Headache & Migraine

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.

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.

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.

Read more.

This supplement to Neurology Reviews features an interview with Stewart J. Tepper, MD, who reviews promising data on monoclonal antibodies that target calcitonin gene-related peptide (CGRP) and discusses how the introduction of these treatments is benefitting patients with migraine. 

"These medications can manifest very different levels of efficacy, safety, and tolerability than we've ever seen before. What I'm seeing in practice can be jaw-dropping." - Stewart J. Tepper, MD

Read more.

Read more.

This supplement to Neurology Reviews features an interview with Stewart J. Tepper, MD, who reviews promising data on monoclonal antibodies that target calcitonin gene-related peptide (CGRP) and discusses how the introduction of these treatments is benefitting patients with migraine. 

"These medications can manifest very different levels of efficacy, safety, and tolerability than we've ever seen before. What I'm seeing in practice can be jaw-dropping." - Stewart J. Tepper, MD

Read more.

Read more.

This supplement to Neurology Reviews features an interview with Stewart J. Tepper, MD, who reviews promising data on monoclonal antibodies that target calcitonin gene-related peptide (CGRP) and discusses how the introduction of these treatments is benefitting patients with migraine. 

"These medications can manifest very different levels of efficacy, safety, and tolerability than we've ever seen before. What I'm seeing in practice can be jaw-dropping." - Stewart J. Tepper, MD

Read more.

Parental migraine is associated with offspring migraine, with a stronger association for maternal migraine, according to a recent study. Therefore, this may indicate maternal-specific transmission. Researchers utilized data from the HUNT Study, a large, population-based cohort study. Using a cross-sectional design, the sample consisted of 13,731 parents and 8970 offspring. Logistic regression was used to calculate odds ratios with 95% confidence intervals for active migraine and non-migrainous headache in offspring, given active maternal or paternal headache. They found:

• There was a significant association between maternal migraine and offspring migraine (odds ratio 2.76).

• A weaker association was found between paternal migraine and offspring migraine (odds ratio 1.67).

• For non-migrainous headache, there was a significant association between mothers and offspring (odds ratio 1.25), but not between fathers and offspring.

Børte S, Zwart J-A, Stendland SØ, Hagen K, Winsvold BS. Parental migraine in relation to migraine in offspring: Family linkage analyses from the HUNT Study. [Published online ahead of print February 2, 2019]. Cephalalgia. doi:10.1177%2F0333102419828989.

Parental migraine is associated with offspring migraine, with a stronger association for maternal migraine, according to a recent study. Therefore, this may indicate maternal-specific transmission. Researchers utilized data from the HUNT Study, a large, population-based cohort study. Using a cross-sectional design, the sample consisted of 13,731 parents and 8970 offspring. Logistic regression was used to calculate odds ratios with 95% confidence intervals for active migraine and non-migrainous headache in offspring, given active maternal or paternal headache. They found:

• There was a significant association between maternal migraine and offspring migraine (odds ratio 2.76).

• A weaker association was found between paternal migraine and offspring migraine (odds ratio 1.67).

• For non-migrainous headache, there was a significant association between mothers and offspring (odds ratio 1.25), but not between fathers and offspring.

Børte S, Zwart J-A, Stendland SØ, Hagen K, Winsvold BS. Parental migraine in relation to migraine in offspring: Family linkage analyses from the HUNT Study. [Published online ahead of print February 2, 2019]. Cephalalgia. doi:10.1177%2F0333102419828989.

Parental migraine is associated with offspring migraine, with a stronger association for maternal migraine, according to a recent study. Therefore, this may indicate maternal-specific transmission. Researchers utilized data from the HUNT Study, a large, population-based cohort study. Using a cross-sectional design, the sample consisted of 13,731 parents and 8970 offspring. Logistic regression was used to calculate odds ratios with 95% confidence intervals for active migraine and non-migrainous headache in offspring, given active maternal or paternal headache. They found:

• There was a significant association between maternal migraine and offspring migraine (odds ratio 2.76).

• A weaker association was found between paternal migraine and offspring migraine (odds ratio 1.67).

• For non-migrainous headache, there was a significant association between mothers and offspring (odds ratio 1.25), but not between fathers and offspring.

Børte S, Zwart J-A, Stendland SØ, Hagen K, Winsvold BS. Parental migraine in relation to migraine in offspring: Family linkage analyses from the HUNT Study. [Published online ahead of print February 2, 2019]. Cephalalgia. doi:10.1177%2F0333102419828989.

Migraine sufferers exhibited impaired conditioned pain modulation of the nociceptive blink reflex, suggesting a deficiency in inhibition of trigeminal nociception, which may contribute to the development of migraine headaches. This according to a recent study that aimed to assess conditioned pain modulation efficiency in persons with and without migraine headaches. Twenty-three adults with and 32 without a history of migraine headaches participated in the study. Four electrocutaneous stimulations of the supraorbital branch of the left trigeminal nerve were delivered at 150% of an individually determined pain threshold. Conditioned pain modulation was assessed by applying a noxious counterstimulus (forearm ischemia) and delivering 4 more electrocutaneous stimulations. After each stimulation, pain and the nociceptive blink reflex were assessed. Researchers found:

• Participants with and without migraine headaches had similar baseline pain responsivity, without significant differences in pain report or nociceptive blink reflexes.

• Pain report was inhibited by conditioned pain modulation in both the migraine and control groups.

• However, unlike non-migraine controls, participants with migraines did not exhibit an inhibition of nociceptive blink reflexes during the ischemia task.

Williams AE, Miller MM, Bartley EJ, McCabe KM, Kerr KL, Rhudy JL. Impairment of inhibition of trigeminal nociception via conditioned pain modulation in persons with migraine headaches. [Published online ahead of print January 25, 2019]. Pain Med. doi:10.1093/pm/pny305.

Migraine sufferers exhibited impaired conditioned pain modulation of the nociceptive blink reflex, suggesting a deficiency in inhibition of trigeminal nociception, which may contribute to the development of migraine headaches. This according to a recent study that aimed to assess conditioned pain modulation efficiency in persons with and without migraine headaches. Twenty-three adults with and 32 without a history of migraine headaches participated in the study. Four electrocutaneous stimulations of the supraorbital branch of the left trigeminal nerve were delivered at 150% of an individually determined pain threshold. Conditioned pain modulation was assessed by applying a noxious counterstimulus (forearm ischemia) and delivering 4 more electrocutaneous stimulations. After each stimulation, pain and the nociceptive blink reflex were assessed. Researchers found:

• Participants with and without migraine headaches had similar baseline pain responsivity, without significant differences in pain report or nociceptive blink reflexes.

• Pain report was inhibited by conditioned pain modulation in both the migraine and control groups.

• However, unlike non-migraine controls, participants with migraines did not exhibit an inhibition of nociceptive blink reflexes during the ischemia task.

Williams AE, Miller MM, Bartley EJ, McCabe KM, Kerr KL, Rhudy JL. Impairment of inhibition of trigeminal nociception via conditioned pain modulation in persons with migraine headaches. [Published online ahead of print January 25, 2019]. Pain Med. doi:10.1093/pm/pny305.

Migraine sufferers exhibited impaired conditioned pain modulation of the nociceptive blink reflex, suggesting a deficiency in inhibition of trigeminal nociception, which may contribute to the development of migraine headaches. This according to a recent study that aimed to assess conditioned pain modulation efficiency in persons with and without migraine headaches. Twenty-three adults with and 32 without a history of migraine headaches participated in the study. Four electrocutaneous stimulations of the supraorbital branch of the left trigeminal nerve were delivered at 150% of an individually determined pain threshold. Conditioned pain modulation was assessed by applying a noxious counterstimulus (forearm ischemia) and delivering 4 more electrocutaneous stimulations. After each stimulation, pain and the nociceptive blink reflex were assessed. Researchers found:

• Participants with and without migraine headaches had similar baseline pain responsivity, without significant differences in pain report or nociceptive blink reflexes.

• Pain report was inhibited by conditioned pain modulation in both the migraine and control groups.

• However, unlike non-migraine controls, participants with migraines did not exhibit an inhibition of nociceptive blink reflexes during the ischemia task.

Williams AE, Miller MM, Bartley EJ, McCabe KM, Kerr KL, Rhudy JL. Impairment of inhibition of trigeminal nociception via conditioned pain modulation in persons with migraine headaches. [Published online ahead of print January 25, 2019]. Pain Med. doi:10.1093/pm/pny305.

Vestibular migraine (VM) typically affects women in their 40s with a personal and family history of migraine, according to a recent study. Typical ictal symptoms were triggered as well as spontaneous vertigo (associated with photophobia and phonophobia), nausea, aural symptoms, and headache. In addition, interictal vestibular symptoms, comorbid psychiatric disorders, and non‐specific interictal neuro‐otologic findings were common. Researchers evaluated a retrospective chart review of 491 patients seen from August 2014 until March 2018 at a tertiary neurology referral center for vestibular disorders to identify patients fulfilling the 2012 VM criteria. There were 131 patients (105 women) identified; mean age of VM onset was 44.3 (±13.7) years. They found:

• Preceding the onset of vestibular symptoms, most had migraine (57.3%) and motion sickness (61.1%).

• It was common to have a family history of migraine (50.8%) and episodic vestibular symptoms (28.1%).

• Common ictal symptoms were triggered (visually induced and head‐motion) and spontaneous vertigo, accompanied by photophobia and phonophobia (118/131 [90.1%] patients), nausea (105/131 [80.2%] patients), aural symptoms (79/131 [60.3%] patients), and headache (65/131 [49.6%] patients).

• Interictally, many experienced visually induced (116/131 [88.6%] patients), head‐motion (86/131 [65.6%] patients), and persistent (67/131 [51.1%] patients) dizziness.

Beh SC, Masrour S, Smith SV, Friedman DI. The spectrum of vestibular migraine: Clinical features, triggers, and examination findings. [Published online ahead of print February 8, 2019]. Headache. doi:10.1111/head.13484.

Vestibular migraine (VM) typically affects women in their 40s with a personal and family history of migraine, according to a recent study. Typical ictal symptoms were triggered as well as spontaneous vertigo (associated with photophobia and phonophobia), nausea, aural symptoms, and headache. In addition, interictal vestibular symptoms, comorbid psychiatric disorders, and non‐specific interictal neuro‐otologic findings were common. Researchers evaluated a retrospective chart review of 491 patients seen from August 2014 until March 2018 at a tertiary neurology referral center for vestibular disorders to identify patients fulfilling the 2012 VM criteria. There were 131 patients (105 women) identified; mean age of VM onset was 44.3 (±13.7) years. They found:

• Preceding the onset of vestibular symptoms, most had migraine (57.3%) and motion sickness (61.1%).

• It was common to have a family history of migraine (50.8%) and episodic vestibular symptoms (28.1%).

• Common ictal symptoms were triggered (visually induced and head‐motion) and spontaneous vertigo, accompanied by photophobia and phonophobia (118/131 [90.1%] patients), nausea (105/131 [80.2%] patients), aural symptoms (79/131 [60.3%] patients), and headache (65/131 [49.6%] patients).

• Interictally, many experienced visually induced (116/131 [88.6%] patients), head‐motion (86/131 [65.6%] patients), and persistent (67/131 [51.1%] patients) dizziness.

Beh SC, Masrour S, Smith SV, Friedman DI. The spectrum of vestibular migraine: Clinical features, triggers, and examination findings. [Published online ahead of print February 8, 2019]. Headache. doi:10.1111/head.13484.

Vestibular migraine (VM) typically affects women in their 40s with a personal and family history of migraine, according to a recent study. Typical ictal symptoms were triggered as well as spontaneous vertigo (associated with photophobia and phonophobia), nausea, aural symptoms, and headache. In addition, interictal vestibular symptoms, comorbid psychiatric disorders, and non‐specific interictal neuro‐otologic findings were common. Researchers evaluated a retrospective chart review of 491 patients seen from August 2014 until March 2018 at a tertiary neurology referral center for vestibular disorders to identify patients fulfilling the 2012 VM criteria. There were 131 patients (105 women) identified; mean age of VM onset was 44.3 (±13.7) years. They found:

• Preceding the onset of vestibular symptoms, most had migraine (57.3%) and motion sickness (61.1%).

• It was common to have a family history of migraine (50.8%) and episodic vestibular symptoms (28.1%).

• Common ictal symptoms were triggered (visually induced and head‐motion) and spontaneous vertigo, accompanied by photophobia and phonophobia (118/131 [90.1%] patients), nausea (105/131 [80.2%] patients), aural symptoms (79/131 [60.3%] patients), and headache (65/131 [49.6%] patients).

• Interictally, many experienced visually induced (116/131 [88.6%] patients), head‐motion (86/131 [65.6%] patients), and persistent (67/131 [51.1%] patients) dizziness.

Beh SC, Masrour S, Smith SV, Friedman DI. The spectrum of vestibular migraine: Clinical features, triggers, and examination findings. [Published online ahead of print February 8, 2019]. Headache. doi:10.1111/head.13484.

Oxygen is a highly effective treatment for cluster headache with few complications, according to patient survey results published in the February issue of Headache. According to the results, triptans also are highly effective, with some side effects. Newer medications deserve further study, the researchers said.

To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, Stuart M. Pearson, a researcher in the department of psychology at the University of West Georgia in Carrollton, and his coauthors analyzed data from the Cluster Headache Questionnaire. Respondents from more than 50 countries completed the online survey; most were from the United States, the United Kingdom, and Canada. The survey included questions about cluster headache diagnostic criteria and medication effectiveness, complications, and access to medications.

In all, 3,251 subjects participated in the questionnaire, and 2,193 respondents met criteria for the study; 1,604 had cluster headache, and 589 had probable cluster headache. Among the respondents with cluster headache, 68.8% were male, 78.0% had episodic cluster headache, and the average age was 46 years. More than half of respondents reported complete or very effective treatment for triptans (54%) and oxygen (also 54%). The proportion of respondents who reported that ergot derivatives, caffeine or energy drinks, and intranasal ketamine were completely or very effective ranged from 14% to 25%. Patients were less likely to report high levels of efficacy for opioids (6%), intranasal capsaicin (5%), and intranasal lidocaine (2%).

Participants experienced few complications from oxygen, with 99% reporting no or minimal physical and medical complications, and 97% reporting no or minimal psychological and emotional complications. Patients also reported few complications from intranasal lidocaine, intranasal ketamine, intranasal capsaicin, and caffeine and energy drinks. For triptans, 74% of respondents reported no or minimal physical and medical complications, and 85% reported no or minimal psychological and emotional complications.

Among the 139 participants with cluster headache who were aged 65 years or older, responses were similar to those for the entire population. In addition, the 589 respondents with probable cluster headache reported similar efficacy data, compared with respondents with a full diagnosis of cluster headache.

“Oxygen in particular had a high rate of complete effectiveness, a low rate of ineffectiveness, and a low rate of physical, medical, emotional, and psychological side effects,” the investigators said. “However, respondents reported that it was difficult to obtain.”

Limited insurance coverage of oxygen may affect access, even though the treatment has a Level A recommendation for the acute treatment of cluster headache in the American Headache Society guidelines, the authors said. Physicians also may pose a barrier. A prior study found that 12% of providers did not prescribe oxygen for cluster headache because they doubted its efficacy or did not know about it. In addition, there may be concerns that the treatment could be a fire hazard in a patient population that has high rates of smoking, the researchers said.

Limitations of the study include the survey’s use of nonvalidated questions, the lack of a formal clinical diagnosis of cluster headache, and the grouping of all triptans, rather than assessing individual triptan medications, such as sumatriptan subcutaneous, alone.

The study received funding from Autonomic Technologies and Clusterbusters. One of the authors has served as a paid consultant to Eli Lilly as a member of the data monitoring committee for clinical trials of galcanezumab for cluster headache and migraine.

This article was updated 3/7/2019.

[email protected]

SOURCE: Pearson SM et al. Headache. 2019 Jan 11. doi: 10.1111/head.13473.

Oxygen is a highly effective treatment for cluster headache with few complications, according to patient survey results published in the February issue of Headache. According to the results, triptans also are highly effective, with some side effects. Newer medications deserve further study, the researchers said.

To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, Stuart M. Pearson, a researcher in the department of psychology at the University of West Georgia in Carrollton, and his coauthors analyzed data from the Cluster Headache Questionnaire. Respondents from more than 50 countries completed the online survey; most were from the United States, the United Kingdom, and Canada. The survey included questions about cluster headache diagnostic criteria and medication effectiveness, complications, and access to medications.

In all, 3,251 subjects participated in the questionnaire, and 2,193 respondents met criteria for the study; 1,604 had cluster headache, and 589 had probable cluster headache. Among the respondents with cluster headache, 68.8% were male, 78.0% had episodic cluster headache, and the average age was 46 years. More than half of respondents reported complete or very effective treatment for triptans (54%) and oxygen (also 54%). The proportion of respondents who reported that ergot derivatives, caffeine or energy drinks, and intranasal ketamine were completely or very effective ranged from 14% to 25%. Patients were less likely to report high levels of efficacy for opioids (6%), intranasal capsaicin (5%), and intranasal lidocaine (2%).

Participants experienced few complications from oxygen, with 99% reporting no or minimal physical and medical complications, and 97% reporting no or minimal psychological and emotional complications. Patients also reported few complications from intranasal lidocaine, intranasal ketamine, intranasal capsaicin, and caffeine and energy drinks. For triptans, 74% of respondents reported no or minimal physical and medical complications, and 85% reported no or minimal psychological and emotional complications.

Among the 139 participants with cluster headache who were aged 65 years or older, responses were similar to those for the entire population. In addition, the 589 respondents with probable cluster headache reported similar efficacy data, compared with respondents with a full diagnosis of cluster headache.

“Oxygen in particular had a high rate of complete effectiveness, a low rate of ineffectiveness, and a low rate of physical, medical, emotional, and psychological side effects,” the investigators said. “However, respondents reported that it was difficult to obtain.”

Limited insurance coverage of oxygen may affect access, even though the treatment has a Level A recommendation for the acute treatment of cluster headache in the American Headache Society guidelines, the authors said. Physicians also may pose a barrier. A prior study found that 12% of providers did not prescribe oxygen for cluster headache because they doubted its efficacy or did not know about it. In addition, there may be concerns that the treatment could be a fire hazard in a patient population that has high rates of smoking, the researchers said.

Limitations of the study include the survey’s use of nonvalidated questions, the lack of a formal clinical diagnosis of cluster headache, and the grouping of all triptans, rather than assessing individual triptan medications, such as sumatriptan subcutaneous, alone.

The study received funding from Autonomic Technologies and Clusterbusters. One of the authors has served as a paid consultant to Eli Lilly as a member of the data monitoring committee for clinical trials of galcanezumab for cluster headache and migraine.

This article was updated 3/7/2019.

[email protected]

SOURCE: Pearson SM et al. Headache. 2019 Jan 11. doi: 10.1111/head.13473.

Oxygen is a highly effective treatment for cluster headache with few complications, according to patient survey results published in the February issue of Headache. According to the results, triptans also are highly effective, with some side effects. Newer medications deserve further study, the researchers said.

To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, Stuart M. Pearson, a researcher in the department of psychology at the University of West Georgia in Carrollton, and his coauthors analyzed data from the Cluster Headache Questionnaire. Respondents from more than 50 countries completed the online survey; most were from the United States, the United Kingdom, and Canada. The survey included questions about cluster headache diagnostic criteria and medication effectiveness, complications, and access to medications.

In all, 3,251 subjects participated in the questionnaire, and 2,193 respondents met criteria for the study; 1,604 had cluster headache, and 589 had probable cluster headache. Among the respondents with cluster headache, 68.8% were male, 78.0% had episodic cluster headache, and the average age was 46 years. More than half of respondents reported complete or very effective treatment for triptans (54%) and oxygen (also 54%). The proportion of respondents who reported that ergot derivatives, caffeine or energy drinks, and intranasal ketamine were completely or very effective ranged from 14% to 25%. Patients were less likely to report high levels of efficacy for opioids (6%), intranasal capsaicin (5%), and intranasal lidocaine (2%).

Participants experienced few complications from oxygen, with 99% reporting no or minimal physical and medical complications, and 97% reporting no or minimal psychological and emotional complications. Patients also reported few complications from intranasal lidocaine, intranasal ketamine, intranasal capsaicin, and caffeine and energy drinks. For triptans, 74% of respondents reported no or minimal physical and medical complications, and 85% reported no or minimal psychological and emotional complications.

Among the 139 participants with cluster headache who were aged 65 years or older, responses were similar to those for the entire population. In addition, the 589 respondents with probable cluster headache reported similar efficacy data, compared with respondents with a full diagnosis of cluster headache.

“Oxygen in particular had a high rate of complete effectiveness, a low rate of ineffectiveness, and a low rate of physical, medical, emotional, and psychological side effects,” the investigators said. “However, respondents reported that it was difficult to obtain.”

Limited insurance coverage of oxygen may affect access, even though the treatment has a Level A recommendation for the acute treatment of cluster headache in the American Headache Society guidelines, the authors said. Physicians also may pose a barrier. A prior study found that 12% of providers did not prescribe oxygen for cluster headache because they doubted its efficacy or did not know about it. In addition, there may be concerns that the treatment could be a fire hazard in a patient population that has high rates of smoking, the researchers said.

Limitations of the study include the survey’s use of nonvalidated questions, the lack of a formal clinical diagnosis of cluster headache, and the grouping of all triptans, rather than assessing individual triptan medications, such as sumatriptan subcutaneous, alone.

The study received funding from Autonomic Technologies and Clusterbusters. One of the authors has served as a paid consultant to Eli Lilly as a member of the data monitoring committee for clinical trials of galcanezumab for cluster headache and migraine.

This article was updated 3/7/2019.

[email protected]

SOURCE: Pearson SM et al. Headache. 2019 Jan 11. doi: 10.1111/head.13473.

In a population of obese adults in the United States, migraineurs showed greater total health care utilization and expenses than non-migraineurs, a recent study found. Therefore, treatment plans that address risk factors associated with migraine and comorbidities may help reduce the utilization of health care services and costs. This 7-year retrospective study used longitudinal panel data from 2006 to 2013 from the Household Component of the Medical Expenditure Panel Survey to identify obese adults reporting migraines. Outcomes compared in migraineurs versus non-migraineurs were as follows: annualized per-person medical care, prescription drug, and total health expenses. Researchers found:

• In 23,596 obese adults, 4.7% reported migraine (n=1025) approximating 3 million civilian non-institutionalized individuals in the United States.
• Logistic regression showed that the following sociodemographic characteristics increased migraine risk: age (18–45 years), females, white race, poor perceived health status, and greater Charlson comorbidity index.
• Migraineurs showed $1401, $813, and $2213 greater annual medical, prescription drug, and total health expenses than non-migraineurs, respectively.
• After adjustment, total health expenses increased by 31.6% in migraineurs versus non-migraineurs.

Wu J, Davis-Ajami ML, Lu ZK. Impact of migraine on health care utilization and expenses in obese adults: A US population-based study. [Published online ahead of print December 31, 2018]. Clinicoecon Outcomes Res. doi:10.2147/CEOR.S189699.

In a population of obese adults in the United States, migraineurs showed greater total health care utilization and expenses than non-migraineurs, a recent study found. Therefore, treatment plans that address risk factors associated with migraine and comorbidities may help reduce the utilization of health care services and costs. This 7-year retrospective study used longitudinal panel data from 2006 to 2013 from the Household Component of the Medical Expenditure Panel Survey to identify obese adults reporting migraines. Outcomes compared in migraineurs versus non-migraineurs were as follows: annualized per-person medical care, prescription drug, and total health expenses. Researchers found:

• In 23,596 obese adults, 4.7% reported migraine (n=1025) approximating 3 million civilian non-institutionalized individuals in the United States.
• Logistic regression showed that the following sociodemographic characteristics increased migraine risk: age (18–45 years), females, white race, poor perceived health status, and greater Charlson comorbidity index.
• Migraineurs showed $1401, $813, and $2213 greater annual medical, prescription drug, and total health expenses than non-migraineurs, respectively.
• After adjustment, total health expenses increased by 31.6% in migraineurs versus non-migraineurs.

Wu J, Davis-Ajami ML, Lu ZK. Impact of migraine on health care utilization and expenses in obese adults: A US population-based study. [Published online ahead of print December 31, 2018]. Clinicoecon Outcomes Res. doi:10.2147/CEOR.S189699.

In a population of obese adults in the United States, migraineurs showed greater total health care utilization and expenses than non-migraineurs, a recent study found. Therefore, treatment plans that address risk factors associated with migraine and comorbidities may help reduce the utilization of health care services and costs. This 7-year retrospective study used longitudinal panel data from 2006 to 2013 from the Household Component of the Medical Expenditure Panel Survey to identify obese adults reporting migraines. Outcomes compared in migraineurs versus non-migraineurs were as follows: annualized per-person medical care, prescription drug, and total health expenses. Researchers found:

• In 23,596 obese adults, 4.7% reported migraine (n=1025) approximating 3 million civilian non-institutionalized individuals in the United States.
• Logistic regression showed that the following sociodemographic characteristics increased migraine risk: age (18–45 years), females, white race, poor perceived health status, and greater Charlson comorbidity index.
• Migraineurs showed $1401, $813, and $2213 greater annual medical, prescription drug, and total health expenses than non-migraineurs, respectively.
• After adjustment, total health expenses increased by 31.6% in migraineurs versus non-migraineurs.

Wu J, Davis-Ajami ML, Lu ZK. Impact of migraine on health care utilization and expenses in obese adults: A US population-based study. [Published online ahead of print December 31, 2018]. Clinicoecon Outcomes Res. doi:10.2147/CEOR.S189699.