Clinical manifestations

Presentation and course

The prevalence of medication overuse headache in the general population is 1%, and as high as 11% to 70% in people with chronic daily headache. Some medications carry an increased risk of developing medication overuse headache. Triptans, opioids, and combination analgesics are most commonly associated with medication overuse headache (32). In the recent decade, the use and overuse of ergots decreased significantly worldwide. In Europe, very few patients overuse the combination of analgesics with barbiturates, which is much more frequent in the United States (28; 132; 11). Patients with medication overuse headache are mostly women, on average 40 to 45 years of age. Most of them have migraine, but some of them have tension-type headache or a combination of both. On average, they suffer from primary headache for 20 years and overuse medication for about five years (28; 132; 11).

Clinical features of medication overuse headache seem to depend on the pharmacology of the overused substances. For example, unlike patients who suffer from medication overuse headaches following ergot or analgesic overuse, migraine patients (but not patients with tension-type headache) who overused triptans did not describe the typical tension-type daily headache but rather a migraine-like daily headache (a unilateral, pulsating headache with autonomic disturbances) or a significant increase in migraine frequency (see the International Headache Society criteria for triptan-induced medication overuse headache). The delay between the frequent medication intake and the development of daily headache is shortest for triptans (1.7 years), longer for ergots (2.7 years), and longest for analgesics (4.8 years).

A study investigated the frequency of acute medication overuse in the migraine population based on the Chronic Migraine Epidemiology and Outcomes (CaMEO) study (ClinicalTrials.gov, NCT01648530) (107). Among the 16,789 respondents with migraine, 2975 (17.7%) met the criteria for acute medication overuse, and about one third of them reported 15 or more headache days a month, potentially meeting criteria for medication overuse headache. Participants with medication overuse were more likely to have moderate-to-severe depression and anxiety as measured by the PHQ-9 and GAC-7 and higher headache-related disability as measured by the MIDAS score. Of note, the study also reported that overuse of opioids was associated with a lower likelihood of employment [OR (95% CI) = 0.61 (0.47–0.79)].

A multicenter, comprehensive medication overuse headache registry (RELEASE) in Korea started enrolling patients with medication overuse headache in 2020 (84). The data of 229 patients were analyzed and demonstrated that the mean duration of chronic headache and medication overuse was 6.5 and 4.3 years, respectively, and patients had headaches 25 days per month, with 25 days of acute medication use before enrollment. Comorbid moderate/severe depression and anxiety were reported in 56% and 35% of patients, respectively. The proportion of patients on preventive treatments increased from 38% to 93% during the study period. The studies demonstrated a high level of disability in migraine patients with medication overuse.

Clinical vignette

A 38-year-old woman presented to the headache clinic and reported suffering from daily headaches. Her migraine had started at the age of 15 years. She usually had two to three migraine attacks per month. During the past 3 to 4 years, the migraine frequency had increased to five to six attacks per month, each lasting 2 to 3 days. She sometimes treated her migraine attacks with triptans or a combination of aspirin, paracetamol, and caffeine. Her migraines increased in frequency, and she consequently increased her drug intake until she was taking medication 15 to 18 days per month. During the last 2 to 3 years, she experienced dull, bilateral headaches in addition to her typical migraine attacks. During the past year, she had taken more headache drugs because of increasing days with bilateral tightening headache.

She was advised to undergo drug withdrawal. She developed a withdrawal headache, which was treated for five days with an oral prednisone taper. A preventive treatment with topiramate was initiated. Two months later, the patient was experiencing three to four migraine attacks per month, each lasting 1 to 2 days. Concomitant, dull daily headache disappeared completely.

Biological basis

Etiology and pathogenesis

The incidence of developing chronic headache for people with episodic headache is about 2% to 3% in one year (101).

According to current knowledge the following risk factors lead to the development of medication overuse headache:

Migraine and tension-type headaches as primary headache. Most headache experts agree that generally patients with migraine and tension-type headaches have a higher risk of developing medication overuse headache than patients with no primary headache using analgesics for other diseases. For example, patients who were consuming fairly large amounts of analgesics regularly for arthritis did not show an increased incidence of headache (67; 07). However, clinical series reported medication overuse headache in patients with cluster headache (82) and shunted hydrocephalus (130; 25), interestingly in those patients with a positive family history of migraine. In both observations, frequency and intensity of headache decreased after reducing analgesic intake.

Overuse of any kind of acute headache medication. A Norwegian study evaluated analgesic use by 32,067 adults in 1984 and again 11 years later. Those who used analgesics daily or weekly at baseline had a higher risk of developing chronic migraine (RR=13.3), of chronic nonmigraine headache (RR=6.2), and of chronic neck pain (RR=2.4) at follow-up (136). In a subsequent follow up 10 years later (HEAD HUNT III), the authors were able to estimate the incidence of medication overuse headache to be 0.72 per 1000 person-years (95% confidence interval 0.62–0.81); the overuse of tranquilizers [(odds ratio 5.2 (3.0–9.0)] or a combination of chronic musculoskeletal complaints, gastrointestinal complaints, anxiety and depression [odds ratio 4.7 (2.4–9.0)], smoking, and physical inactivity were the most important risk factors (51). A population-based study in the United States identified higher headache frequency at baseline and medication overuse as risk factors for developing chronic headache (101). A Danish study investigated a population-based sample of 740 people in 1989 and in 2001 and found that daily intake of analgesics and coexistence of migraine and tension-type headache were associated with frequent headache (02).

The incidence of de novo chronic headache was significantly higher (14%) in a patient population of a specialized headache clinic in Germany (60). Patients who used acute headache medication frequently (more than 10 days per month) had a 20-fold increased risk for chronic headache than patients who used acute headache medication fewer than five days per month. The risk increased to two-fold in patients who used two or more different headache drugs simultaneously.

A very important question of whether use of specific classes of acute headache drugs bears a higher risk for development of medication overuse headache was addressed in the American Migraine Prevalence and Prevention (AMPP) Study. Of 8219 individuals with episodic migraine, 209 developed chronic headache during the following year. The incidence of de novo chronic headache was 2.5%. People using medication containing barbiturates or opiates had a two-fold higher risk of developing chronic headache than those using single analgesics or triptans (11). A large, population-based, case-control study revealed caffeine consumption to be a modest risk factor for chronic daily headache development (100).

Over the past several years, four newer migraine-specific acute medications became available, namely, ubrogepant, rimegepant, zavagepant, which are CGRP receptor antagonist, and lasmiditan, which is a serotonin 5-HT1F agonist. As gepants and CGRP antagonism are also used as preventive therapy for migraine, it is believed those medications do not cause medication overuse headache. This is supported by a rodent model of medication overuse headache study confirming that ubrogepant does not induce latent sensitization (76), whereas lasmiditan has the capacity to induce medication overuse headache as it provoked cutaneous allodynia in a rat model (93).

Socioeconomic status and obesity. Low socioeconomic status is associated with chronic headache and medication overuse headache in Norway (52; 128) and was even more prominent in countries in transition such as Russia and the Republic of Georgia (58; 05).

Obesity and metabolic syndrome have increasingly been recognized as an important risk factor for medication overuse headache (30). In a longitudinal, 1-year, population-based study, Scher and associates demonstrated that obese individuals were five times more likely to develop chronic headache than people of normal weight (101). Another U.S. study found a significant association between obesity and chronic headache (10). The result analysis from the CaMeo study also suggested that patients with acute medication overuse were more likely to have a BMI of 30 kg/m² or greater, less likely to have a 4-year college degree, and more likely to have headaches more than 15 days per month as compared to participants without medication overuse (107).

Psychiatric and other comorbidities. Several studies looked at family history and comorbidities of patients with medication overuse headache. Depression and anxiety are more frequent in patients with medication overuse headache and seem to increase the risk of developing chronic headache by 50% (03; 99). It seems that patients with medication overuse headache more frequently have a positive family history of chronic headache and substance abuse (17). Insomnia (98), temporomandibular disorders (23), mood disorders, dependency like behavior (45), or use of psychoactive substances are more frequent in patients with medication overuse headache (91), especially in those with preexisting episodic tension-type headache (04). Stress seems to be an important factor in chronicity as well. A Danish study that followed 129,150 people demonstrated a strong association of patients with medication overuse headache with healthy lifestyle behavior and stress (129). Another prospective population-based German study demonstrated that increased stress perception was associated with an increase of headache frequency (104).

Pathophysiology. The pathophysiology of medication overuse headache still remains unclear. The number of animal studies has increased significantly. Reuter and colleagues demonstrated that chronic exposure of triptans causes a down-regulation of receptors in trigeminal ganglion and, subsequently, a reduction of receptor function (94). Chronic administration of sumatriptan and zolmitriptan caused a decrease of the 5-HT synthesis in the dorsal raphe nuclei of the brainstem (123; 35).

Triptan given daily resulted in a sensitization of trigeminal nociception, possibly due to increased expression of neuronal nitric oxide synthase in dural afferents (24). Green and colleagues also investigated the electrical threshold for cortical spreading depression and stress-induced activation of trigeminal afferents in a rat model of medication overuse headache. They reported that a previous period of sumatriptan exposure led to increased susceptibility to evoked cortical spreading depression and stressed-induced activation of the trigeminal nucleus caudalis. The authors concluded that lower cortical spreading depression threshold, and enhanced consequences of cortical spreading depression events may represent an underlying mechanism for medication overuse headache (47). Chronic application of analgesics resulted in up-regulation of pronociceptive 5HT2A receptors of platelets in humans (115), in a significant decrease in the maximum number of 5HT2A binding sites and an increase in the maximum number of 5-HT transporter binding sites in the CNS of rats (116).

Genetic studies on medication overuse headache are ambiguous. Park and colleagues reported an association of a serotonin transporter protein gene polymorphism (short allele) with medication overuse in chronic tension-type headache (85). In contrast, an Italian study did not find significant associations between medication overuse headache risk and 5HT2A gene polymorphisms (121). Another study suggested a possible role of Wolframin His611Arg (WFS1) polymorphism in medication overuse and subsequent medication overuse headache. Homozygous or compound heterozygous mutations in WFS1 (chromosome 4p16.1) determine Wolfram syndrome, a neurodegenerative disorder associated with diabetes mellitus, diabetes insipidus, hearing loss, progressive blindness, and a heterogenous combination of psychiatric disorders. Heterozygous Wolfram syndrome carriers are prone to develop psychiatric illness or behavioral problems, such as impulse control and alcohol or illicit drug abuse (34). A systematic review of gene polymorphism studies in medication overuse headache indicated the potential role of candidate polymorphic variants of the dopaminergic gene system as risk factors for medication overuse headache susceptibility. However, the authors indicated that definite conclusions cannot be drawn due to methodological flaw in some studies (14). A case-controlled study in Taiwan analyzed the whole-genome single nucleotide polymorphism genotyping on 605 migraine patients from the headache clinic in a tertiary center as well as 6055 controls from the Taiwan Biobank (57). It reported that patients with migraine carrying human leukocyte antigen (HLA)-B*58:01 or HLA-C*03:02 had 1.63 (1.11-2.39)-fold likelihood to have chronic migraine with medication-overuse headache compared to episodic migraine and that screening for HLA-B*58:01 has the potential to alleviate the burden of medication overuse headache in migraine. The study provides important insights on the genetic basis and potential clinical implication of medication overuse headache (57). Emphasizing the genetic influence of headache disorder, a published review summarized that changes in genes including COMT, GIT2, ZNF234, and SOCS1 have been associated with migraine progression to medication overuse headache (135).

There is growing evidence that central sensitization may play an important role in the pathophysiology of chronic headache. A series of investigations using psychophysical and electrophysiological techniques clearly demonstrated a facilitation of trigeminal pain processing in patients with chronic headache. Decreased pain thresholds have been found in patients with chronic tension-type headache (09). These findings have been confirmed by demonstrating increased amplitudes of laser-evoked cortical potentials in patients with chronic tension-type headache (26). Ayzenberg and colleagues used a novel technique of simultaneously recording blink reflex and nociceptive cortical potentials following nociceptive trigeminal stimulation. The authors were able to demonstrate a temporary facilitation of the trigeminal nociceptive system at a supraspinal level that normalized again after withdrawal (06). Using transcranial magnetic stimulation, Currà and colleagues demonstrated an increase of cortical inhibitory mechanisms in NSAID-induced headache but not in patients overusing triptans (22).

Imaging studies provide further insights into the pathophysiology of medication overuse headache. Both structural (102; 95) and functional (41; 37) changes in the pain matrix of the brain have been identified. For structural neuroimaging, voxel-based morphometry studies showed decreased gray matter volume in pain-processing areas including orbitofrontal cortex (64). Results from functional MRI studies suggested changes in the mesocorticolimbic dopamine pathway (37) as well as the pain modulatory area, especially frontal regions (65). Changes of the pain processing areas and their connections to the antinociceptive nuclei of the brainstem have also been reported (74).

Psychological factors include the reinforcing properties of pain relief by drug consumption, a powerful component of positive conditioning. Many patients report that they take migraine drugs prophylactically because they are worried about missing work or an important social event or they fear an imminent headache. They are often instructed by physicians or by the instructions supplied with the medication to take the migraine drug as early as possible at the start of either the aura or the headache phase of a migraine attack.

Withdrawal headache is an additional factor. When the patient tries to stop or reduce the medication, the preexisting headache worsens. Barbiturates that are contained in drugs used to treat tension-type headache have a high potency for addiction. The stimulating action of analgesics or migraine drugs and their psychotropic side effects, such as sedation or mild euphoria, may lead to drug dependency. Barbiturates, codeine, other opioids, and caffeine are most likely to have this effect. Caffeine increases vigilance, relieves fatigue, and improves performance and mood (48; 49). The typical symptoms of caffeine withdrawal, such as irritability, nervousness, restlessness, and “caffeine withdrawal headache,'' (126; 114), which may last for several days, encourage patients to continue their abuse. Despite the fact that caffeine may enhance the analgesic action of acetylsalicylic acid and acetaminophen, caffeine-containing combinations should not be used. Similarly, caffeine and meprobamate, the main metabolite of carisoprodol, should be removed from ergotamine-containing formulations.

Headache patients can develop physical dependence on codeine and other opioids (134; 38). Although some headache patients have been on codeine for as long as 10 years, no studies have investigated the effects of codeine intake over this time period. It should be remembered that up to 10% of codeine is metabolized to morphine.

Epidemiology

Epidemiological studies on the consumption of analgesics in the general population clearly indicate that analgesics are widely overused all over the world, in developed as well as developing countries. According to these surveys, between 1% and 3% of the general population take analgesics on a daily basis, and up to 7% take them at least once a week (105; 50).

Population-based prevalence studies demonstrate that about 1% to 2% of the general population suffer from chronic daily headache combined with overuse of headache medication. This is true for the United States and Canada, South America, and Europe (16; 89; 68; 19; 117), and it is also true according to the studies for Korea (86). Studies in post-Soviet countries reported a significantly higher prevalence of chronic headache of 10% and of chronic headache with medication overuse of 6% (05). The only study from Africa in Zambia reported a high prevalence of probable medication overuse headache of 7.1% (72). From an analysis of the MAST study (Migraine in America Symptoms and Treatment), acute medication overuse was present in 15% of respondents with migraine, and was more likely in patients who overused triptan, opioid, and barbiturates but less likely in NSAID users (106).

Meskunas and colleagues performed a retrospective analysis in order to evaluate the overuse of acute headache drugs in a United States center over the past 15 years. The proportion of subjects with a diagnosis of medication overuse headache remained stable over the years, varying from 64% of all cases seen in the center in 1990 to 59.3% in 2005. The authors found a significant decrease in the relative frequency of probable ergotamine overuse headache (from 18.6% to 0%) and in probable combination analgesic overuse headache (from 42.2% to 13.6%). The relative frequency increased significantly for the triptans (from 0% to 21.6%), for simple analgesics (from 8.8% to 31.8%), and for combinations of acute medications (from 9.8% to 22.7%). These data indicated that medication overuse headache remained an important problem in tertiary headache care but that the profile of medication overuse has dramatically changed (73).

Several studies addressed the prevalence of chronic headache in adolescents. One Taiwanese study revealed a prevalence of chronic daily headache in a population of adolescents (12 to 14 years of age) of 1.5%. Only 20% of them overused headache medication, confirming previous findings that medication overuse is less prevalent in children and adolescents (127). A study from Canada reported a clinical analysis of 1669 children with headache seen in a neurology outpatient clinic. The prevalence of chronic headache was 3%. The prevalence of medication overuse, however, was significantly higher, at about 52% (75). In contrast, some studies report a higher prevalence of pediatric medication overuse headache both in general practice clinics and tertiary headache institutions (87). A multi-national study in Europe and Latin America demonstrated that use of electronic medical diaries improved the outcome of patients suffering from medication overuse headache after withdrawal from overused drugs (119). A systematic review is currently underway to investigate and report the evidence of the causation, disability, and treatment of medication overuse headache in children and adolescents with a protocol published (125).

Prevention

The most important preventive measure is proper instruction and appropriate surveillance of patients. Restricting the number of doses of any kind of acute headache and migraine drugs to 10 days per month, or 2 to 3 days per week, can be an effective way to avoid medication overuse. Migraine drugs that contain barbiturates, opioids, codeine, or tranquilizers, as well as mixed analgesics, should be avoided completely. Patients who take nonprescription medication should be advised to avoid caffeine combinations. Early migraine prophylaxis, either by medical or behavioral treatment, can be a preventive measure to avoid chronic headache and medication overuse.

Many patients with medication overuse headache bypass a doctor and consult their pharmacist directly. Therefore, pharmacists have an important role in advising these individuals about their medication use. A Swedish study asked 326 pharmacists about their knowledge of headache treatment, and the study demonstrated that pharmacists’ knowledge on medication overuse headache was insufficient. For example, only 8.6% of them knew that overuse of all kinds of acute headache medications could lead to the development of medication overuse headache (55). Campaigns to raise awareness and patient education could also be helpful in reducing the risk of developing MOH (30).

Differential diagnosis

When evaluating chronic headache patients, it is necessary to take a careful history. These patients frequently take several different substances daily despite the fact that their effect is negligible. Patients should record their present and prior use of prescription drugs, nonprescription compounds, and caffeine intake. Many patients also abuse other substances, such as tranquilizers, opioids, decongestants, and laxatives. It is often helpful for patients to keep a diagnostic headache diary for one month in order to actually record headache patterns and drug use. History and examination should also search for possible complications of regular drug intake, such as recurrent gastric ulcers, anemia, and ergotism. A good indicator is the number of physicians the patient has consulted and the number of previous unsuccessful therapies. One study showed that headache patients had consulted an average of 5.5 physicians who had prescribed 8.6 different therapies (29).

All conditions that lead to more than 10 to 12 headache days per month must be considered in the differential diagnosis of medication overuse headache. Chronic tension-type headache is a diffuse, dull, nonlocalized headache with or without minimal autonomic features. Headache intensity is lower than that of migraine. Patients find it difficult to describe the character of pain. Sometimes it is described as a feeling of a metal band around the head or a feeling of increased pressure. Many patients with chronic tension-type headache complain of mild autonomic disturbances such as nausea, photophobia, or phonophobia.

Patients with chronic migraine have a history of episodic migraine attacks that increase in frequency over time. Chronic migraine is diagnosed if patients have headaches for more than 15 days per month, and at least 8 days with migrainous features (eg, unilateral throbbing pain, moderate to severe in intensity; nausea or vomiting; photo- and phonophobia; and headache intensity that is increased by physical activity). The majority of patients are women, 90% of whom have a history of migraine without aura.

Hemicrania continua patients suffer from daily headache of moderate intensity. Superimposed exacerbation of severe headache with ipsilateral autonomic features, such as ptosis, miosis, tearing, and sweating (77; 78) may occur. Some patients have photo- and phonophobia or nausea. In some cases, the head pain alternates sides. Hemicrania continua is differentiated from cluster headache and chronic paroxysmal hemicrania by its continuous pain character; furthermore, the autonomic symptoms during acute pain exacerbations are less pronounced compared with cluster headache or chronic paroxysmal hemicrania.

Patients with new daily persistent headache abruptly develop chronic headache without remission. Many patients remember the exact day the headache started. These patients did not have a previous history of migraine or episodic tension-type headache. In some patients a viral infection was suspected to cause this form of headache (27). The headache usually does not respond to ergots, triptans, or simple analgesics.

Diagnostic workup

Frequent acute medication use may be the cause or consequence of the headache disorder. In the ICHD-2, medication overuse headache excluded a concomitant diagnosis of chronic migraine, and it required the chronic headache to resolve or revert to its previous episodic pattern within two months after discontinuation of the overused medication. However, in the ICHD-3 Beta, because it is unknown whether the overuse of medication is the cause or consequence in an individual case, the patient will receive a diagnosis of both chronic migraine and medication overuse headache when both criteria are met. Taking a good history of the headache characteristics and the pattern of the medication use is crucial in making the medication overuse headache diagnosis.

Concomitant medical problems, stress, sleep disturbance, hormonal factors, depression, and certain nonheadache medications can cause an increase in headache frequency. If no obvious nonorganic cause exists for the change in headache pattern, clinical re-evaluation is advisable. If clinical re-evaluation suggests the possibility of serious medical or neurologic illness, appropriate diagnostic testing, including imaging, is indicated.

Management

There are three main strategies to treat medication overuse headache: abrupt discontinuation of the overused medication without preventive therapy, adding preventive therapy without abrupt discontinuation of the overused medication, or adding preventive therapy plus abrupt discontinuation of the overused medication. Large randomized controlled trials are currently ongoing to compare the above treatment strategies for medication overuse headache. A systematic review of the treatment of medication overuse headache was published from the available literature (18). The majority of the medication overuse headache treatment trials were done to evaluate the efficacy of early discontinuation with preventive medication. The studies showed encouraging outcome in reducing headache frequency and medication consumption. However, most trials were done without control groups. Abrupt discontinuation without preventive therapy is often complicated by withdrawal symptoms and high relapse rate. For preventive therapy without early discontinuation of the overused medication, there are large, randomized control trials supporting the use of onabotulinum toxin A and topiramate, however, the trial was done on patients with chronic migraine and medication overuse and data were obtained from post-hoc analysis.

An open-label, randomized clinical trial was conducted at the Danish Headache Center (15). A total of 120 patients were randomly assigned in a 1:1:1 fashion to (1) withdrawal plus preventive treatment, (2) preventive treatment without withdrawal, or (3) withdrawal with optional preventive treatment two months after withdrawal. At 6-month follow up, the headache days per months were reduced by 12.3, 9.9, and 9.5 in the three groups, respectively. The percentage of patients reverted to episodic headache were 74.2%, 60.0%, and 41.7%. The authors concluded that all three treatment strategies were effective, but withdrawal therapy combined with preventive therapy from the start of withdrawal is recommended as treatment for medication overuse headache. Another large, randomized trial, the Medication Overuse Treatment Strategy (MOTS) Trial is currently ongoing involving 29 sites in the U.S. to compare the effect of (1) adding migraine preventive therapy with immediate discontinuation of the overused medication and (2) migraine preventive therapy without immediate discontinuation of the overused medication.

For abrupt discontinuation of the overused medications, the typical withdrawal symptoms last for 2 to 10 days (average three and a half days) and include withdrawal headache, nausea, vomiting, arterial hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Seizures or hallucinations were only rarely observed, even in patients who were abusing barbiturate-containing migraine drugs.

Drug withdrawal is performed differently. A consensus paper by the German Neurological Society recommends outpatient withdrawal for highly motivated patients who do not take barbiturates or tranquilizers with their analgesics (31). Patients who take tranquilizers, codeine, or barbiturates and who failed to withdraw the drugs as outpatients or who have a high depression score can be offered inpatient treatment. The decision of withdrawal setting, however, differs and depends on the political and economic circumstances in different countries. The medical evidence is scarce.

Brief instruction to patients with medication overuse headache about the importance of restricting use of acute headache medications per postal mail without contact to medical personnel is effective and leads to significant reduction of medication overuse and subsequently to improvement of chronic headache (44). Brief education to patients with medication overuse headache can be done by general practice clinics and is very effective as demonstrated in a BIMOH study in Norway. Here, 50 general practitioners received a 1-day training by headache experts. Thereafter, 25,486 patients allocated to the 50 general practitioners were screened for medication overuse headache. Identified cases were invited by general practitioners to receive a brief education about medication overuse headache. This simple intervention was effective: chronic headache was resolved in 50% of cases, and the headache frequency was reduced by 7.3 days per month (62).

Several studies compared the efficacy of inpatient versus outpatient withdrawal and reported no differences between the two settings (118; 96; 21). Another study demonstrated that psychological education alone is equally effective as a cognitive behavioral contact program (40). Therefore, we suggest an outpatient withdrawal in the first instance in uncomplicated patients with medication overuse headache. Patients with psychiatric or psychological comorbidities should be treated using a multidisciplinary treatment approach (42). An Italian headache group from Pavia established a stratified approach for medication overuse headache patients with and without comorbidities. They were able to show that simple medication overuse headache can be treated equally successfully using in- and outpatient approaches, whereas more complicated patients (eg, psychiatric comorbidities, or overuse of benzodiazepines or barbiturates) could be admitted to the hospital, if necessary (97).

Treatment recommendations for the acute phase of drug withdrawal vary considerably between studies. They include fluid replacement, analgesics, tranquilizers, neuroleptics, amitriptyline, valproate, intravenous dihydroergotamine, oxygen, and electrical stimulation. Studies on cortisone to reduce withdrawal headache are ambiguous. The first open trial showed that cortisone effectively reduced withdrawal symptoms, including rebound headache (63). A small pilot placebo-controlled study in Germany demonstrated the superiority of oral prednisone 100 mg versus placebo (83). Larger studies from Norway and Germany, however, were negative (12; 90).

Management of medication overuse headache should be performed using multimodal approach (eg, involving psychologists and physiotherapists), which results in significant improvement of headache, improvement of well-being, and a reduction of the illness-related costs. On average, about 70% of patients improve significantly. The medication-related costs decrease by 25%, and in patients overusing triptans, it decreases by 43% (109).

Some studies reported protocols for abrupt discontinuation of the overused medication when admission is necessary. In the hospital, all pain or headache medication is stopped abruptly. Fluids should be replaced by infusion if frequent vomiting occurs. Vomiting can be treated with antiemetics (eg, metoclopramide or domperidone). The withdrawal headache can be treated with nonsteroidal anti-inflammatory drugs (eg, naproxen 500 mg twice daily). In some countries, aspirin is available in injectable form and 1000 mg are given every 8 to 12 hours. If the headache has migrainous features and the patient has not abused ergotamine, intravenous dihydroergotamine 1 to 2 mg every 8 hours is given (92; 112; 113). Prednisone 100 mg on the first day, tapering by 20 mg for the next days, is highly effective. Symptoms of opioid withdrawal can be treated with clonidine. The initial dose is 0.1 to 0.2 mg three times daily, and this is titrated up or down based on withdrawal symptoms (tachycardia, tremor, sleeping disturbances). Some patients may require anxiolytic medication; this should be given for no longer than a week. Patients need the support of treating physicians and nurses as well as encouragement from family and friends. Behavioral techniques, such as relaxation therapy and stress management, should be initiated as soon as the withdrawal symptoms fade.

Outpatient treatment is the preferred approach for patients with medication overuse headache. Before more evidence becomes available for the treatment of medication overuse headache, our recommendation is to initiate a preventive medication and to withdraw the overused medications, together with a multidisciplinary approach as outlined above. A short course of oral prednisone or nonsteroidal anti-inflammatory drugs could be considered for withdrawal symptoms. Studies showed that patients respond to prophylactic treatment with beta-blockers, flunarizine, or valproic acid after drug withdrawal despite the fact that these drugs had been unsuccessful before (20).

Calcitonin gene-related peptide (CGRP)-targeted therapy has emerged as an important treatment option for migraine. Although there have not been clinical trials specifically investigating the use of calcitonin gene-related peptide monoclonal antibodies for treating medication overuse headache, several subgroup analyses of phase 3 trials for the treatment of migraine have demonstrated that the calcitonin gene-related peptide monoclonal antibodies are effective in patients who have chronic migraine with medication overuse. For erenumab, post-hoc analysis for patients with medication overuse showed that erenumab, both the 70 or 140 mg groups, had greater reductions than the placebo group at month 3 in monthly migraine days (mean -6.6 and -6.6 vs. -3.5 days, p < 0.001 for both groups vs. placebo), and acute migraine-specific medication treatment days (-5.4 and -4.9 vs. -2.1, p < 0.001 for both groups vs. placebo) (120). For fremanezumab, a post-hoc analysis of the medication overuse subgroup from the fremanezumab phase 3 randomized-controlled trials showed that fremanezumab treatment significantly reduced the days of acute headache medication use over the 12‐week treatment period compared to placebo (−9.0 ± 0.41 vs. −7.1 ± 0.46 days, p=0.0017). Additionally, significantly more fremanezumab‐treated patients reported no medication overuse during the 12‐week treatment period compared to placebo (55% vs. 46% patients, p=0.0389) (111).

Eptinezumab, a CGRP monoclonal antibody designed to be given intravenously every three months, was also shown to be effective and tolerable in phase 3 clinical trials (PROMISE-1 and PROMISE-2) and was approved by the U.S. Food and Drug Administration in February 2020 (01; 110). The PROMISE-2 trials were conducted in patients with chronic migraine who had headaches between 15 and 26 days per month, with at least 8 monthly migraine days. Patients with medication overuse were eligible, with the exception of those who overused opioids or barbiturates (5 or more days of use per month were excluded). A total of 40.2% of patients had medication overuse headache at baseline. There was a significant reduction in acute medication use days at week 12 from baseline compared to placebo in both the 100 mg and 300 mg dose groups (71). Specifically, for the 431 patients who received both a diagnosis of chronic migraine and medication overuse headache at baseline, there was a significant reduction in monthly migraine days in both dose groups (100 mg: -8.4 versus -5.4 days in placebo, p < 0.0001; 300 mg: -8.6 versus -5.4 days in placebo, p < 0.0001). The 50% and 75% responder rates were also higher in patients treated with eptinezumab compared to placebo (33). The results are encouraging as they present more treatment options for patients with medication overuse; however, more data are needed to evaluate the long-term efficacy and safety.

Since CGRP monoclonal antibodies became available in 2018, there have been several real-world patient experiences published around the world. Lambru and colleagues reported a prospective analysis of the patient experience of erenumab treatment in a tertiary headache center in the United Kingdom (66). The study included 162 patients with chronic migraine who had failed at least three preventive treatments, including 91% who had tried onabotulinum toxin A injections. The percentage of patients with medication overuse was reduced from 54% at baseline to 20% at month 3 and 25% at month 6. Ornello and colleagues also reported that in an Italian real-world study that included 89 patients, 64 (71.9%) had medication overuse (81). After three months of erenumab treatment, 53 (69.7%) had a 50% decrease in monthly migraine days. Furthermore, 46 (71.9%) of 64 patients were no longer overusing acute headache medications. Among the 76 patients who completed 6 months of erenumab treatment, the median monthly migraine days decreased from 19 to 4 (p < 0.001). The mean monthly days of acute medication use decreased from 10 to 2 days per month, and the mean number of days of triptan use decreased from 5 to 1 (p< 0.001). Of note, the significant reductions in medication use were observed after the first dose of the injection. The real-world studies provide encouraging results for the treatment of patients with migraine and medication overuse; a significant reduction in monthly migraine days and medication use days occurred without the need for discontinuation of the overused medication.

A systematic review and metaanalysis of randomized controlled studies evaluated the efficacy of topiramate, onabotulinumtoxinA, and CGRP monoclonal antibodies (43). It carefully examined the results of 10 studies and concluded that onabotulinumtoxinA and CGRP monoclonal antibodies were beneficial in reducing monthly migraine days and greater than or equal to 50% response rate, and there is currently insufficient evidence to determine the efficacy of topiramate in patients with chronic migraine and medication overuse, highlighting the need for further randomized controlled studies.

The results of the Medication Overuse Treatment Strategy (MOTS) patient-centered, open-label, pragmatic randomized clinical trial was published in April 2022 (108). The study aimed to determine the effectiveness of two treatment strategies for patients with chronic migraine and medication overuse: (1) switching from the overused medication to an alternative medication that could be used on a maximum of two days per week, and (2) continuing the overused medication without any frequency limit. A total of 720 adult participants were enrolled from various clinics in the United States. The primary outcome measured was the frequency of moderate to severe headache days during weeks 9 to 12, and subsequently during weeks 1 to 2 after randomization. The results demonstrated that migraine preventive medication without switching or limiting the frequency of the overused medication was not inferior to preventive medication with switching for reducing the frequency of moderate to severe headache days. Both treatment strategies demonstrated similar outcomes during the first two weeks as well. The study suggests that when managing chronic migraine with medication overuse, optimizing preventive medication is crucial.

Outcomes

Several studies have addressed the long-term outcome of patients with medication overuse headache after successful withdrawal therapy. Success is defined as no headache at all or an improvement of more than 50% in terms of headache days. The success rate of withdrawal therapy within a time window of the first-year months is about 70% (08; 29; 103; 46; 131; 133; 13). Studies with longer observation time of up to 6 years reported relapse rates between 40% and 50% (103; 36; 39; 88; 124). Predictors for relapses after successful withdrawal therapy remain difficult to analyze. Two aspects appear to be important: the type of primary headache (patients with tension-type headache or co-occurrence of migraine and tension-type headache have a higher relapse risk) (29; 103; 36; 59) and a longer duration of regular drug intake (122; 88).