Introduction

Medication-overuse headache (MOH) is defined as the overuse of simple or combination analgesics, opioids, ergots, triptans, or barbiturate-containing medications in persons with an underlying headache disorder, leading to an increase of headaches.1 This condition, common in those with frequent primary headache disorders, seems to be more prevalent with migraine or tension-type headache.1 It can be difficult to identify MOH because medication overuse may be a result of the primary headache having worsened rather than the increased medication use triggering increased frequency of headache. Historically, MOH was diagnosed after the overused agent was withdrawn and the headache improved.2 Over time, it was recognized that a retrospective diagnosis was not ideal and the criteria were changed so that diagnosis may be arrived at before withdrawal and subsequent improvement in headache.2 In this review, the history of MOH is discussed along with case examples and controversies in the diagnosis and treatment of this disorder.

History and Epidemiology

First described in the 1930s, MOH was initially seen in people overusing ergots for treatment of headache.3 In 1951, a case series described overuse of ergotamine causing headache, with improvement after the withdrawal of ergotamine.4 In the 1950s to 1970s, several withdrawal protocols for ergotamine were published.5 In 1988, the first edition of the International Classification of Headache Disorders introduced the term drug-induced headache, which included headache induced by ergotamine, analgesics, and other substances.6 Over time, with the advent of triptans, the definition of MOH grew to include the overuse of simple and combination analgesics, opioids, and triptans.7 The current classification system includes MOH as a secondary headache disorder occurring in someone with a primary headache disorder who is overusing specific substances.1

The prevalence of MOH is 0.5% to 7.2% in the general population, with variations likely due to changes in the diagnostic criteria over time.8 Although MOH is seen globally, the highest prevalence is in Russia (7.6%).9,10 The condition is more common in midlife and predominant in women (M:F ratio 1:3-4)8 but it also occurs in 21% to 52% of children with chronic headache and in 35% of adults more than age 64 who have headache disorders.11-14 It is more common for people with primary headache disorders to have MOH, especially those with chronic migraine, with an estimated prevalence of 11% to 70%.2

Although studies demonstrate that MOH is more common in migraine and tension-type headache, it has been described in cluster headache if patients have a personal or family history of migraine15 and in individuals with new daily persistent headache.

Clinical Features

Considered a secondary headache disorder, MOH should be identified by the type of medication being overused (ie, triptan, opioid, and multiple drug classes) (Table 1).1 The primary headache disorder must also be identified. Clinical features of MOH are often similar to the underlying primary headache disorder, although people often state they can tell the difference between their MOH attacks and those of their primary headache disorder. For example, in people with migraine, headaches from overuse will also be migraine-like in nature. This contributes to the complexity of making a diagnosis of MOH (see Controversies below).16 In order to make the diagnosis, a comprehensive medical history needs to be obtained along with the history of acute medication use for both the primary headache disorder and other pain syndromes. Physical examination findings should be normal, and no red flags to indicate another secondary headache disorder should be present (See Diagnosing Secondary Headache in this issue).

Risk Factors

The most recognized risk factor for developing MOH is the frequency of acute medication use to treat the primary headache disorder. Epidemiologic studies correlate risk of MOH by examining the frequency of use of acute medication for headache (Table 2).17

There are several other risk factors associated with the development of MOH, including a history or predisposition to develop migraine or tension-type headache, female sex, psychiatric comorbid conditions (eg, depression and/or anxiety), and preexisting pain conditions in people with a primary headache disorder for which pain medication is being used.10 A prospective population-based study of the MOH development in people who did not have chronic daily headache at study onset found that over 11 years, those with migraine were at higher risk for MOH than those with nonmigraine headache.18 Having headache frequency of 7 to 14 days/month vs no headache days/month, age less than 50 years, female sex, and low level of education were also found to be risk factors for MOH.18

Comorbid Conditions

People with MOH are more likely to have psychiatric comorbidities, which can add to the complexity of treatment for MOH. Depression and anxiety are the most common, occurring in up to 50% of people with MOH10 When treating MOH, it is important to remember this relationship and consider treating comorbid mood disorders concurrently.

Pathophysiology

Although the frequent use of acute medication to treat migraine is the largest risk for MOH, there may be an underlying predisposition to structural brain changes that make some people more prone to MOH. For some with MOH, there may be an increase in genetic and brain structural changes that make them predisposed to MOH. Evidence shows that MOH is associated with abnormal brain structure and function in regions of pain processing and in areas possibly involved with addiction.19 With a reversal of MOH, pain processing can normalize, but some regions involved with addiction remain abnormal,19 implying that changes in areas involved in addiction may be present at baseline for those with MOH. Of note, those with MOH are more likely to have a family history of substance abuse. Several polymorphisms are linked to MOH, which is 3 times more prevalent in people with a family history of MOH.19

Research suggests repetitive activation of pain pathways may be a reason for structural changes.20 Besides physiologic and genetic changes, the medications used to treat acute migraine may play a role in MOH. There is concern that overuse of acute migraine medications can directly affect the ability of the brain to continue inhibiting pain. These medications can reduce circulating serotonin levels, thus continuing pain because repetitive medication use alters serotonin receptors.20

Treatment

No specific medication exists to treat MOH, nor is there a single recommended algorithm that has proven to be the most effective in treating MOH. The general expert consensus on the treatment of MOH follows 3 recommended steps: 1) educate the patient about MOH and restrict the frequency of acute medication use, 2) withdraw the overused medication, and 3) start preventive treatment for the primary headache disorder.2 Although these recommendations are based on consensus opinion, it is important to realize that evidence is poor. A recently published systematic review and meta-analysis of treatments for MOH demonstrated no clear benefit of withdrawal of medications or starting prevention in MOH.21 The authors of this study recommended further evaluating treatment strategies in large clinical trials of low bias.

Education

Education can be a helpful tool, allowing the person to understand how to navigate frequent headaches and focus on prevention. The focus should be on lifestyle adjustments, the use of behavioral and nonpharmacologic approaches, and identifying when it would be best to treat acute attacks with medication. Education should not be allowed to make a person feel blamed for or at fault for the worsening of their headaches. When faced with disabling symptoms, it is unnatural to insist on avoiding treatment, but many of our medications have the potential to cause more harm than good. In my clinical practice, I will often discuss the use of neuromodulation (which can carry a high cost), breathing and relaxation techniques, distraction methods, use of ice and analgesic creams or ointments, and requesting work accommodations when possible. I focus on creating a plan with the individual regarding what type of attacks will need acute medication, or, if the attacks are the same every day, when to choose acute medication vs nonpharmacologic approaches. This conversation may need to be repeated at every visit.

Withdrawal of Overused Agents

Withdrawal of the overused acute treatment option should be partnered with education and a plan for an alternative to use medication as needed for more severe headache attacks. Sometimes choosing an acute treatment in a different category can be helpful, but a discussion is needed on how to limit the use of any new medication so as not to end up with MOH from another substance.

Preventive Treatment Initiation

The start of a preventive treatment option that is focused on reducing the frequency of the primary headache disorder should be done at the same time as education.2,10 Clinical trials have restricted the participation of individuals with MOH. More recent trials, however, including those for onabotulinum toxin A and calcitonin gene-related peptide antagonists, have allowed participation of people with MOH and shown that these individuals can experience migraine frequency reduction without withdrawal in acute medication use.22,23

Controversies—A Case-Based Approach

The diagnostic criteria for MOH do not demonstrate the complexity of making the diagnosis of MOH. It is important to realize that medication overuse and MOH are 2 different problems that can have different complications and outcomes. Someone who is overusing medication may not have an increase in headache but may have side effects from overuse of a specific medication (eg, developing peptic ulcer disease with nonsteroidal anti-inflammatory drug (NSAID) overuse. It is also possible that medication is to treat another underlying condition (eg, barbiturates for anxiety or NSAIDs for arthritis pain). Some individuals will develop headache with the acute medication overuse, whereas others may not. In people with a history of headache who use acute medications to treat another pain condition, a portion will notice worsening of their headache disorder.24 Other pain is unlikely to worsen because of medication overuse.16 It is unclear why overuse worsens headache in some people and not others and difficult to know how to address these issues in day-to-day clinical practice. Case examples can help guide practice.

Conclusion

A secondary headache, MOH occurs in 0.5% to 7.2% of the general population and can be difficult both to diagnose and to treat.8 Treating any comorbid conditions or worsening primary headache disorders is essential to long-term success. No specific treatment has been identified for MOH. Current recommendations for treatment include educating the patient about the overuse of medications and the variety of complications this can bring, stopping the overused medication class, and starting a preventive treatment for the underlying headache disorder.

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JA has served as a paid consultant for Allergan, Amgen, Biohaven, Eli Lilly, Lundbeck, Impel, Revance, Satsuma, Teva, Theranica, Zosano; speaker fees from Allergan, Amgen, Biohaven, Eli Lilly, Lundbeck, and Teva; and research funding from American Migraine Foundation, Allergan, Biohaven, and Eli Lilly