Experts Weigh in on Medication Overuse Headache

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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.

Table. Summary of studies evaluating the prevalence of medication overuse headache by publication year and country^5,6
Author (year) (reference)	Country	Age Group	Prevalence of MOH
Castillo et al. (1999)⁷	Spain	≥ 14	1,2%
Wang et al. (2000)⁸	Taiwan	≥ 65	1,0%
Lu et al. (2001)⁹	Taiwan	≥ 15	1,1%
Pascual et al. (2001)¹⁰	Review		1,0-1,9%
Prencipe et al. (2001)¹¹	France	≥ 65	1,7%
Colas et al. (2004)¹²	Spain	≥ 14	1,5%
Zwart et al. (2004)¹³	Norway	≥ 20	0,9-1,0%
Dyb et al. (2006)¹⁴	Norway	13-18	0,2%
Wang et al. (2006)¹⁵	Taiwan	12-14	0,3%
Wiendels (2006)¹⁶	Netherlands	25-55	2,6%
Stovner et al.(2007)¹⁷	Review		0,5-1,0%
Aaseth et al. (2008, 2009)^18,19	Norway	30-44	1,7%
Rueda-Sanchez & Diaz-Martinez (2008)²⁰	Columbia	18-65	4,5%
Katsarava et al. (2009)²¹	Georgia	≥ 16	0,9%
Da Silva et al. (2009)²²	Brazil	10-93	1,6%
Straube et al. (2010)²³	Germany	18-88	1,0%
Jonsson et al. (2011, 2012)^24,25	Sweden	≥ 15	1,8%
Linde et al. (2011)²⁶	Norway	≥ 20	1,0%
Lipton et al. (2011)²⁷	USA	12-17	1,0%
Ayzenberg et al. (2012)²⁸	Russia	18-65	7,2%
Ertas et al. (2012)²⁹	Turkey	18-65	2,1%
Hagen et al. (2012)³⁰	Norway	≥ 20	0,8%
Yu et al. (2012)³¹	China	18-65	0,9%
Shahbeigi et al. (2013)³²	Iran	≥ 10	4,9%
Schramm et al. (2013)³³	Germany	18-65	0,7%
Park et al. (2014)³⁴	South Korea	19-69	0,5%
Kristoffersen & Lundqvist (2014)³⁵	Multinational summary		1,0-2,0%
Steiner (2014)³⁶	Multinational summary		1,0-2,0%
Westergaard et al. (2015)³⁷	Denmark		0,5-7,2%
Bravo (2015)³⁸	Multinational	Older	1,0-7,1%
Mbewe et al. (2015)³⁹	Zambia	18-65	12,7% (adj. 7,1%)
Kulkarni et al. (2015)⁴⁰	India	18-65	1,2%
Westergaard et al. (2016)⁴¹	Denmark	≥ 16	1,6% (adj. 1,8%)
Manandhar et al. (2016)⁴²	Nepal	18-65	2,2%
Zebenigus et al. (2016)⁴³	Ethiopia	18-65	0,8% (adj. 0,7%)
Al-Hashel et al. (2017)⁴⁴	Kuwait	18-65	2,4%
Rastenyte et al. (2017)⁴⁵	Lithuania	18-65	3,5% (adj. 3,2%)
Henning et al. (2018)⁴⁶	Germany	18-65	0,7%
Global Burden of Disease 2017⁴⁷	Global		0,8%

+++

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.⁴This was the first study to examine the effect of stopping the overuse of medication to see the results.

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

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

+++

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