Headache & Migraine

Key clinical point: External trigeminal nerve stimulation (e-TNS) for 2 consecutive hours is an effective, safe, nonpharmacological, and noninvasive acute treatment option for a migraine attack with or without aura.

Major finding: A significantly higher percentage of patients experienced pain freedom (25.5% vs. 18.3%; P < .05) and showed resolution of the most bothersome migraine symptoms (56.4% vs. 42.3%; P < .01) with e-TNS vs. sham treatment, effectuating a therapeutic gain of 7.2% and 14.1%, respectively.

Study details: The intention-to-treat population in this multicenter, prospective, phase 3 study, TEAM, consisted of 538 adult patients with episodic migraine with or without aura who were randomly assigned to receive active (n = 259) or sham (n = 279) stimulation for 2 hours.

Disclosures: The study was sponsored by Cefaly Technology, Belgium. Some authors reported receiving consulting fees, advisory board honoraria, or research grants from various sources. MAL Johnson is the Global Director of Medical Affairs for Cefaly.

Source: Kuruvilla DE et al. Phase 3 randomized, double-blind, sham-controlled Trial of e-TNS for the Acute treatment of Migraine (TEAM). Sci Rep. 2022;12:5110 (Mar 24). Doi: 10.1038/s41598-022-09071-6

Key clinical point: External trigeminal nerve stimulation (e-TNS) for 2 consecutive hours is an effective, safe, nonpharmacological, and noninvasive acute treatment option for a migraine attack with or without aura.

Major finding: A significantly higher percentage of patients experienced pain freedom (25.5% vs. 18.3%; P < .05) and showed resolution of the most bothersome migraine symptoms (56.4% vs. 42.3%; P < .01) with e-TNS vs. sham treatment, effectuating a therapeutic gain of 7.2% and 14.1%, respectively.

Study details: The intention-to-treat population in this multicenter, prospective, phase 3 study, TEAM, consisted of 538 adult patients with episodic migraine with or without aura who were randomly assigned to receive active (n = 259) or sham (n = 279) stimulation for 2 hours.

Disclosures: The study was sponsored by Cefaly Technology, Belgium. Some authors reported receiving consulting fees, advisory board honoraria, or research grants from various sources. MAL Johnson is the Global Director of Medical Affairs for Cefaly.

Source: Kuruvilla DE et al. Phase 3 randomized, double-blind, sham-controlled Trial of e-TNS for the Acute treatment of Migraine (TEAM). Sci Rep. 2022;12:5110 (Mar 24). Doi: 10.1038/s41598-022-09071-6

Key clinical point: External trigeminal nerve stimulation (e-TNS) for 2 consecutive hours is an effective, safe, nonpharmacological, and noninvasive acute treatment option for a migraine attack with or without aura.

Major finding: A significantly higher percentage of patients experienced pain freedom (25.5% vs. 18.3%; P < .05) and showed resolution of the most bothersome migraine symptoms (56.4% vs. 42.3%; P < .01) with e-TNS vs. sham treatment, effectuating a therapeutic gain of 7.2% and 14.1%, respectively.

Study details: The intention-to-treat population in this multicenter, prospective, phase 3 study, TEAM, consisted of 538 adult patients with episodic migraine with or without aura who were randomly assigned to receive active (n = 259) or sham (n = 279) stimulation for 2 hours.

Disclosures: The study was sponsored by Cefaly Technology, Belgium. Some authors reported receiving consulting fees, advisory board honoraria, or research grants from various sources. MAL Johnson is the Global Director of Medical Affairs for Cefaly.

Source: Kuruvilla DE et al. Phase 3 randomized, double-blind, sham-controlled Trial of e-TNS for the Acute treatment of Migraine (TEAM). Sci Rep. 2022;12:5110 (Mar 24). Doi: 10.1038/s41598-022-09071-6

Key clinical point: Fremanezumab lowers the pain and neurological symptom days in patients with episodic migraine (EM) or chronic migraine (CM) with associated neurological dysfunction and inadequate response to 2-4 prior classes of prophylactic medications.

Major finding: Quarterly and monthly fremanezumab vs. placebo significantly reduced monthly mean days with neurological symptoms (least square mean difference −1.7 days and −1.8 days vs. −0.5 days; both P ≤ .01) and monthly migraine days (P < .0001) over 12 weeks.

Study details: This post hoc analysis included 837 patients with difficult-to-treat EM or CM from the phase 3b FOCUS study who received quarterly fremanezumab, monthly fremanezumab, or placebo over 12 weeks and were categorized into patients with (n = 493) and without (n = 344) associated neurological dysfunction.

Disclosures: This study was funded by Teva Branded Pharmaceutical Products R&D, Inc., USA. Some authors declared serving as consultants, speakers, or principal clinical trial investigators for or receiving personal fees from various sources, including Teva, and other authors are employees or stockholders of Teva.

Source: Lampl C et al. Efficacy and quality-of-life improvements with fremanezumab treatment in patients with difficult-to-treat migraine with associated neurological dysfunction. Eur J Neurol. 2022 (Mar 18). Doi: 10.1111/ene.15328

Key clinical point: Fremanezumab lowers the pain and neurological symptom days in patients with episodic migraine (EM) or chronic migraine (CM) with associated neurological dysfunction and inadequate response to 2-4 prior classes of prophylactic medications.

Major finding: Quarterly and monthly fremanezumab vs. placebo significantly reduced monthly mean days with neurological symptoms (least square mean difference −1.7 days and −1.8 days vs. −0.5 days; both P ≤ .01) and monthly migraine days (P < .0001) over 12 weeks.

Study details: This post hoc analysis included 837 patients with difficult-to-treat EM or CM from the phase 3b FOCUS study who received quarterly fremanezumab, monthly fremanezumab, or placebo over 12 weeks and were categorized into patients with (n = 493) and without (n = 344) associated neurological dysfunction.

Disclosures: This study was funded by Teva Branded Pharmaceutical Products R&D, Inc., USA. Some authors declared serving as consultants, speakers, or principal clinical trial investigators for or receiving personal fees from various sources, including Teva, and other authors are employees or stockholders of Teva.

Source: Lampl C et al. Efficacy and quality-of-life improvements with fremanezumab treatment in patients with difficult-to-treat migraine with associated neurological dysfunction. Eur J Neurol. 2022 (Mar 18). Doi: 10.1111/ene.15328

Key clinical point: Fremanezumab lowers the pain and neurological symptom days in patients with episodic migraine (EM) or chronic migraine (CM) with associated neurological dysfunction and inadequate response to 2-4 prior classes of prophylactic medications.

Major finding: Quarterly and monthly fremanezumab vs. placebo significantly reduced monthly mean days with neurological symptoms (least square mean difference −1.7 days and −1.8 days vs. −0.5 days; both P ≤ .01) and monthly migraine days (P < .0001) over 12 weeks.

Study details: This post hoc analysis included 837 patients with difficult-to-treat EM or CM from the phase 3b FOCUS study who received quarterly fremanezumab, monthly fremanezumab, or placebo over 12 weeks and were categorized into patients with (n = 493) and without (n = 344) associated neurological dysfunction.

Disclosures: This study was funded by Teva Branded Pharmaceutical Products R&D, Inc., USA. Some authors declared serving as consultants, speakers, or principal clinical trial investigators for or receiving personal fees from various sources, including Teva, and other authors are employees or stockholders of Teva.

Source: Lampl C et al. Efficacy and quality-of-life improvements with fremanezumab treatment in patients with difficult-to-treat migraine with associated neurological dysfunction. Eur J Neurol. 2022 (Mar 18). Doi: 10.1111/ene.15328

Key clinical point: Consistent with the overall study population results, eptinezumab therapy demonstrated favorable efficacy and safety in patients with episodic migraine (EM) or chronic migraine (CM) and self-reported aura from the PROMISE studies.

Major finding: Over weeks 1-12, monthly migraine days decreased with 100 mg and 300 mg eptinezumab vs. placebo in patients with EM (100 mg, −3.9 days; 300 mg, −4.2 days vs. −3.3 days) and CM (100 mg, −7.1 days; 300 mg, −7.6 days vs. −5.9 days) with aura. Treatment-emergent adverse event rates were similar across treatment groups.

Study details: Of 1741 patients with EM/CM from the PROMISE-1 and PROMISE-2 trials, this post hoc analysis included 877 patients who self-reported migraine with aura at screening and received eptinezumab (n = 583) or placebo (n = 294).

Disclosures: Lundbeck Seattle BioPharmaceuticals, Inc., USA, funded the study. Some authors declared serving as consultants, speakers, advisors, or as a primary trial investigator for and receiving personal fees and research support from various sources, including Lundbeck. Some authors are current or former employees of Lundbeck or its subsidiary company.

Source: Ashina M et al. Efficacy and safety of eptinezumab in patients with migraine and self-reported aura: Post hoc analysis of PROMISE-1 and PROMISE-2. Cephalalgia. 2022 (Mar 18). Doi: 10.1177/03331024221077646

Key clinical point: Consistent with the overall study population results, eptinezumab therapy demonstrated favorable efficacy and safety in patients with episodic migraine (EM) or chronic migraine (CM) and self-reported aura from the PROMISE studies.

Major finding: Over weeks 1-12, monthly migraine days decreased with 100 mg and 300 mg eptinezumab vs. placebo in patients with EM (100 mg, −3.9 days; 300 mg, −4.2 days vs. −3.3 days) and CM (100 mg, −7.1 days; 300 mg, −7.6 days vs. −5.9 days) with aura. Treatment-emergent adverse event rates were similar across treatment groups.

Study details: Of 1741 patients with EM/CM from the PROMISE-1 and PROMISE-2 trials, this post hoc analysis included 877 patients who self-reported migraine with aura at screening and received eptinezumab (n = 583) or placebo (n = 294).

Disclosures: Lundbeck Seattle BioPharmaceuticals, Inc., USA, funded the study. Some authors declared serving as consultants, speakers, advisors, or as a primary trial investigator for and receiving personal fees and research support from various sources, including Lundbeck. Some authors are current or former employees of Lundbeck or its subsidiary company.

Source: Ashina M et al. Efficacy and safety of eptinezumab in patients with migraine and self-reported aura: Post hoc analysis of PROMISE-1 and PROMISE-2. Cephalalgia. 2022 (Mar 18). Doi: 10.1177/03331024221077646

Key clinical point: Consistent with the overall study population results, eptinezumab therapy demonstrated favorable efficacy and safety in patients with episodic migraine (EM) or chronic migraine (CM) and self-reported aura from the PROMISE studies.

Major finding: Over weeks 1-12, monthly migraine days decreased with 100 mg and 300 mg eptinezumab vs. placebo in patients with EM (100 mg, −3.9 days; 300 mg, −4.2 days vs. −3.3 days) and CM (100 mg, −7.1 days; 300 mg, −7.6 days vs. −5.9 days) with aura. Treatment-emergent adverse event rates were similar across treatment groups.

Study details: Of 1741 patients with EM/CM from the PROMISE-1 and PROMISE-2 trials, this post hoc analysis included 877 patients who self-reported migraine with aura at screening and received eptinezumab (n = 583) or placebo (n = 294).

Disclosures: Lundbeck Seattle BioPharmaceuticals, Inc., USA, funded the study. Some authors declared serving as consultants, speakers, advisors, or as a primary trial investigator for and receiving personal fees and research support from various sources, including Lundbeck. Some authors are current or former employees of Lundbeck or its subsidiary company.

Source: Ashina M et al. Efficacy and safety of eptinezumab in patients with migraine and self-reported aura: Post hoc analysis of PROMISE-1 and PROMISE-2. Cephalalgia. 2022 (Mar 18). Doi: 10.1177/03331024221077646

Key clinical point: Galcanezumab is an effective and safe long-term treatment option for chronic migraine.

Major finding: At month 12, patients in the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups showed a mean change of −8.5, −9.0, and −8.0 days in monthly migraine days from the beginning of the double-blind period, respectively (all within-group P < .001). No new safety concerns emerged with extended treatment.

Study details: Findings are from the 9-month open-label extension of the REGAIN trial including 1022 patients with chronic migraine who completed the preceding 3-month double-blind treatment (501, 259, and 262 patients assigned to the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups, respectively) and received a 240-mg galcanezumab loading dose, followed by 120 mg in the next month and flexible dosing thereafter.

Disclosures: This study was sponsored by Eli Lilly and Company. Some authors declared receiving speaker, consultant, or advisory board member honoraria from various sources, including Eli Lilly. Two authors reported being full-time employees and minor stockholders of Eli Lilly.

Source: Pozo-Rosich P et al. Long-term treatment with galcanezumab in patients with chronic migraine: results from the open-label extension of the REGAIN study. Curr Med Res Opin. 2022 (Apr 8). Doi:   10.1080/03007995.2022.2059975

Key clinical point: Galcanezumab is an effective and safe long-term treatment option for chronic migraine.

Major finding: At month 12, patients in the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups showed a mean change of −8.5, −9.0, and −8.0 days in monthly migraine days from the beginning of the double-blind period, respectively (all within-group P < .001). No new safety concerns emerged with extended treatment.

Study details: Findings are from the 9-month open-label extension of the REGAIN trial including 1022 patients with chronic migraine who completed the preceding 3-month double-blind treatment (501, 259, and 262 patients assigned to the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups, respectively) and received a 240-mg galcanezumab loading dose, followed by 120 mg in the next month and flexible dosing thereafter.

Disclosures: This study was sponsored by Eli Lilly and Company. Some authors declared receiving speaker, consultant, or advisory board member honoraria from various sources, including Eli Lilly. Two authors reported being full-time employees and minor stockholders of Eli Lilly.

Source: Pozo-Rosich P et al. Long-term treatment with galcanezumab in patients with chronic migraine: results from the open-label extension of the REGAIN study. Curr Med Res Opin. 2022 (Apr 8). Doi:   10.1080/03007995.2022.2059975

Key clinical point: Galcanezumab is an effective and safe long-term treatment option for chronic migraine.

Major finding: At month 12, patients in the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups showed a mean change of −8.5, −9.0, and −8.0 days in monthly migraine days from the beginning of the double-blind period, respectively (all within-group P < .001). No new safety concerns emerged with extended treatment.

Study details: Findings are from the 9-month open-label extension of the REGAIN trial including 1022 patients with chronic migraine who completed the preceding 3-month double-blind treatment (501, 259, and 262 patients assigned to the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups, respectively) and received a 240-mg galcanezumab loading dose, followed by 120 mg in the next month and flexible dosing thereafter.

Disclosures: This study was sponsored by Eli Lilly and Company. Some authors declared receiving speaker, consultant, or advisory board member honoraria from various sources, including Eli Lilly. Two authors reported being full-time employees and minor stockholders of Eli Lilly.

Source: Pozo-Rosich P et al. Long-term treatment with galcanezumab in patients with chronic migraine: results from the open-label extension of the REGAIN study. Curr Med Res Opin. 2022 (Apr 8). Doi:   10.1080/03007995.2022.2059975

A 35-year-old man comes to clinic for evaluation of new, severe headaches. He reports that these started 3 days ago. His headache is worse when he stands, and resolves when he lies down. Valsalva maneuver makes the headache much worse. The headaches are present in the occipital region. He also has noticed the onset of tinnitus. A physical exam reveals that his blood pressure is 110/70 mm Hg, his pulse is 60 beats per minute, and his temperature is 36.4° C. His standing BP is 105/60 mm Hg and standing pulse is 66 bpm. Both his neurologic exam and noncontrast head CT scan are normal.


Which of the following is the most likely diagnosis?

A) Subarachnoid hemorrhage

B) POTS (Postural orthostatic tachycardia syndrome)

C) Hypnic headache

D) Spontaneous intracranial hypotension (SIH)

E) Acoustic neuroma

The most likely cause for this patient’s headaches given his set of symptoms is spontaneous intracranial hypotension. Orthostatic headaches are common with POTS, but the absence of tachycardia with standing makes this diagnosis unlikely.

Spontaneous intracranial hypotension has symptoms that we are all familiar with in the post–lumbar puncture patient. In patients with post-LP headache, the positional nature makes it easy to diagnose. Patients who have had a lumbar puncture have a clear reason they have a cerebrospinal fluid (CSF) leak, leading to intracranial hypotension. Those with SIH do not.
 

Related research

Schievink summarized a lot of useful information in a review of patients with spontaneous intracranial hypotension.¹ The incidence is about 5/100,000, with the most common age around 40 years old. The most common symptom is orthostatic headache. The headache usually occurs within 15 minutes upon standing, and many patients have the onset of headache rapidly upon standing.

Usually the headache improves with lying down, and it is often brought on with Valsalva maneuver. Many patients report headaches that are worse in the second half of the day.

Orthostatic headache occurs in almost all patients with spontaneous intracranial hypotension, but in one series it occurred only in 77% of patients with SIH.² The patients who did not have typical headaches are more likely to have auditory symptoms such as tinnitus and muffled hearing.³

When you suspect SIH, appropriate workup is to start with brain MR imaging with contrast. Krantz and colleagues found dural enhancement was present in 83% of cases of SIH, venous distention sign in 75%, and brain sagging in 61%.⁴

About 10% of patients with SIH have normal brain imaging, so if the clinical features strongly suggest the diagnosis, moving on to spinal imaging with CT myelography or spinal MR are appropriate next steps.⁵

The causes of SIH are meningeal diverticula (usually in the thoracic or upper lumbar regions), ventral dural tears (usually from osteophytes), and cerebrospinal fluid–venous fistulas. Treatment of SIH has traditionally included a conservative approach of bed rest, oral hydration, and caffeine. The effectiveness of this is unknown, and, in one small series, 61% had headache symptoms at 6 months.⁶

Epidural blood patches are likely more rapidly effective than conservative therapy. In one study comparing the two treatments, Chung and colleagues found that 77% of the patients who received an epidural blood patch had complete headache relief at 4 weeks, compared with 40% of those who received conservative measures (P < .05).⁷
 

Clinical pearls

• Strongly consider SIH in patients with positional headache.
• Brain MR should be the first diagnostic test.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as 3rd-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Schievink WI. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. JAMA. 2006;295:2286-96.

2. Mea E et al. Headache attributed to spontaneous intracranial hypotension. Neurol Sci. 2008;29:164-65.

3. Krantz PG et al. Spontaneous Intracranial Hypotension: 10 Myths and Misperceptions. Headache. 2018;58:948-59.

4. Krantz PG et. al. Imaging signs in spontaneous intracranial hypotension: prevalence and relationship to CSF pressure. AJNR Am J Neuroradiol. 2016;37:1374-8.

5. Krantz PG et al. Spontaneous intracranial hypotension: Pathogenesis, diagnosis, and treatment. Neuroimaging Clin N Am. 2019;29:581-94.

6. Kong D-S et. al. Clinical features and long-term results of spontaneous intracranial hypotension. Neurosurgery. 2005;57:91-6.

7. Chung SJ et al. Short- and long-term outcomes of spontaneous CSF hypovolemia. Eur Neurol. 2005;54:63-7.

A 35-year-old man comes to clinic for evaluation of new, severe headaches. He reports that these started 3 days ago. His headache is worse when he stands, and resolves when he lies down. Valsalva maneuver makes the headache much worse. The headaches are present in the occipital region. He also has noticed the onset of tinnitus. A physical exam reveals that his blood pressure is 110/70 mm Hg, his pulse is 60 beats per minute, and his temperature is 36.4° C. His standing BP is 105/60 mm Hg and standing pulse is 66 bpm. Both his neurologic exam and noncontrast head CT scan are normal.


Which of the following is the most likely diagnosis?

A) Subarachnoid hemorrhage

B) POTS (Postural orthostatic tachycardia syndrome)

C) Hypnic headache

D) Spontaneous intracranial hypotension (SIH)

E) Acoustic neuroma

The most likely cause for this patient’s headaches given his set of symptoms is spontaneous intracranial hypotension. Orthostatic headaches are common with POTS, but the absence of tachycardia with standing makes this diagnosis unlikely.

Spontaneous intracranial hypotension has symptoms that we are all familiar with in the post–lumbar puncture patient. In patients with post-LP headache, the positional nature makes it easy to diagnose. Patients who have had a lumbar puncture have a clear reason they have a cerebrospinal fluid (CSF) leak, leading to intracranial hypotension. Those with SIH do not.
 

Related research

Schievink summarized a lot of useful information in a review of patients with spontaneous intracranial hypotension.¹ The incidence is about 5/100,000, with the most common age around 40 years old. The most common symptom is orthostatic headache. The headache usually occurs within 15 minutes upon standing, and many patients have the onset of headache rapidly upon standing.

Usually the headache improves with lying down, and it is often brought on with Valsalva maneuver. Many patients report headaches that are worse in the second half of the day.

Orthostatic headache occurs in almost all patients with spontaneous intracranial hypotension, but in one series it occurred only in 77% of patients with SIH.² The patients who did not have typical headaches are more likely to have auditory symptoms such as tinnitus and muffled hearing.³

When you suspect SIH, appropriate workup is to start with brain MR imaging with contrast. Krantz and colleagues found dural enhancement was present in 83% of cases of SIH, venous distention sign in 75%, and brain sagging in 61%.⁴

About 10% of patients with SIH have normal brain imaging, so if the clinical features strongly suggest the diagnosis, moving on to spinal imaging with CT myelography or spinal MR are appropriate next steps.⁵

The causes of SIH are meningeal diverticula (usually in the thoracic or upper lumbar regions), ventral dural tears (usually from osteophytes), and cerebrospinal fluid–venous fistulas. Treatment of SIH has traditionally included a conservative approach of bed rest, oral hydration, and caffeine. The effectiveness of this is unknown, and, in one small series, 61% had headache symptoms at 6 months.⁶

Epidural blood patches are likely more rapidly effective than conservative therapy. In one study comparing the two treatments, Chung and colleagues found that 77% of the patients who received an epidural blood patch had complete headache relief at 4 weeks, compared with 40% of those who received conservative measures (P < .05).⁷
 

Clinical pearls

• Strongly consider SIH in patients with positional headache.
• Brain MR should be the first diagnostic test.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as 3rd-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Schievink WI. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. JAMA. 2006;295:2286-96.

2. Mea E et al. Headache attributed to spontaneous intracranial hypotension. Neurol Sci. 2008;29:164-65.

3. Krantz PG et al. Spontaneous Intracranial Hypotension: 10 Myths and Misperceptions. Headache. 2018;58:948-59.

4. Krantz PG et. al. Imaging signs in spontaneous intracranial hypotension: prevalence and relationship to CSF pressure. AJNR Am J Neuroradiol. 2016;37:1374-8.

5. Krantz PG et al. Spontaneous intracranial hypotension: Pathogenesis, diagnosis, and treatment. Neuroimaging Clin N Am. 2019;29:581-94.

6. Kong D-S et. al. Clinical features and long-term results of spontaneous intracranial hypotension. Neurosurgery. 2005;57:91-6.

7. Chung SJ et al. Short- and long-term outcomes of spontaneous CSF hypovolemia. Eur Neurol. 2005;54:63-7.

A 35-year-old man comes to clinic for evaluation of new, severe headaches. He reports that these started 3 days ago. His headache is worse when he stands, and resolves when he lies down. Valsalva maneuver makes the headache much worse. The headaches are present in the occipital region. He also has noticed the onset of tinnitus. A physical exam reveals that his blood pressure is 110/70 mm Hg, his pulse is 60 beats per minute, and his temperature is 36.4° C. His standing BP is 105/60 mm Hg and standing pulse is 66 bpm. Both his neurologic exam and noncontrast head CT scan are normal.


Which of the following is the most likely diagnosis?

A) Subarachnoid hemorrhage

B) POTS (Postural orthostatic tachycardia syndrome)

C) Hypnic headache

D) Spontaneous intracranial hypotension (SIH)

E) Acoustic neuroma

The most likely cause for this patient’s headaches given his set of symptoms is spontaneous intracranial hypotension. Orthostatic headaches are common with POTS, but the absence of tachycardia with standing makes this diagnosis unlikely.

Spontaneous intracranial hypotension has symptoms that we are all familiar with in the post–lumbar puncture patient. In patients with post-LP headache, the positional nature makes it easy to diagnose. Patients who have had a lumbar puncture have a clear reason they have a cerebrospinal fluid (CSF) leak, leading to intracranial hypotension. Those with SIH do not.
 

Related research

Schievink summarized a lot of useful information in a review of patients with spontaneous intracranial hypotension.¹ The incidence is about 5/100,000, with the most common age around 40 years old. The most common symptom is orthostatic headache. The headache usually occurs within 15 minutes upon standing, and many patients have the onset of headache rapidly upon standing.

Usually the headache improves with lying down, and it is often brought on with Valsalva maneuver. Many patients report headaches that are worse in the second half of the day.

Orthostatic headache occurs in almost all patients with spontaneous intracranial hypotension, but in one series it occurred only in 77% of patients with SIH.² The patients who did not have typical headaches are more likely to have auditory symptoms such as tinnitus and muffled hearing.³

When you suspect SIH, appropriate workup is to start with brain MR imaging with contrast. Krantz and colleagues found dural enhancement was present in 83% of cases of SIH, venous distention sign in 75%, and brain sagging in 61%.⁴

About 10% of patients with SIH have normal brain imaging, so if the clinical features strongly suggest the diagnosis, moving on to spinal imaging with CT myelography or spinal MR are appropriate next steps.⁵

The causes of SIH are meningeal diverticula (usually in the thoracic or upper lumbar regions), ventral dural tears (usually from osteophytes), and cerebrospinal fluid–venous fistulas. Treatment of SIH has traditionally included a conservative approach of bed rest, oral hydration, and caffeine. The effectiveness of this is unknown, and, in one small series, 61% had headache symptoms at 6 months.⁶

Epidural blood patches are likely more rapidly effective than conservative therapy. In one study comparing the two treatments, Chung and colleagues found that 77% of the patients who received an epidural blood patch had complete headache relief at 4 weeks, compared with 40% of those who received conservative measures (P < .05).⁷
 

Clinical pearls

• Strongly consider SIH in patients with positional headache.
• Brain MR should be the first diagnostic test.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as 3rd-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Schievink WI. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. JAMA. 2006;295:2286-96.

2. Mea E et al. Headache attributed to spontaneous intracranial hypotension. Neurol Sci. 2008;29:164-65.

3. Krantz PG et al. Spontaneous Intracranial Hypotension: 10 Myths and Misperceptions. Headache. 2018;58:948-59.

4. Krantz PG et. al. Imaging signs in spontaneous intracranial hypotension: prevalence and relationship to CSF pressure. AJNR Am J Neuroradiol. 2016;37:1374-8.

5. Krantz PG et al. Spontaneous intracranial hypotension: Pathogenesis, diagnosis, and treatment. Neuroimaging Clin N Am. 2019;29:581-94.

6. Kong D-S et. al. Clinical features and long-term results of spontaneous intracranial hypotension. Neurosurgery. 2005;57:91-6.

7. Chung SJ et al. Short- and long-term outcomes of spontaneous CSF hypovolemia. Eur Neurol. 2005;54:63-7.

Topiramate, introduced as an antiepileptic drug (AED), is currently most widely used for prevention of migraine headaches.

Because reproductive-aged women represent a population in which migraines are prevalent, clinicians need guidance to help women taking topiramate make sound contraceptive choices.

Several issues are relevant here. First, women who have migraines with aura should avoid estrogen-containing contraceptive pills, patches, and rings. Instead, progestin-only methods, including the contraceptive implant, may be recommended to patients with migraines.

Second, because topiramate, as with a number of other AEDs, is a teratogen, women using this medication need highly effective contraception. This consideration may also lead clinicians to recommend use of the implant in women with migraines.

Finally, topiramate, along with other AEDs (phenytoin, carbamazepine, barbiturates, primidone, and oxcarbazepine) induces hepatic enzymes, which results in reduced serum contraceptive steroid levels.

Because there is uncertainty regarding the degree to which the use of topiramate reduces serum levels of etonogestrel (the progestin released by the implant), investigators performed a prospective study to assess the pharmacokinetic impact of topiramate in women with the implant.

Ongoing users of contraceptive implants who agreed to use additional nonhormonal contraception were recruited to a 6-week study, during which they took topiramate and periodically had blood drawn.

Overall, use of topiramate was found to lower serum etonogestrel levels from baseline on a dose-related basis. At study completion, almost one-third of study participants were found to have serum progestin levels lower than the threshold associated with predictable ovulation suppression.

The results of this carefully conducted study support guidance from the Centers for Disease Control and Prevention that women seeking contraception and using topiramate or other enzyme-inducing AEDs should be encouraged to use intrauterine devices or injectable contraception. The contraceptive efficacy of these latter methods is not diminished by concomitant use of enzyme inducers.

I am Andrew Kaunitz. Please take care of yourself and each other.

Any views expressed above are the author’s own and do not necessarily reflect the views of WebMD or Medscape.

Andrew M. Kaunitz is a professor and Associate Chairman, department of obstetrics and gynecology, University of Florida, Jacksonville.

A version of this article first appeared on Medscape.com.

Topiramate, introduced as an antiepileptic drug (AED), is currently most widely used for prevention of migraine headaches.

Because reproductive-aged women represent a population in which migraines are prevalent, clinicians need guidance to help women taking topiramate make sound contraceptive choices.

Several issues are relevant here. First, women who have migraines with aura should avoid estrogen-containing contraceptive pills, patches, and rings. Instead, progestin-only methods, including the contraceptive implant, may be recommended to patients with migraines.

Second, because topiramate, as with a number of other AEDs, is a teratogen, women using this medication need highly effective contraception. This consideration may also lead clinicians to recommend use of the implant in women with migraines.

Finally, topiramate, along with other AEDs (phenytoin, carbamazepine, barbiturates, primidone, and oxcarbazepine) induces hepatic enzymes, which results in reduced serum contraceptive steroid levels.

Because there is uncertainty regarding the degree to which the use of topiramate reduces serum levels of etonogestrel (the progestin released by the implant), investigators performed a prospective study to assess the pharmacokinetic impact of topiramate in women with the implant.

Ongoing users of contraceptive implants who agreed to use additional nonhormonal contraception were recruited to a 6-week study, during which they took topiramate and periodically had blood drawn.

Overall, use of topiramate was found to lower serum etonogestrel levels from baseline on a dose-related basis. At study completion, almost one-third of study participants were found to have serum progestin levels lower than the threshold associated with predictable ovulation suppression.

The results of this carefully conducted study support guidance from the Centers for Disease Control and Prevention that women seeking contraception and using topiramate or other enzyme-inducing AEDs should be encouraged to use intrauterine devices or injectable contraception. The contraceptive efficacy of these latter methods is not diminished by concomitant use of enzyme inducers.

I am Andrew Kaunitz. Please take care of yourself and each other.

Any views expressed above are the author’s own and do not necessarily reflect the views of WebMD or Medscape.

Andrew M. Kaunitz is a professor and Associate Chairman, department of obstetrics and gynecology, University of Florida, Jacksonville.

A version of this article first appeared on Medscape.com.

Topiramate, introduced as an antiepileptic drug (AED), is currently most widely used for prevention of migraine headaches.

Because reproductive-aged women represent a population in which migraines are prevalent, clinicians need guidance to help women taking topiramate make sound contraceptive choices.

Several issues are relevant here. First, women who have migraines with aura should avoid estrogen-containing contraceptive pills, patches, and rings. Instead, progestin-only methods, including the contraceptive implant, may be recommended to patients with migraines.

Second, because topiramate, as with a number of other AEDs, is a teratogen, women using this medication need highly effective contraception. This consideration may also lead clinicians to recommend use of the implant in women with migraines.

Finally, topiramate, along with other AEDs (phenytoin, carbamazepine, barbiturates, primidone, and oxcarbazepine) induces hepatic enzymes, which results in reduced serum contraceptive steroid levels.

Because there is uncertainty regarding the degree to which the use of topiramate reduces serum levels of etonogestrel (the progestin released by the implant), investigators performed a prospective study to assess the pharmacokinetic impact of topiramate in women with the implant.

Ongoing users of contraceptive implants who agreed to use additional nonhormonal contraception were recruited to a 6-week study, during which they took topiramate and periodically had blood drawn.

Overall, use of topiramate was found to lower serum etonogestrel levels from baseline on a dose-related basis. At study completion, almost one-third of study participants were found to have serum progestin levels lower than the threshold associated with predictable ovulation suppression.

The results of this carefully conducted study support guidance from the Centers for Disease Control and Prevention that women seeking contraception and using topiramate or other enzyme-inducing AEDs should be encouraged to use intrauterine devices or injectable contraception. The contraceptive efficacy of these latter methods is not diminished by concomitant use of enzyme inducers.

I am Andrew Kaunitz. Please take care of yourself and each other.

Any views expressed above are the author’s own and do not necessarily reflect the views of WebMD or Medscape.

Andrew M. Kaunitz is a professor and Associate Chairman, department of obstetrics and gynecology, University of Florida, Jacksonville.

A version of this article first appeared on Medscape.com.

Approximately one in five patients who presented with headache during the acute phase of COVID-19 developed chronic daily headache, according to a study published in Cephalalgia. The greater the headache’s intensity during the acute phase, the greater the likelihood that it would persist.

The research, carried out by members of the Headache Study Group of the Spanish Society of Neurology, evaluated the evolution of headache in more than 900 Spanish patients. Because they found that headache intensity during the acute phase was associated with a more prolonged duration of headache, the team stressed the importance of promptly evaluating patients who have had COVID-19 and who then experience persistent headache.
 

Long-term evolution unknown

Headache is a common symptom of COVID-19, but its long-term evolution remains unknown. The objective of this study was to evaluate the long-term duration of headache in patients who presented with this symptom during the acute phase of the disease.

Recruitment for this multicenter study took place in March and April 2020. The 905 patients who were enrolled came from six level 3 hospitals in Spain. All completed 9 months of neurologic follow-up.

Their median age was 51 years, 66.5% were women, and more than half (52.7%) had a history of primary headache. About half of the patients required hospitalization (50.5%); the rest were treated as outpatients. The most common headache phenotype was holocranial (67.8%) of severe intensity (50.6%).
 

Persistent headache common

In the 96.6% cases for which data were available, the median duration of headache was 14 days. The headache persisted at 1 month in 31.1% of patients, at 2 months in 21.5%, at 3 months in 19%, at 6 months in 16.8%, and at 9 months in 16.0%.

“The median duration of COVID-19 headache is around 2 weeks,” David García Azorín, MD, PhD, a member of the Spanish Society of Neurology and one of the coauthors of the study, said in an interview. “However, almost 20% of patients experience it for longer than that. When still present at 2 months, the headache is more likely to follow a chronic daily pattern.” Dr. García Azorín is a neurologist and clinical researcher at the headache unit of the Hospital Clínico Universitario in Valladolid, Spain.

“So, if the headache isn’t letting up, it’s important to make the most of that window of opportunity and provide treatment in that period of 6-12 weeks,” he continued. “To do this, the best option is to carry out preventive treatment so that the patient will have a better chance of recovering.”

Study participants whose headache persisted at 9 months were older and were mostly women. They were less likely to have had pneumonia or to have experienced stabbing pain, photophobia, or phonophobia. They reported that the headache got worse when they engaged in physical activity but less frequently manifested as a throbbing headache.
 

Secondary tension headaches

On the other hand, Jaime Rodríguez Vico, MD, head of the headache unit at the Jiménez Díaz Foundation Hospital in Madrid, said in an interview that, according to his case studies, the most striking characteristics of post–COVID-19 headaches “in general are secondary, with similarities to tension headaches that patients are able to differentiate from other clinical types of headache. In patients with migraine, very often we see that we’re dealing with a trigger. In other words, more migraines – and more intense ones at that – are brought about.”

He added: “Generally, post–COVID-19 headache usually lasts 1-2 weeks, but we have cases of it lasting several months and even over a year with persistent daily headache. These more persistent cases are probably connected to another type of pathology that makes them more susceptible to becoming chronic, something that occurs in another type of primary headache known as new daily persistent headache.”
 

Primary headache exacerbation

Dr. García Azorín pointed out that it’s not uncommon that among people who already have primary headache, their condition worsens after they become infected with SARS-CoV-2. However, many people differentiate the headache associated with the infection from their usual headache because after becoming infected, their headache is predominantly frontal, oppressive, and chronic.

“Having a prior history of headache is one of the factors that can increase the likelihood that a headache experienced while suffering from COVID-19 will become chronic,” he noted.

This study also found that, more often than not, patients with persistent headache at 9 months had migraine-like pain.

As for headaches in these patients beyond 9 months, “based on our research, the evolution is quite variable,” said Dr. Rodríguez Vico. “Our unit’s numbers are skewed due to the high number of migraine cases that we follow, and therefore our high volume of migraine patients who’ve gotten worse. The same thing happens with COVID-19 vaccines. Migraine is a polygenic disorder with multiple variants and a pathophysiology that we are just beginning to describe. This is why one patient is completely different from another. It’s a real challenge.”

Infections are a common cause of acute and chronic headache. The persistence of a headache after an infection may be caused by the infection becoming chronic, as happens in some types of chronic meningitis, such as tuberculous meningitis. It may also be caused by the persistence of a certain response and activation of the immune system or to the uncovering or worsening of a primary headache coincident with the infection, added Dr. García Azorín.

“Likewise, there are other people who have a biological predisposition to headache as a multifactorial disorder and polygenic disorder, such that a particular stimulus – from trauma or an infection to alcohol consumption – can cause them to develop a headache very similar to a migraine,” he said.
 

Providing prognosis and treatment

Certain factors can give an idea of how long the headache might last. The study’s univariate analysis showed that age, female sex, headache intensity, pressure-like quality, the presence of photophobia/phonophobia, and worsening with physical activity were associated with headache of longer duration. But in the multivariate analysis, only headache intensity during the acute phase remained statistically significant (hazard ratio, 0.655; 95% confidence interval, 0.582-0.737; P < .001).

When asked whether they planned to continue the study, Dr. García Azorín commented, “The main questions that have arisen from this study have been, above all: ‘Why does this headache happen?’ and ‘How can it be treated or avoided?’ To answer them, we’re looking into pain: which factors could predispose a person to it and which changes may be associated with its presence.”

In addition, different treatments that may improve patient outcomes are being evaluated, because to date, treatment has been empirical and based on the predominant pain phenotype.

In any case, most doctors currently treat post–COVID-19 headache on the basis of how similar the symptoms are to those of other primary headaches. “Given the impact that headache has on patients’ quality of life, there’s a pressing need for controlled studies on possible treatments and their effectiveness,” noted Patricia Pozo Rosich, MD, PhD, one of the coauthors of the study.

“We at the Spanish Society of Neurology truly believe that if these patients were to have this symptom correctly addressed from the start, they could avoid many of the problems that arise in the situation becoming chronic,” she concluded.

Dr. García Azorín and Dr. Rodríguez Vico disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Approximately one in five patients who presented with headache during the acute phase of COVID-19 developed chronic daily headache, according to a study published in Cephalalgia. The greater the headache’s intensity during the acute phase, the greater the likelihood that it would persist.

The research, carried out by members of the Headache Study Group of the Spanish Society of Neurology, evaluated the evolution of headache in more than 900 Spanish patients. Because they found that headache intensity during the acute phase was associated with a more prolonged duration of headache, the team stressed the importance of promptly evaluating patients who have had COVID-19 and who then experience persistent headache.
 

Long-term evolution unknown

Headache is a common symptom of COVID-19, but its long-term evolution remains unknown. The objective of this study was to evaluate the long-term duration of headache in patients who presented with this symptom during the acute phase of the disease.

Recruitment for this multicenter study took place in March and April 2020. The 905 patients who were enrolled came from six level 3 hospitals in Spain. All completed 9 months of neurologic follow-up.

Their median age was 51 years, 66.5% were women, and more than half (52.7%) had a history of primary headache. About half of the patients required hospitalization (50.5%); the rest were treated as outpatients. The most common headache phenotype was holocranial (67.8%) of severe intensity (50.6%).
 

Persistent headache common

In the 96.6% cases for which data were available, the median duration of headache was 14 days. The headache persisted at 1 month in 31.1% of patients, at 2 months in 21.5%, at 3 months in 19%, at 6 months in 16.8%, and at 9 months in 16.0%.

“The median duration of COVID-19 headache is around 2 weeks,” David García Azorín, MD, PhD, a member of the Spanish Society of Neurology and one of the coauthors of the study, said in an interview. “However, almost 20% of patients experience it for longer than that. When still present at 2 months, the headache is more likely to follow a chronic daily pattern.” Dr. García Azorín is a neurologist and clinical researcher at the headache unit of the Hospital Clínico Universitario in Valladolid, Spain.

“So, if the headache isn’t letting up, it’s important to make the most of that window of opportunity and provide treatment in that period of 6-12 weeks,” he continued. “To do this, the best option is to carry out preventive treatment so that the patient will have a better chance of recovering.”

Study participants whose headache persisted at 9 months were older and were mostly women. They were less likely to have had pneumonia or to have experienced stabbing pain, photophobia, or phonophobia. They reported that the headache got worse when they engaged in physical activity but less frequently manifested as a throbbing headache.
 

Secondary tension headaches

On the other hand, Jaime Rodríguez Vico, MD, head of the headache unit at the Jiménez Díaz Foundation Hospital in Madrid, said in an interview that, according to his case studies, the most striking characteristics of post–COVID-19 headaches “in general are secondary, with similarities to tension headaches that patients are able to differentiate from other clinical types of headache. In patients with migraine, very often we see that we’re dealing with a trigger. In other words, more migraines – and more intense ones at that – are brought about.”

He added: “Generally, post–COVID-19 headache usually lasts 1-2 weeks, but we have cases of it lasting several months and even over a year with persistent daily headache. These more persistent cases are probably connected to another type of pathology that makes them more susceptible to becoming chronic, something that occurs in another type of primary headache known as new daily persistent headache.”
 

Primary headache exacerbation

Dr. García Azorín pointed out that it’s not uncommon that among people who already have primary headache, their condition worsens after they become infected with SARS-CoV-2. However, many people differentiate the headache associated with the infection from their usual headache because after becoming infected, their headache is predominantly frontal, oppressive, and chronic.

“Having a prior history of headache is one of the factors that can increase the likelihood that a headache experienced while suffering from COVID-19 will become chronic,” he noted.

This study also found that, more often than not, patients with persistent headache at 9 months had migraine-like pain.

As for headaches in these patients beyond 9 months, “based on our research, the evolution is quite variable,” said Dr. Rodríguez Vico. “Our unit’s numbers are skewed due to the high number of migraine cases that we follow, and therefore our high volume of migraine patients who’ve gotten worse. The same thing happens with COVID-19 vaccines. Migraine is a polygenic disorder with multiple variants and a pathophysiology that we are just beginning to describe. This is why one patient is completely different from another. It’s a real challenge.”

Infections are a common cause of acute and chronic headache. The persistence of a headache after an infection may be caused by the infection becoming chronic, as happens in some types of chronic meningitis, such as tuberculous meningitis. It may also be caused by the persistence of a certain response and activation of the immune system or to the uncovering or worsening of a primary headache coincident with the infection, added Dr. García Azorín.

“Likewise, there are other people who have a biological predisposition to headache as a multifactorial disorder and polygenic disorder, such that a particular stimulus – from trauma or an infection to alcohol consumption – can cause them to develop a headache very similar to a migraine,” he said.
 

Providing prognosis and treatment

Certain factors can give an idea of how long the headache might last. The study’s univariate analysis showed that age, female sex, headache intensity, pressure-like quality, the presence of photophobia/phonophobia, and worsening with physical activity were associated with headache of longer duration. But in the multivariate analysis, only headache intensity during the acute phase remained statistically significant (hazard ratio, 0.655; 95% confidence interval, 0.582-0.737; P < .001).

When asked whether they planned to continue the study, Dr. García Azorín commented, “The main questions that have arisen from this study have been, above all: ‘Why does this headache happen?’ and ‘How can it be treated or avoided?’ To answer them, we’re looking into pain: which factors could predispose a person to it and which changes may be associated with its presence.”

In addition, different treatments that may improve patient outcomes are being evaluated, because to date, treatment has been empirical and based on the predominant pain phenotype.

In any case, most doctors currently treat post–COVID-19 headache on the basis of how similar the symptoms are to those of other primary headaches. “Given the impact that headache has on patients’ quality of life, there’s a pressing need for controlled studies on possible treatments and their effectiveness,” noted Patricia Pozo Rosich, MD, PhD, one of the coauthors of the study.

“We at the Spanish Society of Neurology truly believe that if these patients were to have this symptom correctly addressed from the start, they could avoid many of the problems that arise in the situation becoming chronic,” she concluded.

Dr. García Azorín and Dr. Rodríguez Vico disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Approximately one in five patients who presented with headache during the acute phase of COVID-19 developed chronic daily headache, according to a study published in Cephalalgia. The greater the headache’s intensity during the acute phase, the greater the likelihood that it would persist.

The research, carried out by members of the Headache Study Group of the Spanish Society of Neurology, evaluated the evolution of headache in more than 900 Spanish patients. Because they found that headache intensity during the acute phase was associated with a more prolonged duration of headache, the team stressed the importance of promptly evaluating patients who have had COVID-19 and who then experience persistent headache.
 

Long-term evolution unknown

Headache is a common symptom of COVID-19, but its long-term evolution remains unknown. The objective of this study was to evaluate the long-term duration of headache in patients who presented with this symptom during the acute phase of the disease.

Recruitment for this multicenter study took place in March and April 2020. The 905 patients who were enrolled came from six level 3 hospitals in Spain. All completed 9 months of neurologic follow-up.

Their median age was 51 years, 66.5% were women, and more than half (52.7%) had a history of primary headache. About half of the patients required hospitalization (50.5%); the rest were treated as outpatients. The most common headache phenotype was holocranial (67.8%) of severe intensity (50.6%).
 

Persistent headache common

In the 96.6% cases for which data were available, the median duration of headache was 14 days. The headache persisted at 1 month in 31.1% of patients, at 2 months in 21.5%, at 3 months in 19%, at 6 months in 16.8%, and at 9 months in 16.0%.

“The median duration of COVID-19 headache is around 2 weeks,” David García Azorín, MD, PhD, a member of the Spanish Society of Neurology and one of the coauthors of the study, said in an interview. “However, almost 20% of patients experience it for longer than that. When still present at 2 months, the headache is more likely to follow a chronic daily pattern.” Dr. García Azorín is a neurologist and clinical researcher at the headache unit of the Hospital Clínico Universitario in Valladolid, Spain.

“So, if the headache isn’t letting up, it’s important to make the most of that window of opportunity and provide treatment in that period of 6-12 weeks,” he continued. “To do this, the best option is to carry out preventive treatment so that the patient will have a better chance of recovering.”

Study participants whose headache persisted at 9 months were older and were mostly women. They were less likely to have had pneumonia or to have experienced stabbing pain, photophobia, or phonophobia. They reported that the headache got worse when they engaged in physical activity but less frequently manifested as a throbbing headache.
 

Secondary tension headaches

On the other hand, Jaime Rodríguez Vico, MD, head of the headache unit at the Jiménez Díaz Foundation Hospital in Madrid, said in an interview that, according to his case studies, the most striking characteristics of post–COVID-19 headaches “in general are secondary, with similarities to tension headaches that patients are able to differentiate from other clinical types of headache. In patients with migraine, very often we see that we’re dealing with a trigger. In other words, more migraines – and more intense ones at that – are brought about.”

He added: “Generally, post–COVID-19 headache usually lasts 1-2 weeks, but we have cases of it lasting several months and even over a year with persistent daily headache. These more persistent cases are probably connected to another type of pathology that makes them more susceptible to becoming chronic, something that occurs in another type of primary headache known as new daily persistent headache.”
 

Primary headache exacerbation

Dr. García Azorín pointed out that it’s not uncommon that among people who already have primary headache, their condition worsens after they become infected with SARS-CoV-2. However, many people differentiate the headache associated with the infection from their usual headache because after becoming infected, their headache is predominantly frontal, oppressive, and chronic.

“Having a prior history of headache is one of the factors that can increase the likelihood that a headache experienced while suffering from COVID-19 will become chronic,” he noted.

This study also found that, more often than not, patients with persistent headache at 9 months had migraine-like pain.

As for headaches in these patients beyond 9 months, “based on our research, the evolution is quite variable,” said Dr. Rodríguez Vico. “Our unit’s numbers are skewed due to the high number of migraine cases that we follow, and therefore our high volume of migraine patients who’ve gotten worse. The same thing happens with COVID-19 vaccines. Migraine is a polygenic disorder with multiple variants and a pathophysiology that we are just beginning to describe. This is why one patient is completely different from another. It’s a real challenge.”

Infections are a common cause of acute and chronic headache. The persistence of a headache after an infection may be caused by the infection becoming chronic, as happens in some types of chronic meningitis, such as tuberculous meningitis. It may also be caused by the persistence of a certain response and activation of the immune system or to the uncovering or worsening of a primary headache coincident with the infection, added Dr. García Azorín.

“Likewise, there are other people who have a biological predisposition to headache as a multifactorial disorder and polygenic disorder, such that a particular stimulus – from trauma or an infection to alcohol consumption – can cause them to develop a headache very similar to a migraine,” he said.
 

Providing prognosis and treatment

Certain factors can give an idea of how long the headache might last. The study’s univariate analysis showed that age, female sex, headache intensity, pressure-like quality, the presence of photophobia/phonophobia, and worsening with physical activity were associated with headache of longer duration. But in the multivariate analysis, only headache intensity during the acute phase remained statistically significant (hazard ratio, 0.655; 95% confidence interval, 0.582-0.737; P < .001).

When asked whether they planned to continue the study, Dr. García Azorín commented, “The main questions that have arisen from this study have been, above all: ‘Why does this headache happen?’ and ‘How can it be treated or avoided?’ To answer them, we’re looking into pain: which factors could predispose a person to it and which changes may be associated with its presence.”

In addition, different treatments that may improve patient outcomes are being evaluated, because to date, treatment has been empirical and based on the predominant pain phenotype.

In any case, most doctors currently treat post–COVID-19 headache on the basis of how similar the symptoms are to those of other primary headaches. “Given the impact that headache has on patients’ quality of life, there’s a pressing need for controlled studies on possible treatments and their effectiveness,” noted Patricia Pozo Rosich, MD, PhD, one of the coauthors of the study.

“We at the Spanish Society of Neurology truly believe that if these patients were to have this symptom correctly addressed from the start, they could avoid many of the problems that arise in the situation becoming chronic,” she concluded.

Dr. García Azorín and Dr. Rodríguez Vico disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Pregnant women with a history of migraine are at elevated risk for gestational hypertension and preeclampsia, and of delivering their baby preterm, new research suggests. In a large prospective study, researchers also found a link between migraine with aura and increased preeclampsia risk.

Overall, the findings suggest women with a history of migraine may benefit from enhanced monitoring during pregnancy, said coinvestigator Alexandra Purdue-Smithe, PhD, associate epidemiologist at Brigham and Women’s Hospital and instructor of medicine at Harvard Medical School, Boston. “Our results suggest that migraine history may be an important consideration in  obstetric risk assessment,” Dr. Purdue-Smithe added.

The findings will be presented at the 2022 annual meeting of the American Academy of Neurology.
 

Common neurovascular disorder

Migraine is a common neurovascular disorder, affecting about 15% of adults. The condition carries “a pretty remarkable sex bias” as it affects up to three times more women than men, and about a quarter of women in the reproductive age bracket of 18-44 years, Dr. Purdue-Smithe noted.

Despite this, relatively little is known about migraine and pregnancy risks, she said.

What is known is that women with migraine have a higher burden of cardiovascular risk factors such as obesity and chronic hypertension, and these factors can also increase risk for pregnancy complications, she added.

In the study, researchers analyzed data on 30,555 pregnancies in about 19,000 women without a history of cardiovascular disease, type 2 diabetes, or cancer during a 20-year period ending in 2009.

The data came from the Nurses’ Health Study II, a large prospective cohort study established in 1989 when it enrolled women aged 25-42 years. Participants in the ongoing study complete questionnaires every 2 years, reporting information on various health conditions as well as pregnancy and reproductive events.

The investigators estimated associations of physician-diagnosed prepregnancy migraine with preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, and low birth weight (<2,500 grams [5.5 lb]).

About 11% of the women in the study had migraine diagnosed by a physician before pregnancy.

Researchers adjusted for age at pregnancy, race/ethnicity, age at menarche, and prepregnancy chronic hypertension, body mass index, physical activity, smoking status, alcohol intake, history of infertility, parity, oral contraceptive use, and analgesic use.
 

‘A bit surprising’

Results showed that compared with women without a history of migraine, those with such a history had higher risk for preterm delivery (relative risk [RR], 1.17; 95% confidence interval [CI], 1.05-1.30), gestational hypertension (RR, 1.28; 95% CI, 1.11-1.48), and preeclampsia (RR, 1.40; 95% CI, 1.19-1.65).

Prepregnancy migraine was not associated with low birth weight (RR, 0.99; 95% CI, 0.85-1.16) or gestational diabetes (RR, 1.05; 95% CI, .91-1.22).

It was a “bit surprising” that women with migraine had a higher risk for preterm delivery but their babies were not necessarily underweight – although some prior literature had similar findings, said Dr. Purdue-Smithe.

She noted that in her study the association was limited to moderate preterm delivery (gestational age, 32-37 weeks) and not with very preterm births (before 32 weeks).

Researchers also assessed adverse pregnancy outcomes by aura phenotype. “Women with migraine with aura have a higher risk of cardiovascular disease later in life, so we hypothesized that aura might be more strongly associated with adverse pregnancy outcomes with underlying vascular pathology,” Dr. Purdue-Smithe said.

Women with and without aura had elevated risks for preterm delivery and gestational hypertension. Those with aura had a slightly higher risk for preeclampsia (RR, 1.51; 95% CI, 1.22-1.88) than those without aura (RR, 1.29; 95% CI, 1.04-1.61).

As the association between migraine and adverse pregnancy outcomes persisted after adjustment for established cardiovascular and obstetric risk factors, “this suggests there may be subclinical factors that are contributing to elevated risks of these outcomes in women with migraine,” said Dr. Purdue-Smithe.

Such factors could include platelet activation, chronic inflammation, and endothelial dysfunction, she added.

While findings of some previous case-control and retrospective studies suggested a possible link between migraine and adverse pregnancy outcomes, until now few large prospective studies have examined the association.

“Strengths of our study include its prospective design, very large sample size, and more complete adjustment for potential prepregnancy confounders,” Dr. Purdue-Smithe said.
 

Independent risk factor?

In the past, it has been somewhat unclear whether migraine is an independent risk factor for these complications or whether women with migraine just have greater risk factors for adverse pregnancy outcomes.

“Our preliminary findings suggest that migraine is independently associated with these adverse pregnancy outcomes, or at least that’s what it seems,” said Dr. Purdue-Smithe.

The new results could be used by clinicians to “flag” women who may be at risk for complications, she added. “These women may benefit from closer monitoring in pregnancy so that if issues arise, physicians can act quickly.”

She noted that preeclampsia “can come on suddenly and escalate rapidly,” and there are few interventions to treat it besides delivery.

However, low-dose aspirin may be worth investigating. Various health care groups and the U.S. Preventive Services Task Force recommend pregnant women at high risk for preeclampsia take low-dose aspirin (81 mg/d) after 12 weeks’ gestation.

“It would be interesting to see if women with migraine who take aspirin in pregnancy can reduce their risk of preeclampsia, and future research should address this question,” said Dr. Purdue-Smithe.

Additional testing showed that associations with preeclampsia and gestational hypertension did not vary according to age and other obstetrical risks.

The Nurses’ Health Study II did not have information on number and severity of migraine attacks, so the researchers were unable to determine if these factors affect pregnancy outcomes.

“Understanding whether specific migraine features, such as attack frequency, are associated with adverse pregnancy outcomes will be an important area for future research,” said Dr. Purdue-Smithe. She noted prior studies showed the frequency of migraine attacks is related to ischemic stroke and other cardiovascular outcomes.

The authors acknowledged a limitation for the current study: Although migraine history was reported prior to pregnancy, information on migraine aura was collected after most of the pregnancies in the cohort were over. So the findings for migraine aura may have been influenced by participants’ ability to accurately remember their experiences.
 

Collaboration is key

Commenting on the research, Nina Riggins, MD, PhD, director of the Headache and Traumatic Brain Injury Center in the department of neurosciences at the University of California, San Diego, said the study “stands out” because it distinguishes pregnancy complications between those with and without aura among women with migraine. 

Dr. Riggins noted the investigators found the risk of preeclampsia, which on average occurs in about 3%-5% of pregnancies, is higher among women with migraine with aura.  

“The good news is that treatments are available,” she said. “Preconception planning should include this discussion for patients living with migraine.”

However, the study did not compare risks for patients who have frequent migraine attacks versus episodic migraine, Dr. Riggins noted. “We need to learn more about whether any treatments can be safe and effective to decrease risks of complications during pregnancy in this population,” she said.

“I believe, ultimately, what this study reveals is that collaboration among primary care, ob.gyn., maternal-fetal medicine specialists, and neurologists will likely benefit pregnant patients with migraine,” Dr. Riggins said.

The study received funding from the National Institutes of Health. Dr. Purdue-Smithe has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Pregnant women with a history of migraine are at elevated risk for gestational hypertension and preeclampsia, and of delivering their baby preterm, new research suggests. In a large prospective study, researchers also found a link between migraine with aura and increased preeclampsia risk.

Overall, the findings suggest women with a history of migraine may benefit from enhanced monitoring during pregnancy, said coinvestigator Alexandra Purdue-Smithe, PhD, associate epidemiologist at Brigham and Women’s Hospital and instructor of medicine at Harvard Medical School, Boston. “Our results suggest that migraine history may be an important consideration in  obstetric risk assessment,” Dr. Purdue-Smithe added.

The findings will be presented at the 2022 annual meeting of the American Academy of Neurology.
 

Common neurovascular disorder

Migraine is a common neurovascular disorder, affecting about 15% of adults. The condition carries “a pretty remarkable sex bias” as it affects up to three times more women than men, and about a quarter of women in the reproductive age bracket of 18-44 years, Dr. Purdue-Smithe noted.

Despite this, relatively little is known about migraine and pregnancy risks, she said.

What is known is that women with migraine have a higher burden of cardiovascular risk factors such as obesity and chronic hypertension, and these factors can also increase risk for pregnancy complications, she added.

In the study, researchers analyzed data on 30,555 pregnancies in about 19,000 women without a history of cardiovascular disease, type 2 diabetes, or cancer during a 20-year period ending in 2009.

The data came from the Nurses’ Health Study II, a large prospective cohort study established in 1989 when it enrolled women aged 25-42 years. Participants in the ongoing study complete questionnaires every 2 years, reporting information on various health conditions as well as pregnancy and reproductive events.

The investigators estimated associations of physician-diagnosed prepregnancy migraine with preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, and low birth weight (<2,500 grams [5.5 lb]).

About 11% of the women in the study had migraine diagnosed by a physician before pregnancy.

Researchers adjusted for age at pregnancy, race/ethnicity, age at menarche, and prepregnancy chronic hypertension, body mass index, physical activity, smoking status, alcohol intake, history of infertility, parity, oral contraceptive use, and analgesic use.
 

‘A bit surprising’

Results showed that compared with women without a history of migraine, those with such a history had higher risk for preterm delivery (relative risk [RR], 1.17; 95% confidence interval [CI], 1.05-1.30), gestational hypertension (RR, 1.28; 95% CI, 1.11-1.48), and preeclampsia (RR, 1.40; 95% CI, 1.19-1.65).

Prepregnancy migraine was not associated with low birth weight (RR, 0.99; 95% CI, 0.85-1.16) or gestational diabetes (RR, 1.05; 95% CI, .91-1.22).

It was a “bit surprising” that women with migraine had a higher risk for preterm delivery but their babies were not necessarily underweight – although some prior literature had similar findings, said Dr. Purdue-Smithe.

She noted that in her study the association was limited to moderate preterm delivery (gestational age, 32-37 weeks) and not with very preterm births (before 32 weeks).

Researchers also assessed adverse pregnancy outcomes by aura phenotype. “Women with migraine with aura have a higher risk of cardiovascular disease later in life, so we hypothesized that aura might be more strongly associated with adverse pregnancy outcomes with underlying vascular pathology,” Dr. Purdue-Smithe said.

Women with and without aura had elevated risks for preterm delivery and gestational hypertension. Those with aura had a slightly higher risk for preeclampsia (RR, 1.51; 95% CI, 1.22-1.88) than those without aura (RR, 1.29; 95% CI, 1.04-1.61).

As the association between migraine and adverse pregnancy outcomes persisted after adjustment for established cardiovascular and obstetric risk factors, “this suggests there may be subclinical factors that are contributing to elevated risks of these outcomes in women with migraine,” said Dr. Purdue-Smithe.

Such factors could include platelet activation, chronic inflammation, and endothelial dysfunction, she added.

While findings of some previous case-control and retrospective studies suggested a possible link between migraine and adverse pregnancy outcomes, until now few large prospective studies have examined the association.

“Strengths of our study include its prospective design, very large sample size, and more complete adjustment for potential prepregnancy confounders,” Dr. Purdue-Smithe said.
 

Independent risk factor?

In the past, it has been somewhat unclear whether migraine is an independent risk factor for these complications or whether women with migraine just have greater risk factors for adverse pregnancy outcomes.

“Our preliminary findings suggest that migraine is independently associated with these adverse pregnancy outcomes, or at least that’s what it seems,” said Dr. Purdue-Smithe.

The new results could be used by clinicians to “flag” women who may be at risk for complications, she added. “These women may benefit from closer monitoring in pregnancy so that if issues arise, physicians can act quickly.”

She noted that preeclampsia “can come on suddenly and escalate rapidly,” and there are few interventions to treat it besides delivery.

However, low-dose aspirin may be worth investigating. Various health care groups and the U.S. Preventive Services Task Force recommend pregnant women at high risk for preeclampsia take low-dose aspirin (81 mg/d) after 12 weeks’ gestation.

“It would be interesting to see if women with migraine who take aspirin in pregnancy can reduce their risk of preeclampsia, and future research should address this question,” said Dr. Purdue-Smithe.

Additional testing showed that associations with preeclampsia and gestational hypertension did not vary according to age and other obstetrical risks.

The Nurses’ Health Study II did not have information on number and severity of migraine attacks, so the researchers were unable to determine if these factors affect pregnancy outcomes.

“Understanding whether specific migraine features, such as attack frequency, are associated with adverse pregnancy outcomes will be an important area for future research,” said Dr. Purdue-Smithe. She noted prior studies showed the frequency of migraine attacks is related to ischemic stroke and other cardiovascular outcomes.

The authors acknowledged a limitation for the current study: Although migraine history was reported prior to pregnancy, information on migraine aura was collected after most of the pregnancies in the cohort were over. So the findings for migraine aura may have been influenced by participants’ ability to accurately remember their experiences.
 

Collaboration is key

Commenting on the research, Nina Riggins, MD, PhD, director of the Headache and Traumatic Brain Injury Center in the department of neurosciences at the University of California, San Diego, said the study “stands out” because it distinguishes pregnancy complications between those with and without aura among women with migraine. 

Dr. Riggins noted the investigators found the risk of preeclampsia, which on average occurs in about 3%-5% of pregnancies, is higher among women with migraine with aura.  

“The good news is that treatments are available,” she said. “Preconception planning should include this discussion for patients living with migraine.”

However, the study did not compare risks for patients who have frequent migraine attacks versus episodic migraine, Dr. Riggins noted. “We need to learn more about whether any treatments can be safe and effective to decrease risks of complications during pregnancy in this population,” she said.

“I believe, ultimately, what this study reveals is that collaboration among primary care, ob.gyn., maternal-fetal medicine specialists, and neurologists will likely benefit pregnant patients with migraine,” Dr. Riggins said.

The study received funding from the National Institutes of Health. Dr. Purdue-Smithe has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Pregnant women with a history of migraine are at elevated risk for gestational hypertension and preeclampsia, and of delivering their baby preterm, new research suggests. In a large prospective study, researchers also found a link between migraine with aura and increased preeclampsia risk.

Overall, the findings suggest women with a history of migraine may benefit from enhanced monitoring during pregnancy, said coinvestigator Alexandra Purdue-Smithe, PhD, associate epidemiologist at Brigham and Women’s Hospital and instructor of medicine at Harvard Medical School, Boston. “Our results suggest that migraine history may be an important consideration in  obstetric risk assessment,” Dr. Purdue-Smithe added.

The findings will be presented at the 2022 annual meeting of the American Academy of Neurology.
 

Common neurovascular disorder

Migraine is a common neurovascular disorder, affecting about 15% of adults. The condition carries “a pretty remarkable sex bias” as it affects up to three times more women than men, and about a quarter of women in the reproductive age bracket of 18-44 years, Dr. Purdue-Smithe noted.

Despite this, relatively little is known about migraine and pregnancy risks, she said.

What is known is that women with migraine have a higher burden of cardiovascular risk factors such as obesity and chronic hypertension, and these factors can also increase risk for pregnancy complications, she added.

In the study, researchers analyzed data on 30,555 pregnancies in about 19,000 women without a history of cardiovascular disease, type 2 diabetes, or cancer during a 20-year period ending in 2009.

The data came from the Nurses’ Health Study II, a large prospective cohort study established in 1989 when it enrolled women aged 25-42 years. Participants in the ongoing study complete questionnaires every 2 years, reporting information on various health conditions as well as pregnancy and reproductive events.

The investigators estimated associations of physician-diagnosed prepregnancy migraine with preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, and low birth weight (<2,500 grams [5.5 lb]).

About 11% of the women in the study had migraine diagnosed by a physician before pregnancy.

Researchers adjusted for age at pregnancy, race/ethnicity, age at menarche, and prepregnancy chronic hypertension, body mass index, physical activity, smoking status, alcohol intake, history of infertility, parity, oral contraceptive use, and analgesic use.
 

‘A bit surprising’

Results showed that compared with women without a history of migraine, those with such a history had higher risk for preterm delivery (relative risk [RR], 1.17; 95% confidence interval [CI], 1.05-1.30), gestational hypertension (RR, 1.28; 95% CI, 1.11-1.48), and preeclampsia (RR, 1.40; 95% CI, 1.19-1.65).

Prepregnancy migraine was not associated with low birth weight (RR, 0.99; 95% CI, 0.85-1.16) or gestational diabetes (RR, 1.05; 95% CI, .91-1.22).

It was a “bit surprising” that women with migraine had a higher risk for preterm delivery but their babies were not necessarily underweight – although some prior literature had similar findings, said Dr. Purdue-Smithe.

She noted that in her study the association was limited to moderate preterm delivery (gestational age, 32-37 weeks) and not with very preterm births (before 32 weeks).

Researchers also assessed adverse pregnancy outcomes by aura phenotype. “Women with migraine with aura have a higher risk of cardiovascular disease later in life, so we hypothesized that aura might be more strongly associated with adverse pregnancy outcomes with underlying vascular pathology,” Dr. Purdue-Smithe said.

Women with and without aura had elevated risks for preterm delivery and gestational hypertension. Those with aura had a slightly higher risk for preeclampsia (RR, 1.51; 95% CI, 1.22-1.88) than those without aura (RR, 1.29; 95% CI, 1.04-1.61).

As the association between migraine and adverse pregnancy outcomes persisted after adjustment for established cardiovascular and obstetric risk factors, “this suggests there may be subclinical factors that are contributing to elevated risks of these outcomes in women with migraine,” said Dr. Purdue-Smithe.

Such factors could include platelet activation, chronic inflammation, and endothelial dysfunction, she added.

While findings of some previous case-control and retrospective studies suggested a possible link between migraine and adverse pregnancy outcomes, until now few large prospective studies have examined the association.

“Strengths of our study include its prospective design, very large sample size, and more complete adjustment for potential prepregnancy confounders,” Dr. Purdue-Smithe said.
 

Independent risk factor?

In the past, it has been somewhat unclear whether migraine is an independent risk factor for these complications or whether women with migraine just have greater risk factors for adverse pregnancy outcomes.

“Our preliminary findings suggest that migraine is independently associated with these adverse pregnancy outcomes, or at least that’s what it seems,” said Dr. Purdue-Smithe.

The new results could be used by clinicians to “flag” women who may be at risk for complications, she added. “These women may benefit from closer monitoring in pregnancy so that if issues arise, physicians can act quickly.”

She noted that preeclampsia “can come on suddenly and escalate rapidly,” and there are few interventions to treat it besides delivery.

However, low-dose aspirin may be worth investigating. Various health care groups and the U.S. Preventive Services Task Force recommend pregnant women at high risk for preeclampsia take low-dose aspirin (81 mg/d) after 12 weeks’ gestation.

“It would be interesting to see if women with migraine who take aspirin in pregnancy can reduce their risk of preeclampsia, and future research should address this question,” said Dr. Purdue-Smithe.

Additional testing showed that associations with preeclampsia and gestational hypertension did not vary according to age and other obstetrical risks.

The Nurses’ Health Study II did not have information on number and severity of migraine attacks, so the researchers were unable to determine if these factors affect pregnancy outcomes.

“Understanding whether specific migraine features, such as attack frequency, are associated with adverse pregnancy outcomes will be an important area for future research,” said Dr. Purdue-Smithe. She noted prior studies showed the frequency of migraine attacks is related to ischemic stroke and other cardiovascular outcomes.

The authors acknowledged a limitation for the current study: Although migraine history was reported prior to pregnancy, information on migraine aura was collected after most of the pregnancies in the cohort were over. So the findings for migraine aura may have been influenced by participants’ ability to accurately remember their experiences.
 

Collaboration is key

Commenting on the research, Nina Riggins, MD, PhD, director of the Headache and Traumatic Brain Injury Center in the department of neurosciences at the University of California, San Diego, said the study “stands out” because it distinguishes pregnancy complications between those with and without aura among women with migraine. 

Dr. Riggins noted the investigators found the risk of preeclampsia, which on average occurs in about 3%-5% of pregnancies, is higher among women with migraine with aura.  

“The good news is that treatments are available,” she said. “Preconception planning should include this discussion for patients living with migraine.”

However, the study did not compare risks for patients who have frequent migraine attacks versus episodic migraine, Dr. Riggins noted. “We need to learn more about whether any treatments can be safe and effective to decrease risks of complications during pregnancy in this population,” she said.

“I believe, ultimately, what this study reveals is that collaboration among primary care, ob.gyn., maternal-fetal medicine specialists, and neurologists will likely benefit pregnant patients with migraine,” Dr. Riggins said.

The study received funding from the National Institutes of Health. Dr. Purdue-Smithe has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

The endocannabinoid system is a promising therapeutic target for the treatment of migraine, according to Italian researchers at the University of Pavia, and the C. Mondino National Institute of Neurology Foundation. “The complexity of the endocannabinoid system calls for accurate biochemical and pharmacological characterization of any new compounds undergoing testing and development,” noted Rosaria Greco, PhD. She and her colleagues authored a review on the topic that was published online Feb. 18, 2022, in Headache.

Although cannabis has been investigated for both the treatment and prevention of migraine, evidence for its benefit is weak because of lack of controlled studies, they explained. Archival data from a large database “showed greater improvements in men than in women and suggested that concentrated preparations were more effective than flower consumption.” In addition, a small single-center study linked nabilone, a synthetic cannabinoid, to reductions in pain duration, intensity, and daily intake of analgesics among patients with medication overuse headache. Finally, a pilot study reported a reduction in pain intensity among patients with chronic migraine treated with a combination of tested a combination of delta-9-tetrahydrocannabinol and cannabidiol. “Methodologically sound studies are now needed to investigate the possible effects of cannabis in migraine treatment and to define strains, formulations, and dosage,” they noted.
 

Not just cannabis

In addition to exogenous cannabis, there are now preclinical studies suggesting other compounds that interact with the endocannabinoid system “are also able to modulate the pathways involved in migraine-related pain,” the study authors wrote. “But the road ahead is still long. Multiple molecules linked to the endocannabinoid system have emerged as potential therapeutic targets.

The complexity of the system demands caution and precise biochemical and pharmacological characterization of the new compounds to be tested and developed.”

Among these compounds are endogenous ligands such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol that specifically target CB1 and CB2 receptors. Additionally, there are endocannabinoid-based drugs that also target the CB1/CB2 receptors, as well as other substances, such as lipids (palmitoylethanolamide [PEA]) and enzymes, that do not bind to the CB1/CB2 receptors but are responsible for endocannabinoid biosynthesis.

There is some evidence that the endocannabinoid system may be dysfunctional in patients with migraine, and the authors noted their work has shown that PEA plasma levels are increased during experimentally triggered migraine-like attacks. Thus, some preclinical and preliminary evidence suggests that administration of PEA or anandamide may have analgesic and anti-inflammatory effects in migraine.

Another approach is the inhibition of endocannabinoid catabolic enzymes, which could circumvent the adverse effects associated with direct activation of CB receptors. “Endocannabinoid tone enhancement has been proposed as an alternative modality of activation of CB receptors and is possibly devoid of the psychotropic effects reported with CB receptor agonists,” noted the authors, who have shown in animal and preclinical studies that inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase can modulate migraine pain.

Yet another way of indirectly impacting CB receptors is through their allosteric ligands, an approach that “deserves further investigation”, and “might provide interesting leads for clinical development, given that it may have a favorable side-effect profile with limited psychomimetic and depressant effects,” wrote the authors. And finally, inhibition of N-acylethanolamine acid amide hydrolase, the enzyme that preferentially hydrolyzes PEA, might be a promising approach.

“The multiplicity of options and the wealth of data already obtained in animal models underscore the importance of further advancing research in this area,” the authors concluded.
 

Patients are taking cannabinoids; physicians should learn about them

Commenting on the paper, Alan Rapaport, MD, clinical professor of neurology at the University of California, Los Angeles, said “this well-done paper points out the complexity of the endocannabinoid system and the multiple ways of getting it to work for certain patients. It details some of the studies that show beneficial results in migraine, medication overuse headache, chronic migraine, and pain. Patients with headache, other types of pain, anxiety, nausea, sleep issues, and other symptoms are already taking cannabinoids, usually derived from the marijuana plant, that are not well regulated. A few are prescribed drugs which target CB1 and CB2 receptors. Patients often get relief of some of their symptoms, sometimes getting high and many times not.

“The paper makes the point that previous studies are often small, not carefully controlled, or well documented. We do need to start doing larger, properly designed studies and getting them into the literature. Doctors need to learn more about these treatments. The next step will be to get [Food and Drug Administration]–approved treatments, so physicians and nurses will know exactly what we are giving, the beneficial effects to expect in a certain percentage of patients, and the adverse events to warn our patients about. Cannabinoids have been tried by a large percentage of patients with headache and pain. Now we need to standardize the various treatments that are sure to be suggested in the future.”

The study was funded by the Migraine Research Foundation, and the Italian Ministry of Health. The study authors declared no conflicts of interest.

The endocannabinoid system is a promising therapeutic target for the treatment of migraine, according to Italian researchers at the University of Pavia, and the C. Mondino National Institute of Neurology Foundation. “The complexity of the endocannabinoid system calls for accurate biochemical and pharmacological characterization of any new compounds undergoing testing and development,” noted Rosaria Greco, PhD. She and her colleagues authored a review on the topic that was published online Feb. 18, 2022, in Headache.

Although cannabis has been investigated for both the treatment and prevention of migraine, evidence for its benefit is weak because of lack of controlled studies, they explained. Archival data from a large database “showed greater improvements in men than in women and suggested that concentrated preparations were more effective than flower consumption.” In addition, a small single-center study linked nabilone, a synthetic cannabinoid, to reductions in pain duration, intensity, and daily intake of analgesics among patients with medication overuse headache. Finally, a pilot study reported a reduction in pain intensity among patients with chronic migraine treated with a combination of tested a combination of delta-9-tetrahydrocannabinol and cannabidiol. “Methodologically sound studies are now needed to investigate the possible effects of cannabis in migraine treatment and to define strains, formulations, and dosage,” they noted.
 

Not just cannabis

In addition to exogenous cannabis, there are now preclinical studies suggesting other compounds that interact with the endocannabinoid system “are also able to modulate the pathways involved in migraine-related pain,” the study authors wrote. “But the road ahead is still long. Multiple molecules linked to the endocannabinoid system have emerged as potential therapeutic targets.

The complexity of the system demands caution and precise biochemical and pharmacological characterization of the new compounds to be tested and developed.”

Among these compounds are endogenous ligands such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol that specifically target CB1 and CB2 receptors. Additionally, there are endocannabinoid-based drugs that also target the CB1/CB2 receptors, as well as other substances, such as lipids (palmitoylethanolamide [PEA]) and enzymes, that do not bind to the CB1/CB2 receptors but are responsible for endocannabinoid biosynthesis.

There is some evidence that the endocannabinoid system may be dysfunctional in patients with migraine, and the authors noted their work has shown that PEA plasma levels are increased during experimentally triggered migraine-like attacks. Thus, some preclinical and preliminary evidence suggests that administration of PEA or anandamide may have analgesic and anti-inflammatory effects in migraine.

Another approach is the inhibition of endocannabinoid catabolic enzymes, which could circumvent the adverse effects associated with direct activation of CB receptors. “Endocannabinoid tone enhancement has been proposed as an alternative modality of activation of CB receptors and is possibly devoid of the psychotropic effects reported with CB receptor agonists,” noted the authors, who have shown in animal and preclinical studies that inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase can modulate migraine pain.

Yet another way of indirectly impacting CB receptors is through their allosteric ligands, an approach that “deserves further investigation”, and “might provide interesting leads for clinical development, given that it may have a favorable side-effect profile with limited psychomimetic and depressant effects,” wrote the authors. And finally, inhibition of N-acylethanolamine acid amide hydrolase, the enzyme that preferentially hydrolyzes PEA, might be a promising approach.

“The multiplicity of options and the wealth of data already obtained in animal models underscore the importance of further advancing research in this area,” the authors concluded.
 

Patients are taking cannabinoids; physicians should learn about them

Commenting on the paper, Alan Rapaport, MD, clinical professor of neurology at the University of California, Los Angeles, said “this well-done paper points out the complexity of the endocannabinoid system and the multiple ways of getting it to work for certain patients. It details some of the studies that show beneficial results in migraine, medication overuse headache, chronic migraine, and pain. Patients with headache, other types of pain, anxiety, nausea, sleep issues, and other symptoms are already taking cannabinoids, usually derived from the marijuana plant, that are not well regulated. A few are prescribed drugs which target CB1 and CB2 receptors. Patients often get relief of some of their symptoms, sometimes getting high and many times not.

“The paper makes the point that previous studies are often small, not carefully controlled, or well documented. We do need to start doing larger, properly designed studies and getting them into the literature. Doctors need to learn more about these treatments. The next step will be to get [Food and Drug Administration]–approved treatments, so physicians and nurses will know exactly what we are giving, the beneficial effects to expect in a certain percentage of patients, and the adverse events to warn our patients about. Cannabinoids have been tried by a large percentage of patients with headache and pain. Now we need to standardize the various treatments that are sure to be suggested in the future.”

The study was funded by the Migraine Research Foundation, and the Italian Ministry of Health. The study authors declared no conflicts of interest.

The endocannabinoid system is a promising therapeutic target for the treatment of migraine, according to Italian researchers at the University of Pavia, and the C. Mondino National Institute of Neurology Foundation. “The complexity of the endocannabinoid system calls for accurate biochemical and pharmacological characterization of any new compounds undergoing testing and development,” noted Rosaria Greco, PhD. She and her colleagues authored a review on the topic that was published online Feb. 18, 2022, in Headache.

Although cannabis has been investigated for both the treatment and prevention of migraine, evidence for its benefit is weak because of lack of controlled studies, they explained. Archival data from a large database “showed greater improvements in men than in women and suggested that concentrated preparations were more effective than flower consumption.” In addition, a small single-center study linked nabilone, a synthetic cannabinoid, to reductions in pain duration, intensity, and daily intake of analgesics among patients with medication overuse headache. Finally, a pilot study reported a reduction in pain intensity among patients with chronic migraine treated with a combination of tested a combination of delta-9-tetrahydrocannabinol and cannabidiol. “Methodologically sound studies are now needed to investigate the possible effects of cannabis in migraine treatment and to define strains, formulations, and dosage,” they noted.
 

Not just cannabis

In addition to exogenous cannabis, there are now preclinical studies suggesting other compounds that interact with the endocannabinoid system “are also able to modulate the pathways involved in migraine-related pain,” the study authors wrote. “But the road ahead is still long. Multiple molecules linked to the endocannabinoid system have emerged as potential therapeutic targets.

The complexity of the system demands caution and precise biochemical and pharmacological characterization of the new compounds to be tested and developed.”

Among these compounds are endogenous ligands such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol that specifically target CB1 and CB2 receptors. Additionally, there are endocannabinoid-based drugs that also target the CB1/CB2 receptors, as well as other substances, such as lipids (palmitoylethanolamide [PEA]) and enzymes, that do not bind to the CB1/CB2 receptors but are responsible for endocannabinoid biosynthesis.

There is some evidence that the endocannabinoid system may be dysfunctional in patients with migraine, and the authors noted their work has shown that PEA plasma levels are increased during experimentally triggered migraine-like attacks. Thus, some preclinical and preliminary evidence suggests that administration of PEA or anandamide may have analgesic and anti-inflammatory effects in migraine.

Another approach is the inhibition of endocannabinoid catabolic enzymes, which could circumvent the adverse effects associated with direct activation of CB receptors. “Endocannabinoid tone enhancement has been proposed as an alternative modality of activation of CB receptors and is possibly devoid of the psychotropic effects reported with CB receptor agonists,” noted the authors, who have shown in animal and preclinical studies that inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase can modulate migraine pain.

Yet another way of indirectly impacting CB receptors is through their allosteric ligands, an approach that “deserves further investigation”, and “might provide interesting leads for clinical development, given that it may have a favorable side-effect profile with limited psychomimetic and depressant effects,” wrote the authors. And finally, inhibition of N-acylethanolamine acid amide hydrolase, the enzyme that preferentially hydrolyzes PEA, might be a promising approach.

“The multiplicity of options and the wealth of data already obtained in animal models underscore the importance of further advancing research in this area,” the authors concluded.
 

Patients are taking cannabinoids; physicians should learn about them

Commenting on the paper, Alan Rapaport, MD, clinical professor of neurology at the University of California, Los Angeles, said “this well-done paper points out the complexity of the endocannabinoid system and the multiple ways of getting it to work for certain patients. It details some of the studies that show beneficial results in migraine, medication overuse headache, chronic migraine, and pain. Patients with headache, other types of pain, anxiety, nausea, sleep issues, and other symptoms are already taking cannabinoids, usually derived from the marijuana plant, that are not well regulated. A few are prescribed drugs which target CB1 and CB2 receptors. Patients often get relief of some of their symptoms, sometimes getting high and many times not.

“The paper makes the point that previous studies are often small, not carefully controlled, or well documented. We do need to start doing larger, properly designed studies and getting them into the literature. Doctors need to learn more about these treatments. The next step will be to get [Food and Drug Administration]–approved treatments, so physicians and nurses will know exactly what we are giving, the beneficial effects to expect in a certain percentage of patients, and the adverse events to warn our patients about. Cannabinoids have been tried by a large percentage of patients with headache and pain. Now we need to standardize the various treatments that are sure to be suggested in the future.”

The study was funded by the Migraine Research Foundation, and the Italian Ministry of Health. The study authors declared no conflicts of interest.