Jessica Ailani, MDJessica Ailani, MD
For more than 60 million headache sufferers worldwide, attempts to achieve pain relief have ironically led to increased headache frequency and progression.1 The neurology community has redefined medication overuse headache (MOH) many times since it first appeared in the International Classification of Headache Disorders (ICHD) in 2004. The most recent edition (ICHD-3) defines MOH as a headache disorder occurring on 15 or more days per month in a patient with a preexisting primary headache and developing as a consequence of regular overuse of acute or symptomatic headache medication for more than 3 months.2

Prevalence rates for MOH tend to range from 1% to 2%, although certain countries have seen higher rates, and headache centers have reported significantly higher rates (30%-50%). Epidemiologic data suggest that the prevalence of MOH is highest among adults aged 30 to 50 years, with a preponderance of cases in female patients versus male patients (ratio, roughly 3-4:1). Furthermore, between 21% and 52% of pediatric patients with chronic headache meet the diagnostic criteria for MOH.2

Although all acute headache medications can potentially lead to MOH, results of various studies have shown that the risk of MOH is higher with combined analgesics and opioids compared with triptans and ergotamine, with one investigation demonstrating a 2-fold–greater risk of developing chronic headache in patients using barbiturates or opiates compared with those using triptans or single analgesics.2,3 Research has also linked nonsteroidal anti-inflammatory drug (NSAID) use to a higher MOH risk in patients with more than 10 headache days per month.2

Migraine and tension-type headache are the main risk factors for MOH, although some cases have been reported in patients with cluster headache.4 Regular use of tranquilizers (odds ratio, 5.2; 95% CI, 3.0-9.0), chronic musculoskeletal complaints, gastrointestinal complaints, higher scores on the Hospital Anxiety and Depression Scale, and a family history of MOH or substance abuse (more than 3-fold–increased risk) have been identified as additional risk factors.2

“One of the most recent developments in the understanding of MOH has been scientific work published in the past several years showing that MOH may be associated with a genetic predisposition to brain function changes involving pain processing and addiction,” Jessica Ailani, MD, associate professor of clinical neurology at Medstar Georgetown University Hospital and director of the Medstar Georgetown Headache Center in Washington, DC, told NeurologyLive®.

Neuroimaging studies have linked MOH with structural and functional alterations in regions of the brain that have been implicated in pain processing and addiction (FIGURE).2 Although the pain processing effects appear to normalize after discontinuation of the overused drug, some of the abnormalities relevant to addiction may persist after discontinuation, indicating that they represent a “brain trait that predisposes certain individuals to medication overuse and MOH.”5

This diagnosis “continues to be viewed with some skepticism by certain members of the headache research and clinical community,” Elizabeth K. Seng, PhD, research associate professor in the Saul R. Korey Department of Neurology at the Albert Einstein College of Medicine in Bronx, New York, said in an interview with NeurologyLive®. One major point of debate is whether escalating medication overuse is a cause or consequence of the worsening headache trajectory, as individuals with more frequent attacks will logically tend to take acute medications more often than those with less frequent attacks.

Seng noted, however, that several acute medications that seem to be most closely associated with MOH (such as opioids) have demonstrated reduction of pain threshold in both migraine animal models and human and animal studies in other pain conditions. These findings underscore the importance of continued efforts to elucidate the nature of MOH.

“I sometimes feel we are overdiagnosing MOH and considering anyone who is frequently treating migraine to have MOH,” Ailani said. “It is actually very hard to prove that a patient’s migraine is getting worse because of acute medication overuse versus worsening for other reasons and that the patient is just treating symptoms. I find this to be the most challenging part of clinical practice.”

MOH Management

Given the heterogeneity in cases depending on the overused medication and other factors, no standard treatment approach exists for MOH. The expert consensus is that “patients should be educated about overuse of medications and how and when to treat migraine attacks with a variety of treatments—medications but also behavioral techniques, and neuromodulation—preventive medication should be started, and the overused medication should be gradually withdrawn, with alternatives provided to treat migraine attacks,” according to Ailani.

Patient education
Patient education is an essential component of MOH management that appears to be underused. Results of several studies have revealed that most patients with MOH are unaware of the risk of headache chronification related to excessive use of acute headache medications. In one study, only 14.5% of patients surveyed in pharmacies reported that they had ever been advised to limit their intake of acute headache medications, although research supports the effectiveness of educational strategies preventing MOH.2

In a multicenter German study of 182 patients with migraine with frequent use of triptans or analgesics, investigators found both a home-based cognitive behavior therapy program and an educational brochure to be effective in preventing MOH in all participants. In addition, both groups demonstrated significant reductions in the number of headache days, migraine days, and medication intake over the study period, and these improvements were sustained at the long-term follow-up (P <.001 for both groups).6

"Often when patients have MOH, they have other comorbid conditions like anxiety and insomnia that need to be addressed. Looking at the patient as a whole and involving a multidisciplinary approach is especially important for these patients," Ailani stated. 

Along with education’s role in prevention, other research supports the effectiveness of patient education in the treatment of MOH. The randomized controlled BIMOH trial (NCT01314768), published in 2015, investigated the use of brief intervention for MOH, in which general practitioners conducted a simple screening and then educated patients on reducing their use of acute headache medication. Headache days and medication days decreased by 7.3 and 7.9 (95% CI, 3.2-11.3 and 3.2-12.5) days per month, respectively, in the intervention group, and resolution of chronic headache was observed in 50% of these patients versus 6% of the usual-care group.7

In other cases, clinicians may need to facilitate abrupt withdrawal (typically for triptans, ergots, NSAIDs, and simple and combination analgesics) or progressive reduction of the overused medication. Inpatient withdrawal may be indicated for patients taking opioids, barbiturates, and benzodiazepines or those with other complicating factors.2

Prophylaxis
Whether initiating prophylactic treatment at the beginning of withdrawal is more effective than later in the process is yet to be determined. Although some experts believe that immediate prophylaxis is not needed for successful detoxification, it may be warranted in certain patients.

A meta-analysis of random controlled trials (RCTs) determined that insufficient evidence exists to determine the superiority of any particular prophylactic drug compared with the others. Data from a post hoc analysis indicate that topiramate and onabotulinumtoxinA are effective without early discontinuation of the overused drug.2

“Historically, headache experts believed that unless an overused medication was stopped, preventive medication would not work,” said Ailani. “There have been newer studies, including studies with CGRP [calcitonin gene-related peptide] monoclonal antibodies, showing that some preventive treatments can work even if a medication continues to be overused.” For example, a significant number of patients with medication overuse were enrolled in RCTs investigating erenumab, fremanezumab, and galcanezumab for migraine prevention, and these patients did not undergo detoxification prior to treatment initiation.8

A post hoc analysis of data from the phase 3 HALO trial (NCT02638103) found reductions in monthly migraine days and medication overuse in chronic migraineurs receiving fremanezumab. A significantly greater percentage of patients in the monthly (61%) and quarterly (55%) fremanezumab groups reported no medication overuse during the treatment period compared with placebo (46%).8

“Ultimately, the identification of proper prophylaxis should be driven by clinical history, comorbidity, contraindications and [adverse] effects of the possible drugs,” wrote Vandenbussche et al in a 2018 review published in the Journal of Headache and Pain.2 Although their ease of use and safety profile are generally more favorable compared with other agents, CGRP drugs “cannot represent the first-line treatment for migraine prevention” because of their high cost and thus “should be reserved for patients who cannot be managed with the oral treatments or with onabotulinumtoxinA,” the authors wrote.

Emerging findings indicate that the small molecule CGRP receptor antagonists (gepants) may not cause MOH.9 “Gepants block the effect of CGRP, and we know from evidence relating to the CGRP monoclonal antibodies that blocking CGRP reduces migraine frequency,” said Ailani. She further noted that a long-term safety study (NCT03266588) evaluating rimegepant over 52 weeks allowed patients to use the medication up to 15 days per month, and migraine frequency did not increase.10 “Having an acute migraine treatment that does not cause medication overuse is extremely helpful for many patients,” she added.

Comorbidities in MOH
The management of comorbidities is an important component of care for individuals with MOH. “Often when patients have MOH, they have other comorbid conditions like anxiety and insomnia that need to be addressed,” Ailani said. “Looking at the patient as a whole and involving a multidisciplinary approach is especially important for these patients.”

In general, comorbid psychiatric disorders have been linked to poor treatment adherence and outcomes, increased illness burden, and reduced quality of life in patients with headache, highlighting the need to screen patients for anxiety and depression and facilitate appropriate treatment. Although numerous studies have observed high rates of depression and anxiety in patients with MOH—for example, 40.0% and 57.7% in the COMOESTAS trial (NCT02435056)—practitioners should interpret these results with caution.2

“This common stigma, that [patients] who use acute headache medication frequently must have psychiatric issues, is likely an observation based on confounding,” Seng said.

Regarding other recent psychological research in this area, recent work by Peck, Roland, and Smitherman “showed that the overuse of medication was associated with increased escape and avoidance responses to pain. This result tracks with what we know about use of opioid medication in chronic pain conditions,” Seng said.11 She believes that a better understanding of how these responses influence the decision to use acute medication may “improve our ability to coach patients in appropriate use of acute medication during headache attacks.”

Along with acute headache treatments that do not cause MOH, a clearer understanding of why only some patients develop MOH is also needed, according to Ailani. “In the end, I attempt to treat migraine with empathy and education,” she said. “Having some [abortive] options for patients with frequent migraine that needs treatment while we find a good preventive strategy for them has been extremely helpful in my practice.”
REFERENCES  
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10. Lipton RB, Berman G, Kudrow D, et al. Long-term, open-label safety study of rimegepant 75 mg for the treatment of migraine (Study 201): interim analysis of safety and exploratory efficacy. Poster presented at: American Headache Society 2019 Annual Scientific Meeting; July 11-14, 2019; Philadelphia, PA. Poster P235LB. 
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