Alan M. Rapoport

Outcomes of Acute and Preventive Migraine Therapy Based on Patient Sex

I previously have addressed myths about migraine as they pertain to men and women. When I found an interesting study recently published in Cephalalgia investigating the effectiveness of calcitonin gene-related peptide receptor (CGRP-R) antagonists (gepants) for acute care and prevention of episodic migraine and CGRP monoclonal antibodies for preventive treatment of episodic and chronic migraine in men and women, I thought I would discuss it here.

The study’s aim was to discern if patient sex contributed to outcomes in each specific treatment arm. Female sex hormones have been recognized as factors in promoting migraine, and women show increased severity, persistence, and comorbidity in migraine profiles, and increased prevalence of migraine relative to men.

Gepants used for acute therapy (ubrogepant, rimegepant, zavegepant) and preventive therapy (atogepant, rimegepant) were studied in this trial. Erenumab, fremanezumab, galcanezumab, and eptinezumab are monoclonal antibodies that either sit on the CGRP receptor (erenumab) or inactivate the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab) and are used for migraine prevention. CGRP-based therapies are not effective in all patients and understanding which patient groups respond preferentially could reduce trial and error in treatment selection. The effectiveness of treatments targeting CGRP or the CGRP receptor may not be uniform in men and women, highlighting the need for further research and understanding of CGRP neurobiology in both sexes.

Key findings:

• In the trial by Porreca et al: In women, the 3 gepants approved by the FDA for the acute care of migraine (ubrogepant, rimegepant, zavegepant) produced a statistically significant drug effect for the 2-hour pain freedom (2h-PF) endpoint, with an average drug effect of 9.5% (CI: 7.4 to 11.6) and an average number needed to treat (NNT) of 11.
• Men did not show statistically significant effects with the acute use of gepants. The average drug effect was 2.8%, and the average NNT was 36.
• For both men and women, CGRP-targeting therapies for prevention of migraine (the 4 monoclonal antibodies) were equally effective; however, possible sex differences remain uncertain and need further study.
• In patients with chronic migraine, CGRP/CGRP-R antibodies were similarly effective in both men and women.
• For the 2-hour freedom from most bothersome symptom (2h-MBS) endpoint when gepants were given acutely, the effects were much better in women than men, with an average drug effect of 10.2% and an average NNT of 10.
• In men, these medications produced observed treatment effects on 2h-MBS with an average drug effect of 3.2% and an average NNT of 32.
• In men, 5 out of 12 estimates favored placebo over the active treatment, suggesting a treatment with little to no effect.
• The pooled treatment effects for women were 3 times as large, at 9.2% and 10.2%, respectively.
• The placebo response rates for 2 of the 3 ubrogepant studies and one of 2 zavegepant studies were higher in men than in women.

The study concludes that, while small molecule CGRP-R antagonists are dramatically effective for acute therapy of migraine in women, available data do not demonstrate effectiveness in men. The treatment effect was found to always favor active treatment numerically for both men and women for prevention of episodic and chronic migraine. The data highlight possible differential effects of CGRP-targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women. The study also emphasizes the need to understand which patient groups preferentially respond to CGRP-based therapies to reduce trial and error in treatment. Note that rimegepant data on prevention were not available for analysis at the time of the writing.

It would be interesting to perform a meta-analysis of multiple well-done, large, real-world studies to see if the same differences and similarities are found in men versus women for acute care of migraine and prevention of episodic and chronic migraine. I suspect that we would find that acute care results favor women but that some men do well.

The Effectiveness of Prednisolone for Treating Medication Overuse Headache

I often discuss medication overuse headache (MOH), as it is difficult to diagnose and treat, so I wanted to comment on another pertinent study. It is a post hoc analysis of the Registry for Load and Management of Medication Overuse Headache (RELEASE). The RELEASE trial is an ongoing, multicenter, observational, cohort study of MOH that has been conducted in Korea since April 2020. Findings were recently published in Headache by Lee et al.

MOH is a secondary headache disorder that develops in patients with a preexisting primary headache when they overuse acute care headache medications of any type except gepants. This includes prescription medications such as triptans, ergots, butalbital-containing medications; opioids; aspirin; acetaminophen; any type of combination medication often containing caffeine; or a combination of medications. This condition significantly impacts patients’ quality of life and productivity, usually increasing the frequency of headaches per month and leading to higher healthcare-related costs.

Treating MOH is challenging due to the lack of high-quality drug trials specifically designed for MOH and doctor inexperience. Current evidence is based largely on subgroup analyses of drug trials for the treatment of chronic migraine that contain these patient types.

Withdrawal of acute care headache medications that are being overused has traditionally been considered an important aspect of MOH treatment, although this may be changing. Withdrawal symptoms, such as increased intensity of headache pain, frequency of headaches, and other symptoms like agitation and sleep disturbance, can prevent patients from discontinuing overused medications. Systemic corticosteroids are widely used to reduce these withdrawal headaches, but clinical trials are sparse and have failed to meet proper endpoints. Despite this, corticosteroids have shown potential benefits, such as decreasing withdrawal headaches, reducing the use of rescue medications, and lowering headache intensity at certain time points after treatment.

Given these findings, this published study hypothesized that prednisolone may play a role in converting MOH to non-MOH at 3 months after treatment. The objective was to evaluate the outcome of prednisolone therapy in reversing medication overuse at 3 months posttreatment in patients with MOH using prospective multicenter registry data. Prednisolone was prescribed to 59 out of 309 patients (19.1%) enrolled during this observational study period, with doses ranging from 10 to 40 mg/day for 5-14 days. Of these patients, 228 (73.8%) completed the 3-month follow-up period.

Key findings:

• The MOH reversal rates at 3 months postbaseline were 76% (31/41) in the prednisolone group and 57.8% (108/187) in the no prednisolone group (p = 0.034).
• The steroid effect remained significant (adjusted odds ratio, 2.78; 95% confidence interval 1.27-6.1, p = 0.010) after adjusting for the number of monthly headache days at baseline, mode of discontinuation of overused medication, use of early preventive medications, and the number of combined preventive medications.

The study had several strengths, including the multicenter collection of data, prospective follow-ups, and comprehensiveness of data acquisition. However, it also had significant limitations, such as the noninterventional, observational nature of the study, potential bias in steroid prescription (every doctor prescribed what they wanted), and heterogeneity in the patient population. Also, there were a variety of treatments, and they were not standardized. Further external validation may be necessary before generalizing the study results.

Despite these limitations, the results do suggest that prednisolone may be one part of a valid treatment option for patients with MOH. I suspect, if the proper studies are done, we will see that using a good preventive medication, with few adverse events, and with careful education of the patient, formal detoxification will not be necessary when treating many patients with MOH. This has been my experience with MOH treatment utilizing the newer anti-CGRP preventive medications, including the older monoclonal antibodies and the newer gepants.

Outcomes of Acute and Preventive Migraine Therapy Based on Patient Sex

I previously have addressed myths about migraine as they pertain to men and women. When I found an interesting study recently published in Cephalalgia investigating the effectiveness of calcitonin gene-related peptide receptor (CGRP-R) antagonists (gepants) for acute care and prevention of episodic migraine and CGRP monoclonal antibodies for preventive treatment of episodic and chronic migraine in men and women, I thought I would discuss it here.

The study’s aim was to discern if patient sex contributed to outcomes in each specific treatment arm. Female sex hormones have been recognized as factors in promoting migraine, and women show increased severity, persistence, and comorbidity in migraine profiles, and increased prevalence of migraine relative to men.

Gepants used for acute therapy (ubrogepant, rimegepant, zavegepant) and preventive therapy (atogepant, rimegepant) were studied in this trial. Erenumab, fremanezumab, galcanezumab, and eptinezumab are monoclonal antibodies that either sit on the CGRP receptor (erenumab) or inactivate the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab) and are used for migraine prevention. CGRP-based therapies are not effective in all patients and understanding which patient groups respond preferentially could reduce trial and error in treatment selection. The effectiveness of treatments targeting CGRP or the CGRP receptor may not be uniform in men and women, highlighting the need for further research and understanding of CGRP neurobiology in both sexes.

Key findings:

• In the trial by Porreca et al: In women, the 3 gepants approved by the FDA for the acute care of migraine (ubrogepant, rimegepant, zavegepant) produced a statistically significant drug effect for the 2-hour pain freedom (2h-PF) endpoint, with an average drug effect of 9.5% (CI: 7.4 to 11.6) and an average number needed to treat (NNT) of 11.
• Men did not show statistically significant effects with the acute use of gepants. The average drug effect was 2.8%, and the average NNT was 36.
• For both men and women, CGRP-targeting therapies for prevention of migraine (the 4 monoclonal antibodies) were equally effective; however, possible sex differences remain uncertain and need further study.
• In patients with chronic migraine, CGRP/CGRP-R antibodies were similarly effective in both men and women.
• For the 2-hour freedom from most bothersome symptom (2h-MBS) endpoint when gepants were given acutely, the effects were much better in women than men, with an average drug effect of 10.2% and an average NNT of 10.
• In men, these medications produced observed treatment effects on 2h-MBS with an average drug effect of 3.2% and an average NNT of 32.
• In men, 5 out of 12 estimates favored placebo over the active treatment, suggesting a treatment with little to no effect.
• The pooled treatment effects for women were 3 times as large, at 9.2% and 10.2%, respectively.
• The placebo response rates for 2 of the 3 ubrogepant studies and one of 2 zavegepant studies were higher in men than in women.

The study concludes that, while small molecule CGRP-R antagonists are dramatically effective for acute therapy of migraine in women, available data do not demonstrate effectiveness in men. The treatment effect was found to always favor active treatment numerically for both men and women for prevention of episodic and chronic migraine. The data highlight possible differential effects of CGRP-targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women. The study also emphasizes the need to understand which patient groups preferentially respond to CGRP-based therapies to reduce trial and error in treatment. Note that rimegepant data on prevention were not available for analysis at the time of the writing.

It would be interesting to perform a meta-analysis of multiple well-done, large, real-world studies to see if the same differences and similarities are found in men versus women for acute care of migraine and prevention of episodic and chronic migraine. I suspect that we would find that acute care results favor women but that some men do well.

The Effectiveness of Prednisolone for Treating Medication Overuse Headache

I often discuss medication overuse headache (MOH), as it is difficult to diagnose and treat, so I wanted to comment on another pertinent study. It is a post hoc analysis of the Registry for Load and Management of Medication Overuse Headache (RELEASE). The RELEASE trial is an ongoing, multicenter, observational, cohort study of MOH that has been conducted in Korea since April 2020. Findings were recently published in Headache by Lee et al.

MOH is a secondary headache disorder that develops in patients with a preexisting primary headache when they overuse acute care headache medications of any type except gepants. This includes prescription medications such as triptans, ergots, butalbital-containing medications; opioids; aspirin; acetaminophen; any type of combination medication often containing caffeine; or a combination of medications. This condition significantly impacts patients’ quality of life and productivity, usually increasing the frequency of headaches per month and leading to higher healthcare-related costs.

Treating MOH is challenging due to the lack of high-quality drug trials specifically designed for MOH and doctor inexperience. Current evidence is based largely on subgroup analyses of drug trials for the treatment of chronic migraine that contain these patient types.

Withdrawal of acute care headache medications that are being overused has traditionally been considered an important aspect of MOH treatment, although this may be changing. Withdrawal symptoms, such as increased intensity of headache pain, frequency of headaches, and other symptoms like agitation and sleep disturbance, can prevent patients from discontinuing overused medications. Systemic corticosteroids are widely used to reduce these withdrawal headaches, but clinical trials are sparse and have failed to meet proper endpoints. Despite this, corticosteroids have shown potential benefits, such as decreasing withdrawal headaches, reducing the use of rescue medications, and lowering headache intensity at certain time points after treatment.

Given these findings, this published study hypothesized that prednisolone may play a role in converting MOH to non-MOH at 3 months after treatment. The objective was to evaluate the outcome of prednisolone therapy in reversing medication overuse at 3 months posttreatment in patients with MOH using prospective multicenter registry data. Prednisolone was prescribed to 59 out of 309 patients (19.1%) enrolled during this observational study period, with doses ranging from 10 to 40 mg/day for 5-14 days. Of these patients, 228 (73.8%) completed the 3-month follow-up period.

Key findings:

• The MOH reversal rates at 3 months postbaseline were 76% (31/41) in the prednisolone group and 57.8% (108/187) in the no prednisolone group (p = 0.034).
• The steroid effect remained significant (adjusted odds ratio, 2.78; 95% confidence interval 1.27-6.1, p = 0.010) after adjusting for the number of monthly headache days at baseline, mode of discontinuation of overused medication, use of early preventive medications, and the number of combined preventive medications.

The study had several strengths, including the multicenter collection of data, prospective follow-ups, and comprehensiveness of data acquisition. However, it also had significant limitations, such as the noninterventional, observational nature of the study, potential bias in steroid prescription (every doctor prescribed what they wanted), and heterogeneity in the patient population. Also, there were a variety of treatments, and they were not standardized. Further external validation may be necessary before generalizing the study results.

Despite these limitations, the results do suggest that prednisolone may be one part of a valid treatment option for patients with MOH. I suspect, if the proper studies are done, we will see that using a good preventive medication, with few adverse events, and with careful education of the patient, formal detoxification will not be necessary when treating many patients with MOH. This has been my experience with MOH treatment utilizing the newer anti-CGRP preventive medications, including the older monoclonal antibodies and the newer gepants.

Outcomes of Acute and Preventive Migraine Therapy Based on Patient Sex

I previously have addressed myths about migraine as they pertain to men and women. When I found an interesting study recently published in Cephalalgia investigating the effectiveness of calcitonin gene-related peptide receptor (CGRP-R) antagonists (gepants) for acute care and prevention of episodic migraine and CGRP monoclonal antibodies for preventive treatment of episodic and chronic migraine in men and women, I thought I would discuss it here.

The study’s aim was to discern if patient sex contributed to outcomes in each specific treatment arm. Female sex hormones have been recognized as factors in promoting migraine, and women show increased severity, persistence, and comorbidity in migraine profiles, and increased prevalence of migraine relative to men.

Gepants used for acute therapy (ubrogepant, rimegepant, zavegepant) and preventive therapy (atogepant, rimegepant) were studied in this trial. Erenumab, fremanezumab, galcanezumab, and eptinezumab are monoclonal antibodies that either sit on the CGRP receptor (erenumab) or inactivate the CGRP ligand (fremanezumab, galcanezumab, and eptinezumab) and are used for migraine prevention. CGRP-based therapies are not effective in all patients and understanding which patient groups respond preferentially could reduce trial and error in treatment selection. The effectiveness of treatments targeting CGRP or the CGRP receptor may not be uniform in men and women, highlighting the need for further research and understanding of CGRP neurobiology in both sexes.

Key findings:

• In the trial by Porreca et al: In women, the 3 gepants approved by the FDA for the acute care of migraine (ubrogepant, rimegepant, zavegepant) produced a statistically significant drug effect for the 2-hour pain freedom (2h-PF) endpoint, with an average drug effect of 9.5% (CI: 7.4 to 11.6) and an average number needed to treat (NNT) of 11.
• Men did not show statistically significant effects with the acute use of gepants. The average drug effect was 2.8%, and the average NNT was 36.
• For both men and women, CGRP-targeting therapies for prevention of migraine (the 4 monoclonal antibodies) were equally effective; however, possible sex differences remain uncertain and need further study.
• In patients with chronic migraine, CGRP/CGRP-R antibodies were similarly effective in both men and women.
• For the 2-hour freedom from most bothersome symptom (2h-MBS) endpoint when gepants were given acutely, the effects were much better in women than men, with an average drug effect of 10.2% and an average NNT of 10.
• In men, these medications produced observed treatment effects on 2h-MBS with an average drug effect of 3.2% and an average NNT of 32.
• In men, 5 out of 12 estimates favored placebo over the active treatment, suggesting a treatment with little to no effect.
• The pooled treatment effects for women were 3 times as large, at 9.2% and 10.2%, respectively.
• The placebo response rates for 2 of the 3 ubrogepant studies and one of 2 zavegepant studies were higher in men than in women.

The study concludes that, while small molecule CGRP-R antagonists are dramatically effective for acute therapy of migraine in women, available data do not demonstrate effectiveness in men. The treatment effect was found to always favor active treatment numerically for both men and women for prevention of episodic and chronic migraine. The data highlight possible differential effects of CGRP-targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women. The study also emphasizes the need to understand which patient groups preferentially respond to CGRP-based therapies to reduce trial and error in treatment. Note that rimegepant data on prevention were not available for analysis at the time of the writing.

It would be interesting to perform a meta-analysis of multiple well-done, large, real-world studies to see if the same differences and similarities are found in men versus women for acute care of migraine and prevention of episodic and chronic migraine. I suspect that we would find that acute care results favor women but that some men do well.

The Effectiveness of Prednisolone for Treating Medication Overuse Headache

I often discuss medication overuse headache (MOH), as it is difficult to diagnose and treat, so I wanted to comment on another pertinent study. It is a post hoc analysis of the Registry for Load and Management of Medication Overuse Headache (RELEASE). The RELEASE trial is an ongoing, multicenter, observational, cohort study of MOH that has been conducted in Korea since April 2020. Findings were recently published in Headache by Lee et al.

MOH is a secondary headache disorder that develops in patients with a preexisting primary headache when they overuse acute care headache medications of any type except gepants. This includes prescription medications such as triptans, ergots, butalbital-containing medications; opioids; aspirin; acetaminophen; any type of combination medication often containing caffeine; or a combination of medications. This condition significantly impacts patients’ quality of life and productivity, usually increasing the frequency of headaches per month and leading to higher healthcare-related costs.

Treating MOH is challenging due to the lack of high-quality drug trials specifically designed for MOH and doctor inexperience. Current evidence is based largely on subgroup analyses of drug trials for the treatment of chronic migraine that contain these patient types.

Withdrawal of acute care headache medications that are being overused has traditionally been considered an important aspect of MOH treatment, although this may be changing. Withdrawal symptoms, such as increased intensity of headache pain, frequency of headaches, and other symptoms like agitation and sleep disturbance, can prevent patients from discontinuing overused medications. Systemic corticosteroids are widely used to reduce these withdrawal headaches, but clinical trials are sparse and have failed to meet proper endpoints. Despite this, corticosteroids have shown potential benefits, such as decreasing withdrawal headaches, reducing the use of rescue medications, and lowering headache intensity at certain time points after treatment.

Given these findings, this published study hypothesized that prednisolone may play a role in converting MOH to non-MOH at 3 months after treatment. The objective was to evaluate the outcome of prednisolone therapy in reversing medication overuse at 3 months posttreatment in patients with MOH using prospective multicenter registry data. Prednisolone was prescribed to 59 out of 309 patients (19.1%) enrolled during this observational study period, with doses ranging from 10 to 40 mg/day for 5-14 days. Of these patients, 228 (73.8%) completed the 3-month follow-up period.

Key findings:

• The MOH reversal rates at 3 months postbaseline were 76% (31/41) in the prednisolone group and 57.8% (108/187) in the no prednisolone group (p = 0.034).
• The steroid effect remained significant (adjusted odds ratio, 2.78; 95% confidence interval 1.27-6.1, p = 0.010) after adjusting for the number of monthly headache days at baseline, mode of discontinuation of overused medication, use of early preventive medications, and the number of combined preventive medications.

The study had several strengths, including the multicenter collection of data, prospective follow-ups, and comprehensiveness of data acquisition. However, it also had significant limitations, such as the noninterventional, observational nature of the study, potential bias in steroid prescription (every doctor prescribed what they wanted), and heterogeneity in the patient population. Also, there were a variety of treatments, and they were not standardized. Further external validation may be necessary before generalizing the study results.

Despite these limitations, the results do suggest that prednisolone may be one part of a valid treatment option for patients with MOH. I suspect, if the proper studies are done, we will see that using a good preventive medication, with few adverse events, and with careful education of the patient, formal detoxification will not be necessary when treating many patients with MOH. This has been my experience with MOH treatment utilizing the newer anti-CGRP preventive medications, including the older monoclonal antibodies and the newer gepants.

Key Points:

• The “Migraine and Neck Pain Study” analyzed data from nearly 500 adult participants in an effort to uncover an association between migraine-related episodic vertigo and the phases of migraine.
• The study participants included men and women aged 18 to 65, who had episodic migraine with aura and/or without aura.
• Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache.
• 30% of participants reported episodic vertigo at any point during their migraine attack, while 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand.
• The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom.

Alan M. Rapoport, MD:

Vertigo in a migraineur has long created confusion as to diagnosis and treatment. I myself always wondered how much I had to work up vertigo or even dizziness if a patient had migraine. I also did not know what to do when a patient with migraine had attacks of vertigo without headache. Were they manifestations of migraine and should they be treated that way?

This study examined a 500 adult patient population who had migraine with or without aura. Christian Lampl was interested in seeing how many had headache, and the timing of when vertigo occurred. It was carefully measured to determine if it usually occurred during or before the headache phase. Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache, when prodrome occurs.

• The study determined that 30 % of the patients reported vertigo at some point during their migraine attack; 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand., which would have been in the prodromal phase.  
• The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom. This was interesting but it left unanswered one of my questions which is, how many had vertigo unrelated to headache and what is that and how do we treat it.
• Although not addressed in this study, there is consensus that if there is enough vertigo in a migraineur, they should be placed on a migraine preventive therapy. It will be interesting to see what the new monoclonal antibodies to CGRP do to vertigo in a treated migraineur. Some headache specialists will even treat an attack of vertigo without headache with a triptan.

Key Points:

• The “Migraine and Neck Pain Study” analyzed data from nearly 500 adult participants in an effort to uncover an association between migraine-related episodic vertigo and the phases of migraine.
• The study participants included men and women aged 18 to 65, who had episodic migraine with aura and/or without aura.
• Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache.
• 30% of participants reported episodic vertigo at any point during their migraine attack, while 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand.
• The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom.

Alan M. Rapoport, MD:

Vertigo in a migraineur has long created confusion as to diagnosis and treatment. I myself always wondered how much I had to work up vertigo or even dizziness if a patient had migraine. I also did not know what to do when a patient with migraine had attacks of vertigo without headache. Were they manifestations of migraine and should they be treated that way?

This study examined a 500 adult patient population who had migraine with or without aura. Christian Lampl was interested in seeing how many had headache, and the timing of when vertigo occurred. It was carefully measured to determine if it usually occurred during or before the headache phase. Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache, when prodrome occurs.

• The study determined that 30 % of the patients reported vertigo at some point during their migraine attack; 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand., which would have been in the prodromal phase.  
• The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom. This was interesting but it left unanswered one of my questions which is, how many had vertigo unrelated to headache and what is that and how do we treat it.
• Although not addressed in this study, there is consensus that if there is enough vertigo in a migraineur, they should be placed on a migraine preventive therapy. It will be interesting to see what the new monoclonal antibodies to CGRP do to vertigo in a treated migraineur. Some headache specialists will even treat an attack of vertigo without headache with a triptan.

Key Points:

• The “Migraine and Neck Pain Study” analyzed data from nearly 500 adult participants in an effort to uncover an association between migraine-related episodic vertigo and the phases of migraine.
• The study participants included men and women aged 18 to 65, who had episodic migraine with aura and/or without aura.
• Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache.
• 30% of participants reported episodic vertigo at any point during their migraine attack, while 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand.
• The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom.

Alan M. Rapoport, MD:

Vertigo in a migraineur has long created confusion as to diagnosis and treatment. I myself always wondered how much I had to work up vertigo or even dizziness if a patient had migraine. I also did not know what to do when a patient with migraine had attacks of vertigo without headache. Were they manifestations of migraine and should they be treated that way?

This study examined a 500 adult patient population who had migraine with or without aura. Christian Lampl was interested in seeing how many had headache, and the timing of when vertigo occurred. It was carefully measured to determine if it usually occurred during or before the headache phase. Migraines were divided into 3 time segments for evaluation: (1) Onset of headache, (2) less than 2 hours before the onset of headache, and (3) 2 to 48 hours before the onset of headache, when prodrome occurs.

• The study determined that 30 % of the patients reported vertigo at some point during their migraine attack; 16% reported it at the start of headache, 10% reported it within 2 hours before their headache, and just 3% reported symptoms between 2 and 24 hours beforehand., which would have been in the prodromal phase.  
• The study concluded that episodic vertigo could be considered more of a “headache phase phenomenon” rather than a prodromal symptom. This was interesting but it left unanswered one of my questions which is, how many had vertigo unrelated to headache and what is that and how do we treat it.
• Although not addressed in this study, there is consensus that if there is enough vertigo in a migraineur, they should be placed on a migraine preventive therapy. It will be interesting to see what the new monoclonal antibodies to CGRP do to vertigo in a treated migraineur. Some headache specialists will even treat an attack of vertigo without headache with a triptan.

The gepants and monoclonal antibodies (mAbs) against calcitonin gene-related peptide (CGRP) and its receptor appear to be effective, tolerable and safe, according to several posters recently presented at the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia. Information was presented on the 3 gepants being studied for US Food and Drug Administration (FDA) approval: 1 for acute care of migraine, 1 for prevention and 1 for both (though the presented data for rimegepant only covers acute care).

All drugs cause a small degree of adverse events (AEs), somewhat more than placebo. Based on the presented data, it seems that those associated with 3 times higher than normal elevation of liver enzymes, were usually not found to be the cause of that elevation. At no time was bilirubin elevated. This shows that all of these gepants appear to be effective and safe, despite the fact that some were found to have cause liver toxicity many years ago.

The first gepant study to be published was on olcegepant in 2004, in the New England Journal of Medicine. Professor Jes Olesen, MD, was the lead author of the study, which detailed the efficacy and safety of this small molecule CGRP receptor antagonist. Olcegepant was in an intravenous formulation and the plan was to convert it to a tablet, which never happened. Another company then produced telcagepant as a tablet and it was shown to be safe and effective in 2 large, multicenter, double-blind trials. Before receiving FDA approval for the acute care of migraine, it was studied on a daily basis for migraine prevention. It was found to cause some liver toxicity, so development was stopped. At that time several other gepants in development were placed on the shelf, partially for the fear of liver toxicity. The FDA is unlikely to approve a drug with significant liver toxicity, which can cause a range of symptoms including jaundice, itching, abdominal pain, fatigue, loss of appetite, nausea, vomiting, rash, and weight loss.

In the next few years we will have 4 mAbs for the prevention of migraine, and 3 gepants if all studies are positive. Below are the key takeaways from the presented posters on ubrogepant and atogepant, as information that is currently available on rimegepant.
 

Key Takeaways:

• Ubrogepant – Ailani J, Hutchinson S, Lipton R, et al.
  • Intermittent use of ubrogepant for the acute treatment of migraine over 1 year was well-tolerated with no identified safety concerns. Throughout the 1-year, Phase III study of 1254 participants, 22,454 migraine attacks were treated with 31,968 doses of ubrogepant.
  • Twenty cases of ALT/AST ≥3x ULN were reported and adjudicated by an independent panel of liver experts blinded to treatment.
  • Of the 20 cases, 17 (4 usual care, 3 ubrogepant 50-mg, and 10 ubrogepant 100-mg) were determined to be unlikely related based on plausible alternative etiology/confounding factors.
  • Just 2 cases (both ubrogepant 50-mg) were described as possibly related to study medication and 1 case (ubrogepant 100-mg) was adjudicated as probably related; however, confounding factors were noted.
  • All cases were asymptomatic with no concurrent bilirubin elevation. ALT/AST elevations resolved in those who continued dosing.
     
• Atogepant – Goadsby PJ, Dodick DW, Trugman JM, et al.
  • In a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial of adults with a history of migraine, with or without aura, atogepant was well tolerated with no treatment-related serious AEs.
  • Of the 834 randomized subjects, 825 were evaluated in the safety population. Treatment-emergent AEs were reported by 480 subjects (58.2%), and for 170 (20.6%), the AEs were considered treatment-related. Seven subjects (0.8%) reported serious AEs, but none were determined as treatment related.
  • There were 10 cases of treatment-emergent ALT/AST elevations >3x the upper limit of normal, and this was balanced across the treatment dosage groups (10 mg QD, 30 mg QD, 30 mg BID, 60 mg QD, and 60 mg BID).
     
• Rimegepant – See Biogen press release for more information
  • In December 2019, Biohaven announced initial positive results from an ongoing long-term, open-label safety study for rimegepant.
  • The interim results included hepatic safety and tolerability data of rimegepant 75 mg in study participants based on a review of adverse events and regularly scheduled liver function tests.
  • A panel of external independent liver experts provided a consensus based on the Drug-Induced Liver Injury Network (DILIN) causality assessment, determining that there were no liver cases probably related to the study drug and that there were no Hy’s Law cases identified.
  • The panel also concluded that there were no liver safety signals detected and that, compared to placebo arms of other migraine treatments, there was a very low incidence of overall elevations of liver abnormalities.

The gepants and monoclonal antibodies (mAbs) against calcitonin gene-related peptide (CGRP) and its receptor appear to be effective, tolerable and safe, according to several posters recently presented at the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia. Information was presented on the 3 gepants being studied for US Food and Drug Administration (FDA) approval: 1 for acute care of migraine, 1 for prevention and 1 for both (though the presented data for rimegepant only covers acute care).

All drugs cause a small degree of adverse events (AEs), somewhat more than placebo. Based on the presented data, it seems that those associated with 3 times higher than normal elevation of liver enzymes, were usually not found to be the cause of that elevation. At no time was bilirubin elevated. This shows that all of these gepants appear to be effective and safe, despite the fact that some were found to have cause liver toxicity many years ago.

The first gepant study to be published was on olcegepant in 2004, in the New England Journal of Medicine. Professor Jes Olesen, MD, was the lead author of the study, which detailed the efficacy and safety of this small molecule CGRP receptor antagonist. Olcegepant was in an intravenous formulation and the plan was to convert it to a tablet, which never happened. Another company then produced telcagepant as a tablet and it was shown to be safe and effective in 2 large, multicenter, double-blind trials. Before receiving FDA approval for the acute care of migraine, it was studied on a daily basis for migraine prevention. It was found to cause some liver toxicity, so development was stopped. At that time several other gepants in development were placed on the shelf, partially for the fear of liver toxicity. The FDA is unlikely to approve a drug with significant liver toxicity, which can cause a range of symptoms including jaundice, itching, abdominal pain, fatigue, loss of appetite, nausea, vomiting, rash, and weight loss.

In the next few years we will have 4 mAbs for the prevention of migraine, and 3 gepants if all studies are positive. Below are the key takeaways from the presented posters on ubrogepant and atogepant, as information that is currently available on rimegepant.
 

Key Takeaways:

• Ubrogepant – Ailani J, Hutchinson S, Lipton R, et al.
  • Intermittent use of ubrogepant for the acute treatment of migraine over 1 year was well-tolerated with no identified safety concerns. Throughout the 1-year, Phase III study of 1254 participants, 22,454 migraine attacks were treated with 31,968 doses of ubrogepant.
  • Twenty cases of ALT/AST ≥3x ULN were reported and adjudicated by an independent panel of liver experts blinded to treatment.
  • Of the 20 cases, 17 (4 usual care, 3 ubrogepant 50-mg, and 10 ubrogepant 100-mg) were determined to be unlikely related based on plausible alternative etiology/confounding factors.
  • Just 2 cases (both ubrogepant 50-mg) were described as possibly related to study medication and 1 case (ubrogepant 100-mg) was adjudicated as probably related; however, confounding factors were noted.
  • All cases were asymptomatic with no concurrent bilirubin elevation. ALT/AST elevations resolved in those who continued dosing.
     
• Atogepant – Goadsby PJ, Dodick DW, Trugman JM, et al.
  • In a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial of adults with a history of migraine, with or without aura, atogepant was well tolerated with no treatment-related serious AEs.
  • Of the 834 randomized subjects, 825 were evaluated in the safety population. Treatment-emergent AEs were reported by 480 subjects (58.2%), and for 170 (20.6%), the AEs were considered treatment-related. Seven subjects (0.8%) reported serious AEs, but none were determined as treatment related.
  • There were 10 cases of treatment-emergent ALT/AST elevations >3x the upper limit of normal, and this was balanced across the treatment dosage groups (10 mg QD, 30 mg QD, 30 mg BID, 60 mg QD, and 60 mg BID).
     
• Rimegepant – See Biogen press release for more information
  • In December 2019, Biohaven announced initial positive results from an ongoing long-term, open-label safety study for rimegepant.
  • The interim results included hepatic safety and tolerability data of rimegepant 75 mg in study participants based on a review of adverse events and regularly scheduled liver function tests.
  • A panel of external independent liver experts provided a consensus based on the Drug-Induced Liver Injury Network (DILIN) causality assessment, determining that there were no liver cases probably related to the study drug and that there were no Hy’s Law cases identified.
  • The panel also concluded that there were no liver safety signals detected and that, compared to placebo arms of other migraine treatments, there was a very low incidence of overall elevations of liver abnormalities.

The gepants and monoclonal antibodies (mAbs) against calcitonin gene-related peptide (CGRP) and its receptor appear to be effective, tolerable and safe, according to several posters recently presented at the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia. Information was presented on the 3 gepants being studied for US Food and Drug Administration (FDA) approval: 1 for acute care of migraine, 1 for prevention and 1 for both (though the presented data for rimegepant only covers acute care).

All drugs cause a small degree of adverse events (AEs), somewhat more than placebo. Based on the presented data, it seems that those associated with 3 times higher than normal elevation of liver enzymes, were usually not found to be the cause of that elevation. At no time was bilirubin elevated. This shows that all of these gepants appear to be effective and safe, despite the fact that some were found to have cause liver toxicity many years ago.

The first gepant study to be published was on olcegepant in 2004, in the New England Journal of Medicine. Professor Jes Olesen, MD, was the lead author of the study, which detailed the efficacy and safety of this small molecule CGRP receptor antagonist. Olcegepant was in an intravenous formulation and the plan was to convert it to a tablet, which never happened. Another company then produced telcagepant as a tablet and it was shown to be safe and effective in 2 large, multicenter, double-blind trials. Before receiving FDA approval for the acute care of migraine, it was studied on a daily basis for migraine prevention. It was found to cause some liver toxicity, so development was stopped. At that time several other gepants in development were placed on the shelf, partially for the fear of liver toxicity. The FDA is unlikely to approve a drug with significant liver toxicity, which can cause a range of symptoms including jaundice, itching, abdominal pain, fatigue, loss of appetite, nausea, vomiting, rash, and weight loss.

In the next few years we will have 4 mAbs for the prevention of migraine, and 3 gepants if all studies are positive. Below are the key takeaways from the presented posters on ubrogepant and atogepant, as information that is currently available on rimegepant.
 

Key Takeaways:

• Ubrogepant – Ailani J, Hutchinson S, Lipton R, et al.
  • Intermittent use of ubrogepant for the acute treatment of migraine over 1 year was well-tolerated with no identified safety concerns. Throughout the 1-year, Phase III study of 1254 participants, 22,454 migraine attacks were treated with 31,968 doses of ubrogepant.
  • Twenty cases of ALT/AST ≥3x ULN were reported and adjudicated by an independent panel of liver experts blinded to treatment.
  • Of the 20 cases, 17 (4 usual care, 3 ubrogepant 50-mg, and 10 ubrogepant 100-mg) were determined to be unlikely related based on plausible alternative etiology/confounding factors.
  • Just 2 cases (both ubrogepant 50-mg) were described as possibly related to study medication and 1 case (ubrogepant 100-mg) was adjudicated as probably related; however, confounding factors were noted.
  • All cases were asymptomatic with no concurrent bilirubin elevation. ALT/AST elevations resolved in those who continued dosing.
     
• Atogepant – Goadsby PJ, Dodick DW, Trugman JM, et al.
  • In a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial of adults with a history of migraine, with or without aura, atogepant was well tolerated with no treatment-related serious AEs.
  • Of the 834 randomized subjects, 825 were evaluated in the safety population. Treatment-emergent AEs were reported by 480 subjects (58.2%), and for 170 (20.6%), the AEs were considered treatment-related. Seven subjects (0.8%) reported serious AEs, but none were determined as treatment related.
  • There were 10 cases of treatment-emergent ALT/AST elevations >3x the upper limit of normal, and this was balanced across the treatment dosage groups (10 mg QD, 30 mg QD, 30 mg BID, 60 mg QD, and 60 mg BID).
     
• Rimegepant – See Biogen press release for more information
  • In December 2019, Biohaven announced initial positive results from an ongoing long-term, open-label safety study for rimegepant.
  • The interim results included hepatic safety and tolerability data of rimegepant 75 mg in study participants based on a review of adverse events and regularly scheduled liver function tests.
  • A panel of external independent liver experts provided a consensus based on the Drug-Induced Liver Injury Network (DILIN) causality assessment, determining that there were no liver cases probably related to the study drug and that there were no Hy’s Law cases identified.
  • The panel also concluded that there were no liver safety signals detected and that, compared to placebo arms of other migraine treatments, there was a very low incidence of overall elevations of liver abnormalities.

Following the American Headache Society’s Scottsdale Headache Symposium in November 2018, MedPage Today posted an article which shared differing opinions from Drs. Hans-Christoph Diener and Elizabeth Loder on medication overuse headache (MOH). While Dr. Diener noted that “we can identify people with chronic migraine who are at risk to have medication overuse,” and that following successful withdrawal treatment “the majority of patients…revert to episodic migraine,” Dr. Loder pointed out that while MOH may exist and contribute to chronic migraine, “it is over-emphasized and the evidence in support of these concepts is weak.”

For this article, I’ve asked Drs. Marcelo Bigal, Rob Cowan, Jack Schim, and Stewart J. Tepper to share their perspectives on this topic. I also asked both Dr. Diener and Dr. Loder to expand on their comments. We will see Dr. Diener’s response to the article, but we did not hear back from Dr. Loder. Lastly, I will weigh in on the MOH discussion.
 

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

The issue of medication overuse headache (MOH) needs to be disentangled into a few separate but related issues. First, do excessive medications make migraine worse? Second, should MOH be considered a distinct form of headache? And how can evidence inform clinical practice?

Robust evidence supports the fact that excessive acute medication use is associated with increased headache frequency among migraineurs. In a large epidemiological study, we demonstrated that exposure (medication) precedes outcome (increased headache frequency).¹ The risk was higher for barbiturates, followed by opioids and triptans, and was not increased by nonsteroidal anti-inflammatory drugs (NSAIDs). Dose response and critical exposure levels were identified. Based on this study and several others, we argued that criteria of causality had been demonstrated beyond reasonable doubt.²

However, since the effect is specific to migraine in that the exposure only increases the risk in migraineurs, not in individuals with other types of pain, we do not consider MOH a distinct entity. Instead, we believe that excessive medication is a risk factor for chronic migraine (CM). Therefore, we should be able to subdivide CM into 2 groups, one with and one without excessive medication use.

From a clinical perspective, physicians should monitor acute medication consumption in individuals with migraine and should be liberal in starting preventive therapy. In those with CM and excessive acute medication use we don’t advocate abrupt discontinuation of acute medications, since some preventive medications, especially the newer anti-calcitonin gene-related peptide (CGRP) antibodies, seem to work equally well in individuals with and without excessive use of medication,³ allowing more natural and gradual control of acute medication consumption without the need for detoxification.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

As is often the case when 2 smart people take artificially imposed opposite positions, the truth will lie somewhere in the middle. I doubt either of the debaters would argue either extreme position: MOH does not exist, or MOH when present is solely responsible for chronic daily headache (CDH). The argument that the absence of controlled studies negates the proposition fails the common-sense test: Without a controlled study, we can’t be sure that wearing a helmet when bicycling is better than not. In such a case, observational data is sufficient. Could there be confounders (eg, helmet wearers are more inclined to ride safely)? Of course, but is that important? Similarly, does the fact that some MOH patients continue with CDH after cessation of medication overuse warrant a general de-emphasis? Certainly not for the third-to-half of patients who benefit from limiting medication use.

I suspect both Drs. Diener and Loder would agree that we would benefit from better markers of chronification and that earlier intervention with at-risk patients (eg, patients with increasing headache frequency, severity or duration but still in the episodic phase).

Jack Schim, MD
Co-Director, The Headache Center of Southern California

There has long been recognition that overuse of analgesic medications can be linked to progression of headache disorders. MOH was initially described by Dr. Lee Kudrow in 1982, in a chapter entitled, “Paradoxical effects of frequent analgesic use.”⁴ The most recent edition of the International Classification of Headache Disorders (ICHD-3) description does not entail features that imply causality. While there is epidemiologic observation of correlation between frequent analgesic use and progression of primary headache disorders, the causal relationship is often obscured by the facts. Overuse of acute medications is quite common in individuals with CM, but not all with CM overuse medications.

In the article being discussed, Drs. Diener and Loder reviewed facts and opinions. They helped clarify that while MOH is widely recognized, much of what is known is descriptive, and not based on solid science. From their presentations, we can conclude that we can recognize MOH based on ICHD-3 criteria, but we cannot tell an individual with chronic headache whether we can best help them by educating them, or by adjusting preventives, or both. The call to action is clear; we need to evaluate best therapeutic approaches in an empiric fashion. Our best new therapies for migraine prevention, CGRP mAbs, work for the majority of patients, with minimal side effects, even in the face of what has been considered MOH. Now, we need to strategize how best to approach these clinically challenged individuals. We need to avoid further stigmatizing our patients. Let’s recognize that our patients do not fail preventives, the prior preventives have failed our patients. Can the introduction of highly effective, well tolerated preventives at an earlier stage help avoid chronification that may drive medication overuse?

Stewart J. Tepper, MD, FAHS
Professor of Neurology, Geisel School of Medicine at Dartmouth

It is clear that overuse of some acute medication is detrimental to patient health. Examples of this include analgesic nephropathy or peptic ulcer disease, and exacerbation of depression with overuse of barbiturate compounds or benzodiazepines. Few doubt the health merits of reduction of acute medication overuse, regardless of whether the acute medications can be proven to transform episodic migraine (EM) to CM.

The good news is that the issues of the existence of true MOH and its proper management are rapidly becoming less important. OnabotulinumtoxinA use decreases triptan use in multiple randomized controlled trials for CM prevention.

Each of the anti-CGRP and anti-CGRP receptor monoclonal antibodies (mAbs) have been effective in preventing CM with medication overuse. All have lowered acute medication use, both triptans and analgesics. It is worth noting, however, that in both the OnabotulinumtoxinA and mAb trials, over-users of opioids and barbiturates were excluded. The mAbs converted patients from acute medication overuse to non-overuse, and from CM with medication overuse to EM without medication. These changes occurred without specific plans for weaning acute medication in place.

Accordingly, patients with CM with acute medication overuse should be treated with optimal prevention, and the evidence is strongest for use of the mAbs to both reduce mean monthly migraine days and all acute medication use, both triptans and analgesics. The new monoclonal antibody effectiveness may make the old arguments moot.

Hans-Christoph Diener, MD, PhD
University of Essen, Germany

I think no one doubts that MOH exists. The worldwide prevalence is between 1% and 2% (Table). The dilemma is that the diagnosis can only be made after the intake of acute medication has been reduced. There are confounders: migraine can improve irrespective of the reduction of acute medication and many physicians will implement migraine prevention at the time of withdrawal. No randomized trial compared the continuation of unchanged intake of medication to treat migraine attacks with reduction or withdrawal.

+++

Commentary by Alan M. Rapoport, MD

The above comments by my associates are very informative and help the reader to better understand the arguments about MOH. When Dr. Lee Kudrow taught me and my partner Dr. Fred Sheftell about the entity of analgesic and ergotamine overuse headaches in 1979, we set out to find those patients, observe and treat them. We did not have to wait long as so many patients with frequent and severe headaches came to see us with what we now term “medication overuse headache.” They told us that they had fewer headaches several years before and increased the use of acute care medications as their headaches increased in frequency. They were unaware of the probability that their headaches increased in frequency because their medication did. Some would argue that they increased their intake to feel better as the headache increased on their own.

Of course, we were not sure of the cause and effect, but we saw the result of tapering the acute care medications, whether or not we used preventives, hospitalized those patients or treated them with behavioral medicine approaches, etc. We observed that the combination of these treatments seemed to work better than just detox, but we did not do the proper studies to prove it. We also noticed that about 30% to 40% of patients did not improve as well as others, and daily or near-daily headaches continued, often of a lesser intensity. Almost all felt better in general and had fewer adverse events from the medication. The decrease in those medications was undoubtedly better for their brain function, livers and kidneys.

I do believe that medication overuse makes most patients with frequent EM or CM worse and we should educate patients to avoid it. I agree with Dr. Bigal that preventive medications may help some patients to improve despite the excessive use of acute care medication, but I am not sure that the older preventives work as well and certainly not as quickly as the newer ones. Recently I have seen the anti-CGRP mAbs work wonders with some of my patients who could not decrease their triptan intake. They just stop using the triptans as their headaches decrease on these therapies.

There is another interesting phenomenon that I have seen in practice—mostly with butalbital products, which I no longer prescribe. Forty years ago, patients would say that they only had 4 headaches per month lasting 1 to 2 days and I would prescribe 10 pills for them. They would call in 2 weeks and say they needed more. When queried they would invariably say it worked so well on the bad headaches and made them feel so much better, that they took 1 or 2 on days they thought they were going to get a headache and it prevented them from forming. They were soon taking it frequently and over time they were dependent on the medication, and then it stopped working and was difficult to withdraw.

Dr. Loder’s point that the studies on MOH have not proven that medication overuse causes it may be technically true; but it would be unethical to start patients on too much medication and randomize some to stay on and some to taper off. Dr. Kudrow came the closest by taking existing MOH patients and treating half with withdrawal and half of each with preventives. His breakthrough study in 1982 “proved” the existence of analgesic rebound and directed us to the best treatment at that time.⁴ This was the first study to examine the effect of stopping the overuse of medication to see the results.

Finally, I am unhappy that ICHD-3 has defined MOH only by number of days of medication use, not at all considering whether or not the patient develops a new type of headache, a worse type or more frequent headache (the way it was in previous versions). We have all seen patients taking 3 triptans per day on their own or with our suggestion, and many actually do better with no headache, for a period of time. This is medication overuse by definition, but not MOH, as they have little headache. But we do not recognize this entity.

The good news is, with education and anti-CGRP therapies, we will probably see less MOH in the future, or at least know better how to treat it.

+++

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33. Schramm SH, Obermann M, Katsarava Z, Diener HC, Moebus S, Yoon MS. Epidemiological profiles of patients with chronic migraine and chronic tension-type headache. J Headache Pain. 2013;14:40.

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39. Mbewe E, Zairemthiama P, Yeh HH, Paul R, Birbeck GL, Steiner TJ. The epidemiology of primary headache disorders in Zambia: a population-based door-to-door survey. J Headache Pain. 2015;16:515.

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45. Rastenyte D, Mickeviciene D, Stovner LJ, Thomas H, Andree C, Steiner TJ. Prevalence and burden of headache disorders in Lithuania and their public-health and policy implications: a population-based study within the Eurolight Project. J Headache Pain. 2017;18(1):53.

46. Henning V, Katsarava Z, Obermann M, Moebus S, Schramm S. Remission of chronic headache: Rates, potential predictors and the role of medication, follow-up results of the German Headache Consortium (GHC) Study. Cephalalgia. 2018;38(3):551-560.

47. Global Burden of Disease Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16(11):877-897.

Following the American Headache Society’s Scottsdale Headache Symposium in November 2018, MedPage Today posted an article which shared differing opinions from Drs. Hans-Christoph Diener and Elizabeth Loder on medication overuse headache (MOH). While Dr. Diener noted that “we can identify people with chronic migraine who are at risk to have medication overuse,” and that following successful withdrawal treatment “the majority of patients…revert to episodic migraine,” Dr. Loder pointed out that while MOH may exist and contribute to chronic migraine, “it is over-emphasized and the evidence in support of these concepts is weak.”

For this article, I’ve asked Drs. Marcelo Bigal, Rob Cowan, Jack Schim, and Stewart J. Tepper to share their perspectives on this topic. I also asked both Dr. Diener and Dr. Loder to expand on their comments. We will see Dr. Diener’s response to the article, but we did not hear back from Dr. Loder. Lastly, I will weigh in on the MOH discussion.
 

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

The issue of medication overuse headache (MOH) needs to be disentangled into a few separate but related issues. First, do excessive medications make migraine worse? Second, should MOH be considered a distinct form of headache? And how can evidence inform clinical practice?

Robust evidence supports the fact that excessive acute medication use is associated with increased headache frequency among migraineurs. In a large epidemiological study, we demonstrated that exposure (medication) precedes outcome (increased headache frequency).¹ The risk was higher for barbiturates, followed by opioids and triptans, and was not increased by nonsteroidal anti-inflammatory drugs (NSAIDs). Dose response and critical exposure levels were identified. Based on this study and several others, we argued that criteria of causality had been demonstrated beyond reasonable doubt.²

However, since the effect is specific to migraine in that the exposure only increases the risk in migraineurs, not in individuals with other types of pain, we do not consider MOH a distinct entity. Instead, we believe that excessive medication is a risk factor for chronic migraine (CM). Therefore, we should be able to subdivide CM into 2 groups, one with and one without excessive medication use.

From a clinical perspective, physicians should monitor acute medication consumption in individuals with migraine and should be liberal in starting preventive therapy. In those with CM and excessive acute medication use we don’t advocate abrupt discontinuation of acute medications, since some preventive medications, especially the newer anti-calcitonin gene-related peptide (CGRP) antibodies, seem to work equally well in individuals with and without excessive use of medication,³ allowing more natural and gradual control of acute medication consumption without the need for detoxification.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

As is often the case when 2 smart people take artificially imposed opposite positions, the truth will lie somewhere in the middle. I doubt either of the debaters would argue either extreme position: MOH does not exist, or MOH when present is solely responsible for chronic daily headache (CDH). The argument that the absence of controlled studies negates the proposition fails the common-sense test: Without a controlled study, we can’t be sure that wearing a helmet when bicycling is better than not. In such a case, observational data is sufficient. Could there be confounders (eg, helmet wearers are more inclined to ride safely)? Of course, but is that important? Similarly, does the fact that some MOH patients continue with CDH after cessation of medication overuse warrant a general de-emphasis? Certainly not for the third-to-half of patients who benefit from limiting medication use.

I suspect both Drs. Diener and Loder would agree that we would benefit from better markers of chronification and that earlier intervention with at-risk patients (eg, patients with increasing headache frequency, severity or duration but still in the episodic phase).

Jack Schim, MD
Co-Director, The Headache Center of Southern California

There has long been recognition that overuse of analgesic medications can be linked to progression of headache disorders. MOH was initially described by Dr. Lee Kudrow in 1982, in a chapter entitled, “Paradoxical effects of frequent analgesic use.”⁴ The most recent edition of the International Classification of Headache Disorders (ICHD-3) description does not entail features that imply causality. While there is epidemiologic observation of correlation between frequent analgesic use and progression of primary headache disorders, the causal relationship is often obscured by the facts. Overuse of acute medications is quite common in individuals with CM, but not all with CM overuse medications.

In the article being discussed, Drs. Diener and Loder reviewed facts and opinions. They helped clarify that while MOH is widely recognized, much of what is known is descriptive, and not based on solid science. From their presentations, we can conclude that we can recognize MOH based on ICHD-3 criteria, but we cannot tell an individual with chronic headache whether we can best help them by educating them, or by adjusting preventives, or both. The call to action is clear; we need to evaluate best therapeutic approaches in an empiric fashion. Our best new therapies for migraine prevention, CGRP mAbs, work for the majority of patients, with minimal side effects, even in the face of what has been considered MOH. Now, we need to strategize how best to approach these clinically challenged individuals. We need to avoid further stigmatizing our patients. Let’s recognize that our patients do not fail preventives, the prior preventives have failed our patients. Can the introduction of highly effective, well tolerated preventives at an earlier stage help avoid chronification that may drive medication overuse?

Stewart J. Tepper, MD, FAHS
Professor of Neurology, Geisel School of Medicine at Dartmouth

It is clear that overuse of some acute medication is detrimental to patient health. Examples of this include analgesic nephropathy or peptic ulcer disease, and exacerbation of depression with overuse of barbiturate compounds or benzodiazepines. Few doubt the health merits of reduction of acute medication overuse, regardless of whether the acute medications can be proven to transform episodic migraine (EM) to CM.

The good news is that the issues of the existence of true MOH and its proper management are rapidly becoming less important. OnabotulinumtoxinA use decreases triptan use in multiple randomized controlled trials for CM prevention.

Each of the anti-CGRP and anti-CGRP receptor monoclonal antibodies (mAbs) have been effective in preventing CM with medication overuse. All have lowered acute medication use, both triptans and analgesics. It is worth noting, however, that in both the OnabotulinumtoxinA and mAb trials, over-users of opioids and barbiturates were excluded. The mAbs converted patients from acute medication overuse to non-overuse, and from CM with medication overuse to EM without medication. These changes occurred without specific plans for weaning acute medication in place.

Accordingly, patients with CM with acute medication overuse should be treated with optimal prevention, and the evidence is strongest for use of the mAbs to both reduce mean monthly migraine days and all acute medication use, both triptans and analgesics. The new monoclonal antibody effectiveness may make the old arguments moot.

Hans-Christoph Diener, MD, PhD
University of Essen, Germany

I think no one doubts that MOH exists. The worldwide prevalence is between 1% and 2% (Table). The dilemma is that the diagnosis can only be made after the intake of acute medication has been reduced. There are confounders: migraine can improve irrespective of the reduction of acute medication and many physicians will implement migraine prevention at the time of withdrawal. No randomized trial compared the continuation of unchanged intake of medication to treat migraine attacks with reduction or withdrawal.

+++

Commentary by Alan M. Rapoport, MD

The above comments by my associates are very informative and help the reader to better understand the arguments about MOH. When Dr. Lee Kudrow taught me and my partner Dr. Fred Sheftell about the entity of analgesic and ergotamine overuse headaches in 1979, we set out to find those patients, observe and treat them. We did not have to wait long as so many patients with frequent and severe headaches came to see us with what we now term “medication overuse headache.” They told us that they had fewer headaches several years before and increased the use of acute care medications as their headaches increased in frequency. They were unaware of the probability that their headaches increased in frequency because their medication did. Some would argue that they increased their intake to feel better as the headache increased on their own.

Of course, we were not sure of the cause and effect, but we saw the result of tapering the acute care medications, whether or not we used preventives, hospitalized those patients or treated them with behavioral medicine approaches, etc. We observed that the combination of these treatments seemed to work better than just detox, but we did not do the proper studies to prove it. We also noticed that about 30% to 40% of patients did not improve as well as others, and daily or near-daily headaches continued, often of a lesser intensity. Almost all felt better in general and had fewer adverse events from the medication. The decrease in those medications was undoubtedly better for their brain function, livers and kidneys.

I do believe that medication overuse makes most patients with frequent EM or CM worse and we should educate patients to avoid it. I agree with Dr. Bigal that preventive medications may help some patients to improve despite the excessive use of acute care medication, but I am not sure that the older preventives work as well and certainly not as quickly as the newer ones. Recently I have seen the anti-CGRP mAbs work wonders with some of my patients who could not decrease their triptan intake. They just stop using the triptans as their headaches decrease on these therapies.

There is another interesting phenomenon that I have seen in practice—mostly with butalbital products, which I no longer prescribe. Forty years ago, patients would say that they only had 4 headaches per month lasting 1 to 2 days and I would prescribe 10 pills for them. They would call in 2 weeks and say they needed more. When queried they would invariably say it worked so well on the bad headaches and made them feel so much better, that they took 1 or 2 on days they thought they were going to get a headache and it prevented them from forming. They were soon taking it frequently and over time they were dependent on the medication, and then it stopped working and was difficult to withdraw.

Dr. Loder’s point that the studies on MOH have not proven that medication overuse causes it may be technically true; but it would be unethical to start patients on too much medication and randomize some to stay on and some to taper off. Dr. Kudrow came the closest by taking existing MOH patients and treating half with withdrawal and half of each with preventives. His breakthrough study in 1982 “proved” the existence of analgesic rebound and directed us to the best treatment at that time.⁴ This was the first study to examine the effect of stopping the overuse of medication to see the results.

Finally, I am unhappy that ICHD-3 has defined MOH only by number of days of medication use, not at all considering whether or not the patient develops a new type of headache, a worse type or more frequent headache (the way it was in previous versions). We have all seen patients taking 3 triptans per day on their own or with our suggestion, and many actually do better with no headache, for a period of time. This is medication overuse by definition, but not MOH, as they have little headache. But we do not recognize this entity.

The good news is, with education and anti-CGRP therapies, we will probably see less MOH in the future, or at least know better how to treat it.

+++

References

1. Bigal ME, Serrano D, Buse D, et al. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48(8):1157-68. doi: 10.1111/j.1526-4610.2008.01217.x. PubMed PMID: 18808500.

2. Bigal ME, Lipton RB. Overuse of acute migraine medications and migraine chronification. Curr Pain Headache Rep. 2009;13(4):301-7. PubMed PMID: 19586594.

3. Bigal ME, Edvinsson L, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14(11):1091-100. doi: 10.1016/S1474-4422(15)00245-8. PubMed PMID: 26432181.

4. Kudrow L. Paradoxical Effects of Frequent Analgesic Use. Advances in Neurology. 1982;33:335-341.

5. Diener HC, Holle D, Dresler T, Gaul C. Chronic Headache Due to Overuse of Analgesics and Anti-Migraine Agents. Dtsch Arztebl Int. 2018;115(22):365-370.

6. Westergaard ML, Glumer C, Hansen EH, Jensen RH. Prevalence of chronic headache with and without medication overuse: associations with socioeconomic position and physical and mental health status. Pain. 2014;155(10):2005-2013.

7. Castillo J, Munoz P, Guitera V, Pascual J. Epidemiology of chronic daily headache in the general population. Headache. 1999;39:190-196.

8. Wang SJ, Fuh JL, Lu SR, et al. Chronic daily headache in chinese elderly - prevalence, risk factors, and biannual follow-up. Neurology. 2000;54:314-319.

9. Lu SR, Fuh JL, Chen WT, Juang KD, Wang SJ. Chronic daily headache in Taipei, Taiwan: prevalence, follow-up and outcome predictors. Cephalalgia. 2001;21:980-986.

10. Pascual J, Colas R, Castillo J. Epidemiology of chronic daily headache. Curr Pain Headache Rep. 2001;5(6):529-536.

11. Prencipe M, Casini AR, Ferretti C, et al. Prevalence of headache in an elderly population: attack frequency, disability, and use of medication. J Neurol Neurosurg Psychiatry. 2001;70(3):377-381.

12. Colas R, Munoz P, Temprano R, Gomez C, Pascual J. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Neurology. 2004;62:1338-1342.

13. Zwart J, Dyb G, Hagen K, Svebak S, Stovner L, Holmen J. Analgesic overuse among subjects with headache, neck, and low back pain. Neurology. 2004;62:1540-1544.

14. Dyb G, Holmen TL, Zwart JA. Analgesic overuse among adolescents with headache: the Head-HUNT-Youth Study. Neurology. 2006;66(2):198-201.

15. Wang SJ, Fuh JL, Lu SR, Juang KD. Chronic daily headache in adolescents: prevalence, impact, and medication overuse. Neurology. 2006;66(2):193-197.

16. Wiendels NJ, Knuistingh NA, Rosendaal FR, et al. Chronic frequent headache in the general population: prevalence and associated factors. Cephalalgia. 2006;26(12):1434-1442.

17. Stovner L, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27(3):193-210.

18. Aaseth K, Grande RB, Kvaerner KJ, Gulbrandsen P, Lundqvist C, Russell MB. Prevalence of secondary chronic headaches in a population-based sample of 30-44-year-old persons. The Akershus study of chronic headache. Cephalalgia. 2008;28(7):705-713.

19. Aaseth K, Grande RB, Lundqvist C, Russell MB. What is chronic headache in the general population? The Akershus study of chronic headache. Acta Neurol Scand Suppl. 2009;(189):30-32.

20. Rueda-Sanchez M, Diaz-Martinez LA. Prevalence and associated factors for episodic and chronic daily headache in the Colombian population. Cephalalgia. 2008;28(3):216-225.

21. Katsarava Z, Dzagnidze A, Kukava M, et al. Primary headache disorders in the Republic of Georgia: prevalence and risk factors. Neurology. 2009;73(21):1796-1803.

22. da Silva A, Jr., Costa EC, Gomes JB, et al. Chronic headache and comorbidities: a two-phase, population-based, cross-sectional study. Headache. 2010;50(8):1306-1312.

23. Straube A, Pfaffenrath V, Ladwig KH, et al. Prevalence of chronic migraine and medication overuse headache in Germany--the German DMKG headache study. Cephalalgia. 2010;30(2):207-213.

24. Jonsson P, Hedenrud T, Linde M. Epidemiology of medication overuse headache in the general Swedish population. Cephalalgia. 2011;31(9):1015-1022.

25. Jonsson P, Linde M, Hensing G, Hedenrud T. Sociodemographic differences in medication use, health-care contacts and sickness absence among individuals with medication-overuse headache. J Headache Pain. 2012;13(4):281-290.

26. Linde M, Stovner LJ, Zwart JA, Hagen K. Time trends in the prevalence of headache disorders. The Nord-Trondelag Health Studies (HUNT 2 and HUNT 3). Cephalalgia. 2011;31(5):585-596.

27. Lipton RB, Manack A, Ricci JA, Chee E, Turkel CC, Winner P. Prevalence and burden of chronic migraine in adolescents: results of the chronic daily headache in adolescents study (C-dAS). Headache. 2011;51(5):693-706.

28. Ayzenberg I, Katsarava Z, Sborowski A, et al. The prevalence of primary headache disorders in Russia: a countrywide survey. Cephalalgia. 2012;32(5):373-381.

29. Ertas M, Baykan B, Orhan EK, et al. One-year prevalence and the impact of migraine and tension-type headache in Turkey: a nationwide home-based study in adults. J Headache Pain. 2012;13(2):147-157.

30. Hagen K, Linde M, Steiner TJ, Stovner LJ, Zwart JA. Risk factors for medication-overuse headache: an 11-year follow-up study. The Nord-Trondelag Health Studies. Pain. 2012;153(1):56-61.

31. Yu S, Liu R, Zhao G, et al. The prevalence and burden of primary headaches in China: a population-based door-to-door survey. Headache. 2012;52(4):582-591.

32. Shahbeigi S, Fereshtehnejad SM, Mohammadi N, et al. Epidemiology of headaches in Tehran urban area: a population-based cross-sectional study in district 8, year 2010. Neurol Sci. 2013;34(7):1157-66.

33. Schramm SH, Obermann M, Katsarava Z, Diener HC, Moebus S, Yoon MS. Epidemiological profiles of patients with chronic migraine and chronic tension-type headache. J Headache Pain. 2013;14:40.

34. Park JW, Moon HS, Kim JM, Lee KS, Chu MK. Chronic daily headache in Korea: prevalence, clinical characteristics, medical consultation and management. J Clin Neurol. 2014;10(3):236-243.

35. Kristoffersen ES, Lundqvist C. Medication-overuse headache: epidemiology, diagnosis and treatment. Ther Adv Drug Saf. 2014;5(2):87-99.

36. Steiner TJ, Stovner LJ, Katsarava Z, et al. The impact of headache in Europe: principal results of the Eurolight project. J Headache Pain. 2014;15:31.

37. Westergaard ML, Hansen EH, Glumer C, Jensen RH. Prescription pain medications and chronic headache in Denmark: implications for preventing medication overuse. Eur J Clin Pharmacol. 2015;71(7):851-860.

38. Bravo TP. Headaches of the elderly. Curr Neurol Neurosci Rep. 2015;15(6):30.

39. Mbewe E, Zairemthiama P, Yeh HH, Paul R, Birbeck GL, Steiner TJ. The epidemiology of primary headache disorders in Zambia: a population-based door-to-door survey. J Headache Pain. 2015;16:515.

40. Kulkarni GB, Rao GN, Gururaj G, Stovner LJ, Steiner TJ. Headache disorders and public ill-health in India: prevalence estimates in Karnataka State. J Headache Pain. 2015;16:67.

41. Westergaard ML, Glumer C, Hansen EH, Jensen RH. Medication overuse, healthy lifestyle behaviour and stress in chronic headache: Results from a population-based representative survey. Cephalalgia. 2016;36(1):15-28.

42. Manandhar K, Risal A, Linde M, Steiner TJ. The burden of headache disorders in Nepal: estimates from a population-based survey. J Headache Pain. 2015;17:3.

43. Zebenigus M, Tekle-Haimanot R, Worku DK, Thomas H, Steiner TJ. The prevalence of primary headache disorders in Ethiopia. J Headache Pain. 2016;17(1):110.

44. Al-Hashel JY, Ahmed SF, Alroughani R. Prevalence of Primary Headache Disorders in Kuwait. Neuroepidemiology. 2017;48(3-4):138-146.

45. Rastenyte D, Mickeviciene D, Stovner LJ, Thomas H, Andree C, Steiner TJ. Prevalence and burden of headache disorders in Lithuania and their public-health and policy implications: a population-based study within the Eurolight Project. J Headache Pain. 2017;18(1):53.

46. Henning V, Katsarava Z, Obermann M, Moebus S, Schramm S. Remission of chronic headache: Rates, potential predictors and the role of medication, follow-up results of the German Headache Consortium (GHC) Study. Cephalalgia. 2018;38(3):551-560.

47. Global Burden of Disease Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16(11):877-897.

Following the American Headache Society’s Scottsdale Headache Symposium in November 2018, MedPage Today posted an article which shared differing opinions from Drs. Hans-Christoph Diener and Elizabeth Loder on medication overuse headache (MOH). While Dr. Diener noted that “we can identify people with chronic migraine who are at risk to have medication overuse,” and that following successful withdrawal treatment “the majority of patients…revert to episodic migraine,” Dr. Loder pointed out that while MOH may exist and contribute to chronic migraine, “it is over-emphasized and the evidence in support of these concepts is weak.”

For this article, I’ve asked Drs. Marcelo Bigal, Rob Cowan, Jack Schim, and Stewart J. Tepper to share their perspectives on this topic. I also asked both Dr. Diener and Dr. Loder to expand on their comments. We will see Dr. Diener’s response to the article, but we did not hear back from Dr. Loder. Lastly, I will weigh in on the MOH discussion.
 

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

The issue of medication overuse headache (MOH) needs to be disentangled into a few separate but related issues. First, do excessive medications make migraine worse? Second, should MOH be considered a distinct form of headache? And how can evidence inform clinical practice?

Robust evidence supports the fact that excessive acute medication use is associated with increased headache frequency among migraineurs. In a large epidemiological study, we demonstrated that exposure (medication) precedes outcome (increased headache frequency).¹ The risk was higher for barbiturates, followed by opioids and triptans, and was not increased by nonsteroidal anti-inflammatory drugs (NSAIDs). Dose response and critical exposure levels were identified. Based on this study and several others, we argued that criteria of causality had been demonstrated beyond reasonable doubt.²

However, since the effect is specific to migraine in that the exposure only increases the risk in migraineurs, not in individuals with other types of pain, we do not consider MOH a distinct entity. Instead, we believe that excessive medication is a risk factor for chronic migraine (CM). Therefore, we should be able to subdivide CM into 2 groups, one with and one without excessive medication use.

From a clinical perspective, physicians should monitor acute medication consumption in individuals with migraine and should be liberal in starting preventive therapy. In those with CM and excessive acute medication use we don’t advocate abrupt discontinuation of acute medications, since some preventive medications, especially the newer anti-calcitonin gene-related peptide (CGRP) antibodies, seem to work equally well in individuals with and without excessive use of medication,³ allowing more natural and gradual control of acute medication consumption without the need for detoxification.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

As is often the case when 2 smart people take artificially imposed opposite positions, the truth will lie somewhere in the middle. I doubt either of the debaters would argue either extreme position: MOH does not exist, or MOH when present is solely responsible for chronic daily headache (CDH). The argument that the absence of controlled studies negates the proposition fails the common-sense test: Without a controlled study, we can’t be sure that wearing a helmet when bicycling is better than not. In such a case, observational data is sufficient. Could there be confounders (eg, helmet wearers are more inclined to ride safely)? Of course, but is that important? Similarly, does the fact that some MOH patients continue with CDH after cessation of medication overuse warrant a general de-emphasis? Certainly not for the third-to-half of patients who benefit from limiting medication use.

I suspect both Drs. Diener and Loder would agree that we would benefit from better markers of chronification and that earlier intervention with at-risk patients (eg, patients with increasing headache frequency, severity or duration but still in the episodic phase).

Jack Schim, MD
Co-Director, The Headache Center of Southern California

There has long been recognition that overuse of analgesic medications can be linked to progression of headache disorders. MOH was initially described by Dr. Lee Kudrow in 1982, in a chapter entitled, “Paradoxical effects of frequent analgesic use.”⁴ The most recent edition of the International Classification of Headache Disorders (ICHD-3) description does not entail features that imply causality. While there is epidemiologic observation of correlation between frequent analgesic use and progression of primary headache disorders, the causal relationship is often obscured by the facts. Overuse of acute medications is quite common in individuals with CM, but not all with CM overuse medications.

In the article being discussed, Drs. Diener and Loder reviewed facts and opinions. They helped clarify that while MOH is widely recognized, much of what is known is descriptive, and not based on solid science. From their presentations, we can conclude that we can recognize MOH based on ICHD-3 criteria, but we cannot tell an individual with chronic headache whether we can best help them by educating them, or by adjusting preventives, or both. The call to action is clear; we need to evaluate best therapeutic approaches in an empiric fashion. Our best new therapies for migraine prevention, CGRP mAbs, work for the majority of patients, with minimal side effects, even in the face of what has been considered MOH. Now, we need to strategize how best to approach these clinically challenged individuals. We need to avoid further stigmatizing our patients. Let’s recognize that our patients do not fail preventives, the prior preventives have failed our patients. Can the introduction of highly effective, well tolerated preventives at an earlier stage help avoid chronification that may drive medication overuse?

Stewart J. Tepper, MD, FAHS
Professor of Neurology, Geisel School of Medicine at Dartmouth

It is clear that overuse of some acute medication is detrimental to patient health. Examples of this include analgesic nephropathy or peptic ulcer disease, and exacerbation of depression with overuse of barbiturate compounds or benzodiazepines. Few doubt the health merits of reduction of acute medication overuse, regardless of whether the acute medications can be proven to transform episodic migraine (EM) to CM.

The good news is that the issues of the existence of true MOH and its proper management are rapidly becoming less important. OnabotulinumtoxinA use decreases triptan use in multiple randomized controlled trials for CM prevention.

Each of the anti-CGRP and anti-CGRP receptor monoclonal antibodies (mAbs) have been effective in preventing CM with medication overuse. All have lowered acute medication use, both triptans and analgesics. It is worth noting, however, that in both the OnabotulinumtoxinA and mAb trials, over-users of opioids and barbiturates were excluded. The mAbs converted patients from acute medication overuse to non-overuse, and from CM with medication overuse to EM without medication. These changes occurred without specific plans for weaning acute medication in place.

Accordingly, patients with CM with acute medication overuse should be treated with optimal prevention, and the evidence is strongest for use of the mAbs to both reduce mean monthly migraine days and all acute medication use, both triptans and analgesics. The new monoclonal antibody effectiveness may make the old arguments moot.

Hans-Christoph Diener, MD, PhD
University of Essen, Germany

I think no one doubts that MOH exists. The worldwide prevalence is between 1% and 2% (Table). The dilemma is that the diagnosis can only be made after the intake of acute medication has been reduced. There are confounders: migraine can improve irrespective of the reduction of acute medication and many physicians will implement migraine prevention at the time of withdrawal. No randomized trial compared the continuation of unchanged intake of medication to treat migraine attacks with reduction or withdrawal.

+++

Commentary by Alan M. Rapoport, MD

The above comments by my associates are very informative and help the reader to better understand the arguments about MOH. When Dr. Lee Kudrow taught me and my partner Dr. Fred Sheftell about the entity of analgesic and ergotamine overuse headaches in 1979, we set out to find those patients, observe and treat them. We did not have to wait long as so many patients with frequent and severe headaches came to see us with what we now term “medication overuse headache.” They told us that they had fewer headaches several years before and increased the use of acute care medications as their headaches increased in frequency. They were unaware of the probability that their headaches increased in frequency because their medication did. Some would argue that they increased their intake to feel better as the headache increased on their own.

Of course, we were not sure of the cause and effect, but we saw the result of tapering the acute care medications, whether or not we used preventives, hospitalized those patients or treated them with behavioral medicine approaches, etc. We observed that the combination of these treatments seemed to work better than just detox, but we did not do the proper studies to prove it. We also noticed that about 30% to 40% of patients did not improve as well as others, and daily or near-daily headaches continued, often of a lesser intensity. Almost all felt better in general and had fewer adverse events from the medication. The decrease in those medications was undoubtedly better for their brain function, livers and kidneys.

I do believe that medication overuse makes most patients with frequent EM or CM worse and we should educate patients to avoid it. I agree with Dr. Bigal that preventive medications may help some patients to improve despite the excessive use of acute care medication, but I am not sure that the older preventives work as well and certainly not as quickly as the newer ones. Recently I have seen the anti-CGRP mAbs work wonders with some of my patients who could not decrease their triptan intake. They just stop using the triptans as their headaches decrease on these therapies.

There is another interesting phenomenon that I have seen in practice—mostly with butalbital products, which I no longer prescribe. Forty years ago, patients would say that they only had 4 headaches per month lasting 1 to 2 days and I would prescribe 10 pills for them. They would call in 2 weeks and say they needed more. When queried they would invariably say it worked so well on the bad headaches and made them feel so much better, that they took 1 or 2 on days they thought they were going to get a headache and it prevented them from forming. They were soon taking it frequently and over time they were dependent on the medication, and then it stopped working and was difficult to withdraw.

Dr. Loder’s point that the studies on MOH have not proven that medication overuse causes it may be technically true; but it would be unethical to start patients on too much medication and randomize some to stay on and some to taper off. Dr. Kudrow came the closest by taking existing MOH patients and treating half with withdrawal and half of each with preventives. His breakthrough study in 1982 “proved” the existence of analgesic rebound and directed us to the best treatment at that time.⁴ This was the first study to examine the effect of stopping the overuse of medication to see the results.

Finally, I am unhappy that ICHD-3 has defined MOH only by number of days of medication use, not at all considering whether or not the patient develops a new type of headache, a worse type or more frequent headache (the way it was in previous versions). We have all seen patients taking 3 triptans per day on their own or with our suggestion, and many actually do better with no headache, for a period of time. This is medication overuse by definition, but not MOH, as they have little headache. But we do not recognize this entity.

The good news is, with education and anti-CGRP therapies, we will probably see less MOH in the future, or at least know better how to treat it.

+++

References

1. Bigal ME, Serrano D, Buse D, et al. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48(8):1157-68. doi: 10.1111/j.1526-4610.2008.01217.x. PubMed PMID: 18808500.

2. Bigal ME, Lipton RB. Overuse of acute migraine medications and migraine chronification. Curr Pain Headache Rep. 2009;13(4):301-7. PubMed PMID: 19586594.

3. Bigal ME, Edvinsson L, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14(11):1091-100. doi: 10.1016/S1474-4422(15)00245-8. PubMed PMID: 26432181.

4. Kudrow L. Paradoxical Effects of Frequent Analgesic Use. Advances in Neurology. 1982;33:335-341.

5. Diener HC, Holle D, Dresler T, Gaul C. Chronic Headache Due to Overuse of Analgesics and Anti-Migraine Agents. Dtsch Arztebl Int. 2018;115(22):365-370.

6. Westergaard ML, Glumer C, Hansen EH, Jensen RH. Prevalence of chronic headache with and without medication overuse: associations with socioeconomic position and physical and mental health status. Pain. 2014;155(10):2005-2013.

7. Castillo J, Munoz P, Guitera V, Pascual J. Epidemiology of chronic daily headache in the general population. Headache. 1999;39:190-196.

8. Wang SJ, Fuh JL, Lu SR, et al. Chronic daily headache in chinese elderly - prevalence, risk factors, and biannual follow-up. Neurology. 2000;54:314-319.

9. Lu SR, Fuh JL, Chen WT, Juang KD, Wang SJ. Chronic daily headache in Taipei, Taiwan: prevalence, follow-up and outcome predictors. Cephalalgia. 2001;21:980-986.

10. Pascual J, Colas R, Castillo J. Epidemiology of chronic daily headache. Curr Pain Headache Rep. 2001;5(6):529-536.

11. Prencipe M, Casini AR, Ferretti C, et al. Prevalence of headache in an elderly population: attack frequency, disability, and use of medication. J Neurol Neurosurg Psychiatry. 2001;70(3):377-381.

12. Colas R, Munoz P, Temprano R, Gomez C, Pascual J. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Neurology. 2004;62:1338-1342.

13. Zwart J, Dyb G, Hagen K, Svebak S, Stovner L, Holmen J. Analgesic overuse among subjects with headache, neck, and low back pain. Neurology. 2004;62:1540-1544.

14. Dyb G, Holmen TL, Zwart JA. Analgesic overuse among adolescents with headache: the Head-HUNT-Youth Study. Neurology. 2006;66(2):198-201.

15. Wang SJ, Fuh JL, Lu SR, Juang KD. Chronic daily headache in adolescents: prevalence, impact, and medication overuse. Neurology. 2006;66(2):193-197.

16. Wiendels NJ, Knuistingh NA, Rosendaal FR, et al. Chronic frequent headache in the general population: prevalence and associated factors. Cephalalgia. 2006;26(12):1434-1442.

17. Stovner L, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27(3):193-210.

18. Aaseth K, Grande RB, Kvaerner KJ, Gulbrandsen P, Lundqvist C, Russell MB. Prevalence of secondary chronic headaches in a population-based sample of 30-44-year-old persons. The Akershus study of chronic headache. Cephalalgia. 2008;28(7):705-713.

19. Aaseth K, Grande RB, Lundqvist C, Russell MB. What is chronic headache in the general population? The Akershus study of chronic headache. Acta Neurol Scand Suppl. 2009;(189):30-32.

20. Rueda-Sanchez M, Diaz-Martinez LA. Prevalence and associated factors for episodic and chronic daily headache in the Colombian population. Cephalalgia. 2008;28(3):216-225.

21. Katsarava Z, Dzagnidze A, Kukava M, et al. Primary headache disorders in the Republic of Georgia: prevalence and risk factors. Neurology. 2009;73(21):1796-1803.

22. da Silva A, Jr., Costa EC, Gomes JB, et al. Chronic headache and comorbidities: a two-phase, population-based, cross-sectional study. Headache. 2010;50(8):1306-1312.

23. Straube A, Pfaffenrath V, Ladwig KH, et al. Prevalence of chronic migraine and medication overuse headache in Germany--the German DMKG headache study. Cephalalgia. 2010;30(2):207-213.

24. Jonsson P, Hedenrud T, Linde M. Epidemiology of medication overuse headache in the general Swedish population. Cephalalgia. 2011;31(9):1015-1022.

25. Jonsson P, Linde M, Hensing G, Hedenrud T. Sociodemographic differences in medication use, health-care contacts and sickness absence among individuals with medication-overuse headache. J Headache Pain. 2012;13(4):281-290.

26. Linde M, Stovner LJ, Zwart JA, Hagen K. Time trends in the prevalence of headache disorders. The Nord-Trondelag Health Studies (HUNT 2 and HUNT 3). Cephalalgia. 2011;31(5):585-596.

27. Lipton RB, Manack A, Ricci JA, Chee E, Turkel CC, Winner P. Prevalence and burden of chronic migraine in adolescents: results of the chronic daily headache in adolescents study (C-dAS). Headache. 2011;51(5):693-706.

28. Ayzenberg I, Katsarava Z, Sborowski A, et al. The prevalence of primary headache disorders in Russia: a countrywide survey. Cephalalgia. 2012;32(5):373-381.

29. Ertas M, Baykan B, Orhan EK, et al. One-year prevalence and the impact of migraine and tension-type headache in Turkey: a nationwide home-based study in adults. J Headache Pain. 2012;13(2):147-157.

30. Hagen K, Linde M, Steiner TJ, Stovner LJ, Zwart JA. Risk factors for medication-overuse headache: an 11-year follow-up study. The Nord-Trondelag Health Studies. Pain. 2012;153(1):56-61.

31. Yu S, Liu R, Zhao G, et al. The prevalence and burden of primary headaches in China: a population-based door-to-door survey. Headache. 2012;52(4):582-591.

32. Shahbeigi S, Fereshtehnejad SM, Mohammadi N, et al. Epidemiology of headaches in Tehran urban area: a population-based cross-sectional study in district 8, year 2010. Neurol Sci. 2013;34(7):1157-66.

33. Schramm SH, Obermann M, Katsarava Z, Diener HC, Moebus S, Yoon MS. Epidemiological profiles of patients with chronic migraine and chronic tension-type headache. J Headache Pain. 2013;14:40.

34. Park JW, Moon HS, Kim JM, Lee KS, Chu MK. Chronic daily headache in Korea: prevalence, clinical characteristics, medical consultation and management. J Clin Neurol. 2014;10(3):236-243.

35. Kristoffersen ES, Lundqvist C. Medication-overuse headache: epidemiology, diagnosis and treatment. Ther Adv Drug Saf. 2014;5(2):87-99.

36. Steiner TJ, Stovner LJ, Katsarava Z, et al. The impact of headache in Europe: principal results of the Eurolight project. J Headache Pain. 2014;15:31.

37. Westergaard ML, Hansen EH, Glumer C, Jensen RH. Prescription pain medications and chronic headache in Denmark: implications for preventing medication overuse. Eur J Clin Pharmacol. 2015;71(7):851-860.

38. Bravo TP. Headaches of the elderly. Curr Neurol Neurosci Rep. 2015;15(6):30.

39. Mbewe E, Zairemthiama P, Yeh HH, Paul R, Birbeck GL, Steiner TJ. The epidemiology of primary headache disorders in Zambia: a population-based door-to-door survey. J Headache Pain. 2015;16:515.

40. Kulkarni GB, Rao GN, Gururaj G, Stovner LJ, Steiner TJ. Headache disorders and public ill-health in India: prevalence estimates in Karnataka State. J Headache Pain. 2015;16:67.

41. Westergaard ML, Glumer C, Hansen EH, Jensen RH. Medication overuse, healthy lifestyle behaviour and stress in chronic headache: Results from a population-based representative survey. Cephalalgia. 2016;36(1):15-28.

42. Manandhar K, Risal A, Linde M, Steiner TJ. The burden of headache disorders in Nepal: estimates from a population-based survey. J Headache Pain. 2015;17:3.

43. Zebenigus M, Tekle-Haimanot R, Worku DK, Thomas H, Steiner TJ. The prevalence of primary headache disorders in Ethiopia. J Headache Pain. 2016;17(1):110.

44. Al-Hashel JY, Ahmed SF, Alroughani R. Prevalence of Primary Headache Disorders in Kuwait. Neuroepidemiology. 2017;48(3-4):138-146.

45. Rastenyte D, Mickeviciene D, Stovner LJ, Thomas H, Andree C, Steiner TJ. Prevalence and burden of headache disorders in Lithuania and their public-health and policy implications: a population-based study within the Eurolight Project. J Headache Pain. 2017;18(1):53.

46. Henning V, Katsarava Z, Obermann M, Moebus S, Schramm S. Remission of chronic headache: Rates, potential predictors and the role of medication, follow-up results of the German Headache Consortium (GHC) Study. Cephalalgia. 2018;38(3):551-560.

47. Global Burden of Disease Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16(11):877-897.

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

Neurology Reviews recently shared two poll questions with our Facebook followers about treatment medication overuse headache (MOH). I was very interested to see the results of our poll. While the number of responses was somewhat low, we do get some sense of what respondents are saying. In this commentary, I will first tell you my perspective on the answers and then we will see what some other headache specialists say about the answers to these questions.

Poll Results:
 

Can MOH be treated with preventive medications without detoxification?

33 votes

YES, 39%

NO, 61%

Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor) without detoxification?

26 votes

YES, 38%

NO, 62%

My Commentary:

Let me explain in more detail my thoughts on the first question, “Can MOH be treated with preventive medications without detoxification?”

If a patient had the diagnosis of MOH – meaning 15 or more headache days per month for at least 3 months, with use of stronger medications (triptans, ergots, opiates, butalbital-containing medications) for 10 days per month or milder treatment (aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) for 15 days per month – can they improve by being put on a traditional preventive medication without intentionally reducing their overused acute medications by a detoxification protocol ordered by a doctor or nurse?

Only 39% of our audience said yes. Yet some studies have shown that patients placed on onabotulinumtoxinA or topiramate might improve without them going through a detoxification of the overused medications. As a physician, I would suggest simultaneously decreasing in their acute medications. I think in some cases this approach creates additional improvement and makes the patient feel better. It would be better for their quality of life, as well as for their kidneys and possibly even their brains.

Here are my thoughts on the second question, “Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor), without detoxification?”

If a patient has MOH, can you expect them to improve after being placed on 1 of the 4 monoclonal antibodies to CGRP ligand or its receptor – all of which are either recently approved or currently in development – without suggesting that they decrease their overused acute care medications? Note that erenumab (Aimovig-aaoe) has been approved by the FDA and marketed as of the time of this writing; we expect 2 more products to be approved very soon.

Almost an identical percentage of our audience (38%) said yes. There is evidence in published clinical trials that those patients given these new medications did about as well with or without the presence of MOH, and both groups did better than the placebo patients. Note that most trials prohibited overuse of opiates and butalbital.

I am a firm believer of detoxifying patients from their overused over-the-counter (OTC) or prescription medications. I believe that opiates and butalbital-containing medications, when overused, are worse for patients than OTCs, NSAIDs, ergot and triptans, but all of these can cause MOH. There are many studies showing that both inpatient and outpatient detoxification alone can really help. However, it is difficult to detoxify patients and some refuse to try this approach.

So, what should we do as physicians? If a patient has MOH, I educate them, try to detoxify them slowly on an outpatient basis, and if I feel it will help, start them on a preventive medication, even before the detoxification begins so they can reach therapeutic levels. In the future, will I use one of the standard preventives, approved or off-label, for migraine prevention (beta blockers, topiramate and other anticonvulsants, antidepressants, angiotensin receptor blockers, onabotulinumtoxinA and others)? It remains to be seen. I am leaning towards the anti CGRP ligand and receptor monoclonal antibodies and preventive small molecule oral CGRP receptor blockers. While that might be enough to start with, I will continue explaining to my patients why they should actively begin a slow detoxification.

Let us see what some headache specialists said about both questions.

Robert Cowan, MD, FAAN:

There have been studies that show migraine can improve without the discontinuation of medication overuse. But that is not what the question asks. The question as posed is whether MOH can be treated with a preventive medication without detoxification. Since the diagnosis of MOH has, in the past, required the cessation of overuse leading to an improvement in the underlying headache, then technically, the answer would be “no.” But that being said, there is ample evidence that the number of headache days/months and other measures of headache can, in fact, improve with the introduction of a preventive, along with other measures such as lifestyle modification. The other ambiguity in the question has to do with what is meant by “detoxification.” Is this a hospital-based detox, or is a gradual decrease in the offending medicine in combination with the addition of a preventive, still considered “detoxification?” Also, does the response imply a sequential relationship between the detoxification and initiation of the preventive? Without further clarification, this response ratio to the question is very difficult to interpret.

There is animal data that suggests acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and anti-CGRP antibodies may be useful for the MOH (Cephalalgia. 2017;37(6):560-570. doi: 10.1177/0333102416650702). While there are no published CGRP antibody studies that did not exclude MOH patients to my knowledge, an abstract by Silberstein et al at the recent AHS Scientific Meeting reported decreased use of overused medication with fremanazumab (Headache. 2018;58(S2):76-78).

Ira Turner, MD

There is clear data to suggest that it is not necessary to detoxify these patients before starting preventive therapy. This is true for the older and newer medications. In fact, not only do these preventive therapies still work in the presence of medication overuse, but they also help to reduce medication overuse. The one caveat that must be mentioned is that this may not apply to opiate overuse. Opiate over-users were excluded from these studies.

While it is of course our goal to reduce and stop acute medication overuse, it should not be done at the expense of delaying preventive therapy. In fact, it is desirable to do both simultaneously. This applies to oral preventive medications, botulinum toxin and CGRP monoclonal antibodies.

In view of this well-established data, it was quite surprising to me to see the results of the 2 polls cited. It seems as if we still have a lot of educating to do regarding migraine prevention in general and with medication overuse in migraine in particular.

Stewart Tepper, MD

Dr. Tepper did not have time to comment, but suggested we show you an abstract presented at the recent AHS meeting. It shows that erenumab-aaoe helps patients with MOH who have not been detoxified (Headache. 2018;58(S2):160-162).

###

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, MD

Editor-in-Chief

Migraine Resource Center

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA

Los Angeles, California

Neurology Reviews recently shared two poll questions with our Facebook followers about treatment medication overuse headache (MOH). I was very interested to see the results of our poll. While the number of responses was somewhat low, we do get some sense of what respondents are saying. In this commentary, I will first tell you my perspective on the answers and then we will see what some other headache specialists say about the answers to these questions.

Poll Results:
 

Can MOH be treated with preventive medications without detoxification?

33 votes

YES, 39%

NO, 61%

Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor) without detoxification?

26 votes

YES, 38%

NO, 62%

My Commentary:

Let me explain in more detail my thoughts on the first question, “Can MOH be treated with preventive medications without detoxification?”

If a patient had the diagnosis of MOH – meaning 15 or more headache days per month for at least 3 months, with use of stronger medications (triptans, ergots, opiates, butalbital-containing medications) for 10 days per month or milder treatment (aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) for 15 days per month – can they improve by being put on a traditional preventive medication without intentionally reducing their overused acute medications by a detoxification protocol ordered by a doctor or nurse?

Only 39% of our audience said yes. Yet some studies have shown that patients placed on onabotulinumtoxinA or topiramate might improve without them going through a detoxification of the overused medications. As a physician, I would suggest simultaneously decreasing in their acute medications. I think in some cases this approach creates additional improvement and makes the patient feel better. It would be better for their quality of life, as well as for their kidneys and possibly even their brains.

Here are my thoughts on the second question, “Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor), without detoxification?”

If a patient has MOH, can you expect them to improve after being placed on 1 of the 4 monoclonal antibodies to CGRP ligand or its receptor – all of which are either recently approved or currently in development – without suggesting that they decrease their overused acute care medications? Note that erenumab (Aimovig-aaoe) has been approved by the FDA and marketed as of the time of this writing; we expect 2 more products to be approved very soon.

Almost an identical percentage of our audience (38%) said yes. There is evidence in published clinical trials that those patients given these new medications did about as well with or without the presence of MOH, and both groups did better than the placebo patients. Note that most trials prohibited overuse of opiates and butalbital.

I am a firm believer of detoxifying patients from their overused over-the-counter (OTC) or prescription medications. I believe that opiates and butalbital-containing medications, when overused, are worse for patients than OTCs, NSAIDs, ergot and triptans, but all of these can cause MOH. There are many studies showing that both inpatient and outpatient detoxification alone can really help. However, it is difficult to detoxify patients and some refuse to try this approach.

So, what should we do as physicians? If a patient has MOH, I educate them, try to detoxify them slowly on an outpatient basis, and if I feel it will help, start them on a preventive medication, even before the detoxification begins so they can reach therapeutic levels. In the future, will I use one of the standard preventives, approved or off-label, for migraine prevention (beta blockers, topiramate and other anticonvulsants, antidepressants, angiotensin receptor blockers, onabotulinumtoxinA and others)? It remains to be seen. I am leaning towards the anti CGRP ligand and receptor monoclonal antibodies and preventive small molecule oral CGRP receptor blockers. While that might be enough to start with, I will continue explaining to my patients why they should actively begin a slow detoxification.

Let us see what some headache specialists said about both questions.

Robert Cowan, MD, FAAN:

There have been studies that show migraine can improve without the discontinuation of medication overuse. But that is not what the question asks. The question as posed is whether MOH can be treated with a preventive medication without detoxification. Since the diagnosis of MOH has, in the past, required the cessation of overuse leading to an improvement in the underlying headache, then technically, the answer would be “no.” But that being said, there is ample evidence that the number of headache days/months and other measures of headache can, in fact, improve with the introduction of a preventive, along with other measures such as lifestyle modification. The other ambiguity in the question has to do with what is meant by “detoxification.” Is this a hospital-based detox, or is a gradual decrease in the offending medicine in combination with the addition of a preventive, still considered “detoxification?” Also, does the response imply a sequential relationship between the detoxification and initiation of the preventive? Without further clarification, this response ratio to the question is very difficult to interpret.

There is animal data that suggests acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and anti-CGRP antibodies may be useful for the MOH (Cephalalgia. 2017;37(6):560-570. doi: 10.1177/0333102416650702). While there are no published CGRP antibody studies that did not exclude MOH patients to my knowledge, an abstract by Silberstein et al at the recent AHS Scientific Meeting reported decreased use of overused medication with fremanazumab (Headache. 2018;58(S2):76-78).

Ira Turner, MD

There is clear data to suggest that it is not necessary to detoxify these patients before starting preventive therapy. This is true for the older and newer medications. In fact, not only do these preventive therapies still work in the presence of medication overuse, but they also help to reduce medication overuse. The one caveat that must be mentioned is that this may not apply to opiate overuse. Opiate over-users were excluded from these studies.

While it is of course our goal to reduce and stop acute medication overuse, it should not be done at the expense of delaying preventive therapy. In fact, it is desirable to do both simultaneously. This applies to oral preventive medications, botulinum toxin and CGRP monoclonal antibodies.

In view of this well-established data, it was quite surprising to me to see the results of the 2 polls cited. It seems as if we still have a lot of educating to do regarding migraine prevention in general and with medication overuse in migraine in particular.

Stewart Tepper, MD

Dr. Tepper did not have time to comment, but suggested we show you an abstract presented at the recent AHS meeting. It shows that erenumab-aaoe helps patients with MOH who have not been detoxified (Headache. 2018;58(S2):160-162).

###

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, MD

Editor-in-Chief

Migraine Resource Center

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA

Los Angeles, California

Neurology Reviews recently shared two poll questions with our Facebook followers about treatment medication overuse headache (MOH). I was very interested to see the results of our poll. While the number of responses was somewhat low, we do get some sense of what respondents are saying. In this commentary, I will first tell you my perspective on the answers and then we will see what some other headache specialists say about the answers to these questions.

Poll Results:
 

Can MOH be treated with preventive medications without detoxification?

33 votes

YES, 39%

NO, 61%

Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor) without detoxification?

26 votes

YES, 38%

NO, 62%

My Commentary:

Let me explain in more detail my thoughts on the first question, “Can MOH be treated with preventive medications without detoxification?”

If a patient had the diagnosis of MOH – meaning 15 or more headache days per month for at least 3 months, with use of stronger medications (triptans, ergots, opiates, butalbital-containing medications) for 10 days per month or milder treatment (aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) for 15 days per month – can they improve by being put on a traditional preventive medication without intentionally reducing their overused acute medications by a detoxification protocol ordered by a doctor or nurse?

Only 39% of our audience said yes. Yet some studies have shown that patients placed on onabotulinumtoxinA or topiramate might improve without them going through a detoxification of the overused medications. As a physician, I would suggest simultaneously decreasing in their acute medications. I think in some cases this approach creates additional improvement and makes the patient feel better. It would be better for their quality of life, as well as for their kidneys and possibly even their brains.

Here are my thoughts on the second question, “Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor), without detoxification?”

If a patient has MOH, can you expect them to improve after being placed on 1 of the 4 monoclonal antibodies to CGRP ligand or its receptor – all of which are either recently approved or currently in development – without suggesting that they decrease their overused acute care medications? Note that erenumab (Aimovig-aaoe) has been approved by the FDA and marketed as of the time of this writing; we expect 2 more products to be approved very soon.

Almost an identical percentage of our audience (38%) said yes. There is evidence in published clinical trials that those patients given these new medications did about as well with or without the presence of MOH, and both groups did better than the placebo patients. Note that most trials prohibited overuse of opiates and butalbital.

I am a firm believer of detoxifying patients from their overused over-the-counter (OTC) or prescription medications. I believe that opiates and butalbital-containing medications, when overused, are worse for patients than OTCs, NSAIDs, ergot and triptans, but all of these can cause MOH. There are many studies showing that both inpatient and outpatient detoxification alone can really help. However, it is difficult to detoxify patients and some refuse to try this approach.

So, what should we do as physicians? If a patient has MOH, I educate them, try to detoxify them slowly on an outpatient basis, and if I feel it will help, start them on a preventive medication, even before the detoxification begins so they can reach therapeutic levels. In the future, will I use one of the standard preventives, approved or off-label, for migraine prevention (beta blockers, topiramate and other anticonvulsants, antidepressants, angiotensin receptor blockers, onabotulinumtoxinA and others)? It remains to be seen. I am leaning towards the anti CGRP ligand and receptor monoclonal antibodies and preventive small molecule oral CGRP receptor blockers. While that might be enough to start with, I will continue explaining to my patients why they should actively begin a slow detoxification.

Let us see what some headache specialists said about both questions.

Robert Cowan, MD, FAAN:

There have been studies that show migraine can improve without the discontinuation of medication overuse. But that is not what the question asks. The question as posed is whether MOH can be treated with a preventive medication without detoxification. Since the diagnosis of MOH has, in the past, required the cessation of overuse leading to an improvement in the underlying headache, then technically, the answer would be “no.” But that being said, there is ample evidence that the number of headache days/months and other measures of headache can, in fact, improve with the introduction of a preventive, along with other measures such as lifestyle modification. The other ambiguity in the question has to do with what is meant by “detoxification.” Is this a hospital-based detox, or is a gradual decrease in the offending medicine in combination with the addition of a preventive, still considered “detoxification?” Also, does the response imply a sequential relationship between the detoxification and initiation of the preventive? Without further clarification, this response ratio to the question is very difficult to interpret.

There is animal data that suggests acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and anti-CGRP antibodies may be useful for the MOH (Cephalalgia. 2017;37(6):560-570. doi: 10.1177/0333102416650702). While there are no published CGRP antibody studies that did not exclude MOH patients to my knowledge, an abstract by Silberstein et al at the recent AHS Scientific Meeting reported decreased use of overused medication with fremanazumab (Headache. 2018;58(S2):76-78).

Ira Turner, MD

There is clear data to suggest that it is not necessary to detoxify these patients before starting preventive therapy. This is true for the older and newer medications. In fact, not only do these preventive therapies still work in the presence of medication overuse, but they also help to reduce medication overuse. The one caveat that must be mentioned is that this may not apply to opiate overuse. Opiate over-users were excluded from these studies.

While it is of course our goal to reduce and stop acute medication overuse, it should not be done at the expense of delaying preventive therapy. In fact, it is desirable to do both simultaneously. This applies to oral preventive medications, botulinum toxin and CGRP monoclonal antibodies.

In view of this well-established data, it was quite surprising to me to see the results of the 2 polls cited. It seems as if we still have a lot of educating to do regarding migraine prevention in general and with medication overuse in migraine in particular.

Stewart Tepper, MD

Dr. Tepper did not have time to comment, but suggested we show you an abstract presented at the recent AHS meeting. It shows that erenumab-aaoe helps patients with MOH who have not been detoxified (Headache. 2018;58(S2):160-162).

###

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, MD

Editor-in-Chief

Migraine Resource Center

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA

Los Angeles, California