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September 19, 2017; 89 (12) Views & Reviews

Medication overuse headache

An entrenched idea in need of scrutiny

Ann I. Scher, Paul B. Rizzoli, Elizabeth W. Loder
First published August 18, 2017, DOI: https://doi.org/10.1212/WNL.0000000000004371
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Abstract

It is a widely accepted idea that medications taken to relieve acute headache pain can paradoxically worsen headache if used too often. This type of secondary headache is referred to as medication overuse headache (MOH); previously used terms include rebound headache and drug-induced headache. In the absence of consensus about the duration of use, amount, and type of medication needed to cause MOH, the default position is conservative. A common recommendation is to limit treatment to no more than 10 or 15 days per month (depending on medication type) to prevent headache frequency progression. Medication withdrawal is often recommended as a first step in treatment of patients with very frequent headaches. Existing evidence, however, does not provide a strong basis for such causal claims about the relationship between medication use and frequent headache. Observational studies linking treatment patterns with headache frequency are by their nature confounded by indication. Medication withdrawal studies have mostly been uncontrolled and often have high dropout rates. Evaluation of this evidence suggests that only a minority of patients required to limit the use of symptomatic medication may benefit from treatment limitation. Similarly, only a minority of patients deemed to be overusing medications may benefit from withdrawal. These findings raise serious questions about the value of withholding or withdrawing symptom-relieving medications from people with frequent headaches solely to prevent or treat MOH. The benefits of doing so are smaller, and the harms larger, than currently recognized. The concept of MOH should be viewed with more skepticism. Until the evidence is better, we should avoid dogmatism about the use of symptomatic medication. Frequent use of symptom-relieving headache medications should be viewed more neutrally, as an indicator of poorly controlled headaches, and not invariably a cause.

GLOSSARY

CVD=
cardiovascular disease;
ICHD=
International Classification of Headache Disorders;
MOH=
medication overuse headache;
PCORI=
Patient-Centered Outcomes Research Institute

It is a widely accepted idea that medications taken to relieve headache pain can paradoxically worsen headache when used too often. This concept of medication overuse headache (MOH) is embedded in diagnostic criteria and is extensively reflected in guidelines, treatment recommendations, and proposed quality standards for headache care,1,–,4 and ultimately disseminated to the general public at patient-oriented websites.5,–,8

In the absence of consensus about the duration of use, amount, and type of medication needed to cause MOH, the default position is conservative. Most pain medications, including acetaminophen and aspirin, are believed to cause it.1,2 Many authorities recommend that symptom-relieving medications should be used no more than 10 or 15 d/mo depending on medication type.1,4

Sometimes called rebound or drug-induced headache, the current version of the International Classification of Headache Disorders (ICHD) defines MOH as headache occurring ≥15 d/mo in a patient with a preexisting headache disorder who has regularly exceeded specific thresholds of symptomatic medication use (table 1). Previous versions required that headache had “developed or markedly worsened” during medication overuse, and resolved or reverted “to its previous pattern within 2 months” of discontinuation.9 These requirements have been eliminated in favor of the presumption that MOH exists if arbitrary thresholds for headache frequency and medication intake are met, while still allowing for physician judgment.1 The authors of the ICHD identify medication overuse as “the most common cause of symptoms suggestive of chronic migraine.”1

View this table:
Table 1

Subtypes of medication overuse headache (MOH) (International Classification of Headache Disorders-3-beta)1

THE SHORTCOMINGS OF EXISTING EVIDENCE

In this Viewpoint, we argue that the well-established dominance of the MOH narrative stands in considerable contrast to the strength of the underlying scientific evidence—evidence that does not meet the standards that are usually applied to other treatments for headache. We argue that the evidence does not provide a strong basis for causal claims about the role of medication overuse in worsening headaches. We discuss harms that result from the incorporation of poorly supported views about MOH into clinical thinking and practice, including stigmatization and undertreatment of pain. Finally, we propose reevaluation of this belief system and make recommendations for future research.

Evidence of cause and effect is weak.

High-quality evidence supporting the existence of MOH is inherently difficult to obtain. A gold standard clinical trial would randomly assign individuals with episodic headaches to overuse or not overuse medication and compare rates of headache progression in the 2 groups. Such a study has not been done nor will it ever be done.

Observational studies provide data related to the natural history of headache frequency as well as describe risk factors that predict headache improvement or worsening. Some of these studies have calculated prevalence or incidence of chronic headache or migraine in individuals who use different types of medication or who take medication above a critical threshold.10,–,13

Only a few such studies are longitudinal, such as that done by Bigal et al.10 In this well-designed population-based study, individuals with episodic migraine were followed for a year. The outcome of chronic migraine was compared among those who used particular types of medication at several levels of frequency. People with episodic migraine who used medication containing opioids or barbiturates were more likely to progress to chronic migraine than the reference group of acetaminophen users after controlling for sex, headache frequency and severity, and preventive medication use. Frequency of medication use by itself was not associated with chronic migraine incidence after controlling for headache frequency, although there was a dose-response relationship for frequency of use of barbiturates. In a separate remission analysis based on the same study population by Manack et al.,14 use of preventives predicted a worse prognosis although this association disappeared after controlling for baseline headache frequency. Frequent medication use, defined as ≥10 days per month of over-the-counter or prescription medication, did not predict remission in crude or adjusted analysis.

Observational studies that show an association between frequency or type of medication used and worsening headache can provide useful prognostic information. They cannot, however, answer the question of whether treatment patterns are a cause or, alternatively, a consequence of frequent headaches—or whether the association is bidirectional. We argue that causal inferences will be threatened by confounding by indication, even when there is control for factors that drive treatment preference or headache occurrence (e.g., baseline headache frequency or important comorbidities such as depression).

Confounding by indication (and the related concepts of confounding by severity or confounding by contraindication) is a concept that is relevant to observational studies that measure or compare the efficacy of different disease therapies.15 Since treatments are not assigned randomly in practice, choice of treatment will be based in part on factors that may be related to how well the patient would have done even without treatment. Factors could include disease severity, previous failed treatments, contraindications, or comorbidities, among others. Thus, if patients with refractory disease are more likely to be prescribed third-line medication A, then treatment A may look worse than other treatments in observational studies even though it may be efficacious. While it is possible to control for known prognostic factors or indications using various adjustment strategies such as propensity score matching,16,–,18 the effectiveness of statistical control always depends on how well-understood (and how well-measured) these other factors are.15 In the present example, the indication (e.g., refractory disease) may have a much larger influence on treatment success than the treatment itself, so it is critically important that the chosen analytic strategy effectively separates the effect of treatment from the effect of the indication for treatment. Relevant examples of observational study results that may be due in part to confounding by indication include the finding that migraineurs who use migraine preventive medications have a worse prognosis than those who do not12,14 and lack of increased risk of incident cardiovascular disease (CVD) in migraineurs who were prescribed triptans compared to migraineurs who were not prescribed triptans.19,20 The confounding would be positive in the first example since the indication for preventives (frequent headaches) is itself a strong risk factor for headache progression. The confounding would be negative in the second example since triptan use is contraindicated in patients with CVD risk factors and therefore patients for whom doctors prescribe triptans would be expected to have a lower risk of CVD than other migraineurs.

The concept of confounding by indication in MOH studies can be illustrated by a simple thought experiment. Suppose the Bigal et al.10/Manack et al.14 studies or a similar observational study had instead been conducted in patients with asthma, and it had been observed that the patients who frequently used symptom-controlling medications had a worse prognosis than others, even after adjusting for all known prognostic variables. Would this level of evidence be sufficient to recommend that patients limit their use of these medications? Is not the more plausible interpretation simply that medication overuse is an indicator of poorly controlled asthma, not a cause of it?21 A number of studies have identified comorbidities and biomarkers that are associated with medication overuse, including genetic polymorphisms as well as electrophysiologic and neuroimaging abnormalities. As with medication overuse itself, however, all of these things may simply be markers of severe or poorly controlled headache conditions.22

We note that many people with frequent headaches are not overusing medication (table 2), and overuse of medication does not invariably produce MOH.10 The authors of a recent systematic review identified 18 population-based studies that reported the prevalence of medication overuse among people with very frequent headache.34 Prevalence estimates based on raw, unadjusted data ranged from 11% to 68%. This illustrates substantial uncertainty about the magnitude of the problem. It also suggests that even if medication overuse produces worsening headache in some people, it is not the only and possibly not even the most frequent cause of chronic headache. Table 2 lists a subset of these studies.

View this table:
Table 2

Selected population-based studies examining the proportion of individuals with chronic daily headache (≥15 headache d/mo) who are overusing medication

Finally, evidence is inconsistent about the association between specific types of symptomatic medications and increased frequency of headaches. The evidence that simple analgesics might produce MOH is especially weak. ICHD criteria allow a diagnosis of MOH to be made in people with frequent headache who are using simple analgesics such as aspirin or ibuprofen 15 or more days per month. Yet in one observational study, headache patients who reported regular use of aspirin or ibuprofen had a decreased risk of headache progression.29 This may be an example of confounding by indication or reverse causality, since patients with very frequent headaches may avoid these medications due to side effects. However, evidence from 2 randomized placebo-controlled trials of daily aspirin showed improvement rather than worsening in migraineurs who were assigned to the aspirin group.35,36 A guideline issued in 2012 by the American Academy of Neurology and the American Headache Society concluded that several nonsteroidal anti-inflammatory drugs, including ibuprofen, naproxen, and ketoprofen, are “probably effective and should be considered for migraine prevention.”37 It is difficult to reconcile this evidence with the widespread belief that regular use of these medications worsens headache.

Four interesting studies have considered whether MOH occurs when pain medications are used for other conditions. The populations evaluated were postcolectomy patients,38 rheumatology patients,39,40 and patients with degenerative musculoskeletal disease.41 Two studies40,41 concluded that there was no association between regular or frequent use of medication for nonheadache pain and the development of chronic headache. The other 2 studies38,39 concluded that frequent analgesic use for nonheadache pain was associated with the development of chronic migraine only in those with a preexisting history of migraine. All 4 studies are small and have important limitations that do not support strong conclusions at this time.

Medication withdrawal does not help most patients with frequent headaches.

Another line of evidence supporting the existence of MOH relates to treatment by withdrawing medications (sometimes referred to as detoxification). If MOH is reversible, then withdrawal of overused medications (alone) should improve headache frequency, yet the evidence it does so is weak. Despite this, the authors of ICHD-3-beta say “the majority” of patients with frequent headaches who meet criteria for MOH will improve after withdrawal.

A systematic review of treatment strategies for MOH evaluated withdrawal alone or with other preventive strategies. The authors of the review concluded, “The level of evidence to support early discontinuation of overused medications alone is low due to the absence of controlled studies.”42 They recommended instead the addition of preventive therapy to the regimens of patients with very frequent headache and presumed MOH.

The 4 withdrawal-only studies identified in this review are listed in table 3 along with 2 relevant studies published after the date range encompassed by the review.43,–,48 The 6 studies used a variety of withdrawal strategies ranging from simple advice to reduce medication intake to inpatient withdrawal. Only one study had a nontreatment control group and none was blinded. Success, usually defined as >50% improvement in headache frequency, was ≤33% in 5 of the 6 studies at the follow-up time period closest to 2–3 months, using intention-to-treat analysis.

View this table:
Table 3

Proportion of patients with presumed medication overuse headache who improved with medication withdrawal as the sole treatment

Intention-to-treat analyses are particularly important in the evaluation of these studies. Some studies show success rates for those patients who complete drug withdrawal treatment, but this can be misleading because many patients do not tolerate drug withdrawal. Patients who cannot or will not tolerate withdrawal are not a random subset of participants. Excluding them when results are calculated inflates estimates of treatment success, because those who remain in treatment are presumably more likely to be placebo responders or patients who would have improved anyway. Improvement in the patients who can tolerate withdrawal is then interpreted incorrectly as evidence that medication withdrawal was effective. Returning to the asthma analogy, this is equivalent to conducting an uncontrolled interventional trial on asthma patients who can tolerate going without rescue inhalers for 2–3 months, and then extrapolating the results to all people with asthma. Reasons for nonparticipation in the 6 studies are described in appendix e-1 at Neurology.org and the reader can evaluate the extent to which exclusion of the dropouts/noncompleters would have led to an overestimate of treatment effectiveness. Our intention-to-treat analysis in table 3 uses the most conservative assumption, which is that those who did not successfully withdraw or were otherwise lost to follow-up were treatment failures.

Given that most studies described in table 3 lacked a control group, we are left to wonder whether a ∼33% response rate is greater than the percentage of patients who might have improved due to natural history, regression to the mean, or nonspecific placebo effects. Some clues can be gleaned from natural history studies and placebo-controlled trials. Headache frequency is highly variable when assessed over multiple time points and a substantial proportion of people with very frequent headaches, probably the majority in the general population at least, will drop below the arbitrary 15 headache days per month threshold at follow-up interviews.14,30,31,49,50

One can also observe response rates in the placebo arms of 4 randomized controlled trials for chronic migraine that reported results for the subgroup with medication overuse (table 4).51,–,54 In these trials, the proportion of MOH patients in the placebo arm who experienced a greater than 50% reduction in headache days over the course of the trial ranged from 0% in 2 small (based on the size of the MOH subgroup) topiramate studies to 30%–32% in the onabotulinumtoxinA trials. In the aggregate, these population and clinical studies illustrate the considerable uncertainty about the course of high-frequency headache and underscore the critical need for rigorous controlled trials before medication withdrawal can be recommended as an effective treatment.

View this table:
Table 4

Medication overuse headache remission in placebo arm of randomized controlled trials of preventive treatments

THE HARMS AND IMPLICATIONS OF AN MOH DIAGNOSIS OR TREATMENT

The harms of an MOH diagnosis or treatment for it have not been well-studied, but deserve consideration. These include (1) unnecessary suffering, (2) blame and stigmatization, and (3) diversion of research and clinical attention.

Suffering.

In the case of a patient with daily headaches—not an uncommon scenario in specialty headache care—ICHD-3-beta criteria suggest that, depending on medication type, MOH should be suspected in patients who treat one-third or one-half of attacks. Limiting treatment for acute attacks to below this level is thought to protect patients from headache frequency progression, although there is no evidence to support this view. In fact, it is plausible that, for most patients with frequent headache, strict medication limitation involves harm from undertreatment of pain and does not result in benefit in terms of reduced frequency. Table 5 shows the hypothetical number of migraine patients who must forgo or limit symptomatic treatment of headaches in order to avoid one case of incident chronic migraine, based on the risk estimates from the observational Bigal et al.10 study. Assuming causality (that is, assuming headache prognosis was solely related to treatment patterns rather than unmeasured confounders or natural history), the hypothetical number needed to undertreat ranges from 3.4 to 4.7 for the high-frequency headache group.

View this table:
Table 5

Number needed to undertreat to avoid one case of incident chronic (transformed) migraine (after Bigal et al.10)

Medication withdrawal also involves a poor balance of benefit and harm, especially since evidence suggests that preventive treatment to reduce headache frequency may in fact be effective even if symptom-relieving medications are not withdrawn.44,55 Furthermore, many patients who undergo withdrawal do not complete the treatment but still must endure long periods without effective relief of pain. In the largest study of this approach (table 3), patients were advised that they would not be offered specific headache treatment unless they were able to do without all symptomatic medication including caffeine for 2–3 months.48 Intention-to-treat analysis (including the approximate one-third of patients who could not or would not complete withdrawal) shows a treatment response of just 27%, defined as >50% reduction in headache frequency.

Very similar results were seen in the second largest study, with about one-third of patients not completing withdrawal and an intention-to-treat response of 29%, defined in this study as > 0% reduction in headache frequency.46 This corresponds to a number needed to undertreat of roughly 3. Put another way, at best 3 patients had to suffer months of unrelieved headache pain in order for one patient to be helped—this assuming that all improvement was due to withdrawal per se and that none improved due to natural history, regression to the mean, or placebo response.

Blame and stigmatization.

Patients may suffer if they are viewed as the architects of their own headache problem. Caregivers may believe that help is not deserved or, as in the study described above, even withhold other treatments until patients complete a medication withdrawal program. Patients may experience a sense of failure if they are unable to limit medication use or may actually conceal medication use from their doctor.

The stigma associated with perceptions of medication overuse only adds to the sense of shame experienced by those with chronic headaches, who already “worry about what their doctors will think of them if they complain or fail their treatments.”56 Moreover, this burden of blame is not equally distributed: patients with the most severe, unusual, or intractable headache disorders would be affected by an inflexible view of medication overuse as a cause of chronic or refractory headache.

Diversion of attention.

A less apparent but important harm is the diversion of time, attention, and resources away from activities that would benefit patients more than medication limitation or withdrawal. Clinicians may be more interested in limiting or reducing symptomatic medication than investigating alternative evidence-based explanations or treatments for chronic headaches. Pressed to recommend treatment of some sort, they may suggest treatments that are expensive, are invasive, or lack good quality evidence of benefit. These options may actually increase costs and produce worse outcomes. Researchers may be dissuaded from studying other causes of headache progression, or find it difficult to secure money from funders who believe strongly in the explanation of MOH. These opportunity costs are an important argument against overly broad generalizations about the connection between medication use and frequent headaches.

A NEED FOR REASSESSMENT

MOH is an entrenched belief that has gained plausibility and acceptance through repetition.57 Why has the concept of MOH proved so popular and enduring despite the weakness of the scientific evidence supporting its existence? Why is the evidence supporting MOH treatment not evaluated as critically as the evidence for other interventions, such as, for example, patent foramen ovale closure and other surgical treatments?58,–,60

There are several possible explanations for its appeal. First, the idea of MOH aligns with the clinical experience of medical practitioners: patients taking a lot of medication tend to be those who do poorly and whose headaches do not respond well to treatment. Second, MOH provides a convenient explanation for treatment failure—although it does so by placing blame on the patient for overusing medications rather than on the inadequacies of existing treatments.

Finally, there are many good reasons other than fear of MOH to avoid excessive use of symptomatic medication. MOH provides an explanation for physicians to avoid prescribing medications such as opioids or barbiturates that (for many good reasons) they do not want to use. Opioid or barbiturate-containing medications impair alertness and are associated with a risk of addiction or dependence syndromes; nonsteroidal anti-inflammatory medications may produce gastrointestinal bleeding or kidney damage, for example. We are not suggesting that frequent use of symptomatic medication is desirable. Our point is a narrower one, which is that the specific harm of MOH has been overstated.

The MOH narrative also ignores what we know about the potency of other risk factors and biological phenomena. How can it be possible that exposure beyond an arbitrary threshold of medication intake could produce chronic headache in most patients? The complexity of the interaction among individual susceptibility, the pharmacology of different medications, and diverse underlying causes of headache suggests this is an oversimplification. If MOH is real, it is more plausible that a spectrum of susceptibility exists so that not everyone exposed develops the problem, and that other factors must be involved.

FUTURE DIRECTIONS

Better evidence is needed. One encouraging development is the recent announcement by the Patient-Centered Outcomes Research Institute (PCORI) that it will fund a large pragmatic trial that compares 2 treatment strategies for patients with chronic migraine who are deemed to be overusing medications to abort headache attacks. The study will compare early discontinuation of the overused medication plus migraine prophylaxis with a strategy of migraine prophylaxis without early discontinuation of overused medication.61 Consistent with PCORI research priorities (e.g., comparative effectiveness of accepted therapies), the study does not include a control group, so it will not be able to demonstrate the extent to which either strategy is preferable to maintaining the status quo.

While evidence in this area is inherently difficult to obtain, there are some methodologic considerations that could improve the quality of research. As previously mentioned, it is essential that studies of medication withdrawal include dropouts in analyses in accordance with standard methodology. Another hindrance to research in this area has been the use of arbitrary cutpoints for defining chronic headache and medication overuse.62 As previously described, use of such cutpoints results in spurious “remission” and “incidence” estimates, which can be substantial depending on the extent of natural variability or measurement error.63 While this source of error may be unbiased, it is important to consider when interpreting uncontrolled interventional studies (which may have an artificially high response rate) or observational studies (in which the true effect of risk factors may be obscured). A number of headache researchers have considered these and other methodologic issues in detail and have made suggestions to improve the rigor and usefulness of observational and interventional studies in chronic headache research including MOH.62,–,67

The concept of MOH has been embraced too enthusiastically and should be viewed with more skepticism. Until the evidence is better, we should avoid dogmatism. It is not intellectually honest, or fair to patients, to pretend that the rigor of the evidence is strong. Instead, frequent use of symptom-relieving headache medications should be viewed more neutrally, as a marker of poor headache control. This in turn may reflect illness severity, the shortcomings of current therapies, social or economic effects, or the complex interplay of these factors. Not all of these are amenable to intervention. Meanwhile, patients and physicians should recognize that we cannot yet answer with certainty the question “How much medication is too much?”

DISCLAIMER

The views expressed in this article are those of the authors and do not necessarily reflect the official policy of the Uniformed Services University of the Health Sciences, the Department of Defense, or the US Government.

AUTHOR CONTRIBUTIONS

Ann Scher: study concept and design, analysis and interpretation, approval of final version. Elizabeth Loder: study concept and design, critical revision of the manuscript for important intellectual content, approval of final version. Paul Rizzoli: critical revision of the manuscript for important intellectual content, approval of final version.

STUDY FUNDING

No targeted funding reported.

DISCLOSURE

A. Scher: consultant/advisory board member for Allergan. P. Rizzoli and E. Loder report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Editorial, page 1206

  • Received January 24, 2017.
  • Accepted in final form May 10, 2017.

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