mean Migraine Impact and Disability Assessment Scale score decreased from 56.5 (range 27-63) at baseline to 13.1 (range 11-37) at 9 months, with 71% of patients being responders even at 1 year.

Study details: The data come from a prospective study of 303 patients with chronic migraine complicated by MOH who received CGRP antagonists for at least 6 months up to 1 year.

Disclosures: No source of funding was declared. The authors declared no competing interests.

Source: Curone M et al. Overview on effectiveness of erenumab, fremanezumab, and galcanezumab in reducing medication overuse headache in chronic migraine patients. Neurol Sci. 2022 (Jul 14). Doi: 10.1007/s10072-022-06265-8

Key clinical point: The occurrence of unclear days, defined as headache-free but not crystal-clear days, is prevalent in migraine, with the number of crystal-clear days being significantly lower and unclear days being significantly higher in participants with migraine vs non-migraine headache.

Major finding: Overall, 97.1% of participants had unclear days, with the number of crystal-clear days per 30 days being significantly lower (median, 20.0 vs 25.0) and the number of severe headache days (2.0 vs 1.0), days with acute medications (2.0 vs 1.0), and unclear days (4.0 vs 1.0) per 30 days being significantly higher in participants with vs without migraine headache (all P < .001).

Study details: The data come from a cross-sectional and case-control analysis of longitudinally collected data from 170 and 1768 participants with migraine and nonmigraine headaches, respectively.

Disclosures: This study was funded by the National Research Foundation of Korea. S-J Cho and MK Chu declared being site investigators of a multicenter trial or an advisory board members or receiving lecture honoraria or grants from various sources.

Source: Lee W et al. Crystal-clear days and unclear days in migraine: A population-based study. Headache. 2022;62: 818- 827 (Jul 14). Doi: 10.1111/head.14359

Key clinical point: The occurrence of unclear days, defined as headache-free but not crystal-clear days, is prevalent in migraine, with the number of crystal-clear days being significantly lower and unclear days being significantly higher in participants with migraine vs non-migraine headache.

Major finding: Overall, 97.1% of participants had unclear days, with the number of crystal-clear days per 30 days being significantly lower (median, 20.0 vs 25.0) and the number of severe headache days (2.0 vs 1.0), days with acute medications (2.0 vs 1.0), and unclear days (4.0 vs 1.0) per 30 days being significantly higher in participants with vs without migraine headache (all P < .001).

Study details: The data come from a cross-sectional and case-control analysis of longitudinally collected data from 170 and 1768 participants with migraine and nonmigraine headaches, respectively.

Disclosures: This study was funded by the National Research Foundation of Korea. S-J Cho and MK Chu declared being site investigators of a multicenter trial or an advisory board members or receiving lecture honoraria or grants from various sources.

Source: Lee W et al. Crystal-clear days and unclear days in migraine: A population-based study. Headache. 2022;62: 818- 827 (Jul 14). Doi: 10.1111/head.14359

Key clinical point: The occurrence of unclear days, defined as headache-free but not crystal-clear days, is prevalent in migraine, with the number of crystal-clear days being significantly lower and unclear days being significantly higher in participants with migraine vs non-migraine headache.

Major finding: Overall, 97.1% of participants had unclear days, with the number of crystal-clear days per 30 days being significantly lower (median, 20.0 vs 25.0) and the number of severe headache days (2.0 vs 1.0), days with acute medications (2.0 vs 1.0), and unclear days (4.0 vs 1.0) per 30 days being significantly higher in participants with vs without migraine headache (all P < .001).

Study details: The data come from a cross-sectional and case-control analysis of longitudinally collected data from 170 and 1768 participants with migraine and nonmigraine headaches, respectively.

Disclosures: This study was funded by the National Research Foundation of Korea. S-J Cho and MK Chu declared being site investigators of a multicenter trial or an advisory board members or receiving lecture honoraria or grants from various sources.

Source: Lee W et al. Crystal-clear days and unclear days in migraine: A population-based study. Headache. 2022;62: 818- 827 (Jul 14). Doi: 10.1111/head.14359