Medication overuse headache: Treatment and prognosis

INTRODUCTION — 

Medication overuse headache (MOH) is a secondary headache condition that occurs when overuse of acute medications to treat other headache disorders results in an increased headache burden with attacks occurring on 15 or more days per month for at least three months. MOH has also been called analgesic rebound headache, drug-induced headache, medication adaptation headache, and medication-misuse headache. It requires an effective treatment strategy of withdrawing the overused medication to reduce headache burden and permit more effective treatment of the underlying headache disorder.

This topic will review the treatment and prognosis of MOH. The causes, clinical features, and diagnosis of MOH are discussed separately. (See "Medication overuse headache: Etiology, clinical features, and diagnosis".)

Other types of chronic daily headache are reviewed elsewhere. (See "Chronic daily headache: Associated syndromes, evaluation, and management".)

PATIENT EDUCATION — 

Treatment begins with patient education about the detrimental effects of overuse of medications used for acute headache treatment [1]. Patients need to understand that underutilization of preventive therapies and/or excessive exposure to acute medications has the potential to worsen headache symptoms, leading to MOH, and also may cause medication adverse effects or toxicities [2]. (See "Medication overuse headache: Etiology, clinical features, and diagnosis", section on 'Pathophysiology'.)

Some evidence suggests many patients are unaware of MOH, indicating that primary prevention via education and advice is essential [3]. A national awareness campaign conducted in Denmark reached 10 percent of the population and improved knowledge about MOH [4].

Several small studies have demonstrated that patient education may be helpful for reducing medication intake [5-9]. One prospective, unblinded trial of 120 patients with migraine plus MOH compared inpatient and outpatient detoxification strategies; all groups were also provided education on stopping the overused medication [5]. Approximately 75 percent of patients in all groups successfully discontinued the overused medications. The trial excluded patients who overused agents containing opioids, benzodiazepines, and barbiturates, and those with coexisting medical or psychiatric illness; thus, the results may not be generalizable to all patients with MOH.

Education may also reduce the risk of relapse. In a trial of 663 patients with MOH weaning from an overused headache medication, patients assigned to additional education with an electronic monitoring and alert tool had lower relapse rates at six months than those assigned to a headache diary (27 versus 36 percent) [10].

INITIAL MANAGEMENT — 

Several strategies have been used to treat MOH. Management generally involves discontinuing the problematic overused medication and providing appropriate alternative treatment to manage symptoms. Headache symptoms often temporarily worsen when the overused medication is discontinued before improving [11].

Our approach — Our approach to the management of MOH typically includes (table 1) [1-5]:

●Weaning or discontinuing the overused medication, AND

●Providing acute therapy for breakthrough pain or short-term preventive (bridge) therapy for patients with severe symptoms, AND

●Starting longer-term preventive therapy.

However, the specific strategy used should be individualized based on the nature and extent of the overused medication, patient preferences, and available resources. Some acutely symptomatic patients may be unwilling or unable to wean the overused medication until effective alternative acute and preventive treatments have improved severe symptoms; others who wish to minimize exposure to pharmacotherapy may elect to stop the overused medication immediately and not start a preventive medication. Follow-up to monitor the efficacy of treatment is important to help prevent relapse for all patients.

After successful initial treatment of MOH, an ongoing headache treatment regimen is needed for both acute and preventive therapy, since most patients will continue to have intermittent headaches. Close follow-up is imperative to evaluate progress and prevent relapse of MOH. (See 'Follow-up and relapse prevention' below.)

Wean the overused medication — Discontinuation or a substantial reduction in the frequency of the overused medication is a chief aim of treating MOH [1,3]. In a meta-analysis of 17 studies and 1101 patients with MOH, resolution or substantial reduction in headache burden (>50 percent reduction in monthly headache days) following withdrawal of the offending agent was reported in 72 percent within one- to six-month follow-up [12].

Several medications used for the acute treatment of headache commonly cause MOH (table 2). These agents are discussed separately. (See "Medication overuse headache: Etiology, clinical features, and diagnosis", section on 'Causal medications'.)

Weaning strategies — There are several transitional strategies that may be used to help discontinue the overused medication and reduce headache burden. For most patients with MOH, we suggest initial weaning of the overused medication rather than initial continuation. Weaning may reduce the risk of adverse effects associated with excessive medication use. However, the selection of a weaning strategy should be individualized based on the class and dose of the overused medication, risk of adverse effects, patient preferences, and available resources.

Weaning should occur in most cases while starting an alternative temporary acute medication and adding a preventive medication for longer-term management. (See 'Provide acute or bridge therapy' below and 'Start preventive therapy' below.)

●Stop the overused medication – Discontinuing the overused medication is an appealing option for patients with MOH to eliminate exposure to the offending agent. In many cases, MOH occurs when the dosing of an ineffective acute medication is excessively increased in an attempt to achieve beneficial effect. This approach is also appropriate when the overused medication is a nonspecific agent (eg, analgesic, opioid) and/or other classes of more effective headache-specific medications are available (eg, triptan).

The pace of weaning varies by medication and dose exposure. (See 'Weaning protocols' below.)

●Reduce the dose and/or frequency of the overused medication – Reducing the dose and/or frequency of the overused medication below thresholds expected to sustain or cause MOH (table 2) may be an appropriate strategy for patients with a prior history of effective headache control using the overused medication at an appropriate lower dose (eg, a triptan, nonsteroidal anti-inflammatory drug [NSAID], or acetaminophen) and those with an intolerance or nonresponsiveness to other classes of acute headache medications.

We generally do not continue barbiturates, opioids, or benzodiazepines at lower doses due to the limited data supporting their use for acute headache treatment and their high risks of recurrent MOH.

●Continue the overused medication during initial treatment – A delayed weaning strategy of initially continuing the overused medication may be appropriate for some patients unable or unwilling to stop the overused medication. Effective temporary and preventive therapies are typically added, and the acute medication can then be tapered gradually as the headache frequency decreases. This strategy is only used when there are no immediate concerns for toxicity or adverse events related to the overused medication.

Either immediate weaning or initial continuation of the overused medication may be effective components of MOH treatment strategies. In an open-label trial of 726 patients with MOH randomized to start a preventive medication, patients were assigned either to continue the overused medication or to wean and switch to another class of medication used ≤2 days/week for symptomatic management [13]. At baseline, patients had a mean of 13 moderate to severe headache days over four weeks. By weeks 9 to 12, both groups had fewer moderate to severe headache days. The frequency of moderate to severe headache days was similar for patients who continued the overused medication and those who were switched to a different medication (9.3 versus 9.1). The frequency of moderate to severe headaches during the first two weeks was also similar between groups. However, the prevalence of medication overuse and the mean frequency of days using acute medications by week 12 was lower in the group that was switched to a different medication. Adverse events were similar for both groups.

Weaning protocols — The pace at which overused headache medications should be tapered varies by medication pharmacokinetics, dose exposure, and risk of adverse effects associated with weaning.

●For patients discontinuing butalbital, we taper butalbital by 25 to 50 percent every three to seven days. In addition, we add a phenobarbital taper for seizure prophylaxis when butalbital is stopped abruptly or when high doses are being used. Our preferred regimen is 30 mg of phenobarbital per day for every 100 mg of butalbital that was being used, given that each 100 mg of butalbital is pharmacologically equivalent to 30 mg of phenobarbital. Assuming the total daily dose of butalbital is no higher than 300 mg, the recommended maximum, the initial phenobarbital dose should not exceed 90 mg and can be tapered by 30 mg every three to seven days following butalbital discontinuation [14].

●For patients discontinuing opioids, we taper slowly to minimize the risk of withdrawal symptoms and adverse effects. Strategies for opioid tapering are discussed in detail separately. (See "Opioid tapering for patients with chronic pain", section on 'Opioid tapering strategy'.)

●For patients discontinuing benzodiazepines, we taper slowly based on the pharmacokinetics of the specified overused medication, typically reducing by 25 to 50 percent every one to two weeks. Benzodiazepine weaning is discussed in greater detail separately. (See "Benzodiazepine use disorder", section on 'Medically supervised taper'.)

●For patients discontinuing other medications (eg, triptans, NSAIDs, analgesics), we typically discontinue without a taper.

During weaning, we typically provide acute therapy for breakthrough attacks and bridge therapy for patients with severe symptoms or those discontinuing barbiturates, opioids, and benzodiazepines. For most patients, we also start preventive therapy to provide longer-term benefit. (See 'Provide acute or bridge therapy' below and 'Start preventive therapy' below.)

Clinical setting — Withdrawal of overused acute medications can be accomplished on an outpatient or inpatient basis [11]. Most patients can be managed as outpatients, but inpatient treatment may be warranted for patients with severe or refractory symptoms or those weaning from high-risk medications.

●Outpatient discontinuation is particularly appropriate for patients who are highly motivated and those taking typical acute headache medications (eg, NSAIDs, triptans, ergotamines) or taking lower doses of barbiturates, opioids, or benzodiazepines that can be tapered gradually [15].

●Inpatient discontinuation may be appropriate for patients taking high or frequent doses of barbiturates, opioids, or benzodiazepines, those at risk for adverse effects from discontinuation or associated with comorbid medical conditions (eg, depression and anxiety), and patients who have been unsuccessful with prior attempts at outpatient discontinuation.

A multicenter observational study of patients with MOH compared inpatient detoxification with outpatient detoxification [16]. At six months, two-thirds of all patients were no longer overusing acute medications and had reverted to an episodic headache pattern (ie, fewer than 15 headache days per month). Inpatient and outpatient strategies were both effective, but there was a higher dropout rate in the outpatient group.

Significant complications may occur when withdrawing from opioids, benzodiazepines, and barbiturates, and the choice between outpatient and inpatient withdrawal of these agents remains an area of debate [17]. Some experts favor inpatient withdrawal with close observation and medical monitoring in the first several days [18]. However, it is often reasonable to try outpatient treatment first unless serious withdrawal problems develop or are considered likely.

In addition to the number and type of overused substances, variables influencing the choice between outpatient and inpatient management include social support structure, patient motivation, medical stability, presence of coexisting medical illness, psychologic and psychiatric comorbidities, and need for patient monitoring during administration of medical therapies [18,19].

Provide acute or bridge therapy — Acute or short-term daily bridge therapy using an alternative medication to treat or prevent breakthrough attacks is used to provide additional symptom relief while the overused medication is being weaned. During the period of acute medication discontinuation, the headaches may worsen before subsequently improving [11]. In addition to increased headache, withdrawal symptoms can include nausea, vomiting, restlessness, anxiety, nervousness, and disturbed sleep [11,12].

Expected duration of withdrawal — Withdrawal symptoms typically last 2 to 10 days [12] but occasionally can persist for as long as two to four weeks [11].

The duration and severity of withdrawal headache depend on the type of overused agent. In one prospective study of 95 patients, the mean duration of withdrawal headache was 4.1 days for triptans, 6.7 days for ergots, and 9.5 days for analgesics (most of which were combined with codeine, caffeine, or barbiturates) [20]. Overall, withdrawal from triptan-induced MOH was less severe than withdrawal from other analgesics.

Acute therapy for infrequent breakthrough attacks — For patients with MOH weaning from an overused acute medication who have intermittent headache attacks or milder symptoms, we provide an alternative medication to treat or prevent breakthrough attacks to be used ≤2 days each week.

We typically use an acute headache treatment from a different class than the overused medication. Acute therapy is used ≤2 days/week. As examples, for patients weaning from barbiturates or opioids, common options include NSAIDs, triptans, calcitonin gene-related peptide antagonists, or lasmiditan. Acute therapies for management of common forms of headache are discussed in detail separately.

●(See "Acute treatment of migraine in adults".)

●(See "Tension-type headache in adults: Acute treatment".)

●(See "Cluster headache: Treatment and prognosis", section on 'Acute interventions'.)

Acute therapy may be appropriate for patients with milder symptoms or less frequent headache attacks who can manage with intermittent acute therapies. The utility of acute therapy as a component of MOH treatment has been shown in multiple studies [13,21,22].

Bridge therapy for patients with severe symptoms — Patients with frequent or persistent headaches, severe symptoms, and those treated in inpatient settings typically warrant a short course of daily (bridge) therapy to provide symptom relief during weaning. Bridge therapy consists of adding a daily medication to reduce the frequency and severity of headaches that are expected to occur during the initial one to two weeks following discontinuation of the overused medication. Bridge therapy may consist of oral agents administered in the outpatient setting or parenteral agents used in inpatient or other monitored settings.

The data supporting bridge therapy strategies are largely from case series, retrospective chart reviews, prospective uncontrolled studies, and expert opinion [11]. No high-quality comparative studies exist regarding the different options for bridge therapy.

Outpatient setting — For patients using bridge therapy in the outpatient setting, we use either long-acting NSAIDs or glucocorticoids, using patient preferences and medication risk profiles to select between these options. Antiemetic agents may also be added for patients with significant nausea and/or vomiting.

●Glucocorticoids — We commonly use prednisone as bridge therapy for patients using glucocorticoids, starting at 60 mg on day 1 and reducing by 10 mg decrements every one to two days.

Other glucocorticoid bridge protocols used in patients with MOH or similar patients with status migrainosus include intravenous (IV) methylprednisolone 100 to 200 mg or dexamethasone 4 mg, each every 12 hours for two to three days [11,21-23].

Data showing the effectiveness of glucocorticoids for MOH bridge therapy are limited and conflicting. A 2017 meta-analysis of patients with migraine who developed MOH identified four randomized controlled trials comparing prednisone with placebo or celecoxib after medication withdrawal and concluded that there was low- to very low-quality evidence of limited benefit with prednisone [24]. In addition, it is not clear whether patients with primary headache types other than migraine (eg, chronic tension-type headache) might benefit from glucocorticoids [25]. According to 2011 European guidelines, however, prednisone at a dose of at least 60 mg is possibly effective in the treatment of withdrawal symptoms [26]. Larger randomized controlled trials are needed to clarify the role of glucocorticoid bridge therapy in the management of MOH.

●Nonsteroidal anti-inflammatory drugs — For patients using NSAIDs for outpatient bridge therapy, we prefer naproxen sodium 550 mg twice daily for two to four weeks while the overused acute medication is weaned [11]. An alternative is naproxen sodium 550 mg twice daily for one week and then once daily for one week.

Evidence from small studies suggests that naproxen is useful as bridge therapy during withdrawal of overused analgesic medications [27,28]. In a series of 22 patients with MOH, patients who received naproxen 500 mg twice daily had less pain, nausea, vomiting, and restlessness at eight-day follow-up than those given acute medications (antiemetics, analgesics, hydration) as needed [29].

●Tizanidine plus nonsteroidal anti-inflammatory drugs — Bridge therapy using tizanidine combined with an NSAID may also be effective for MOH.

A retrospective study of a subset of 55 outpatients with chronic migraine and MOH evaluated the effect of tizanidine (started at 2 mg at bedtime) plus a long-acting NSAID (eg, piroxicam, naproxen, ketoprofen sustained release, or celecoxib) [30]. Patients were instructed to stop frequent use of the suspected offending analgesics and to self-administer triptans or dihydroergotamine (DHE) for severe headache; triptans were not permitted if they were the offending drugs. Tizanidine was titrated up by 2 mg every three to five days until a therapeutic effect or sedation occurred. The mean daily tizanidine dose was 3.6 mg (range 2 to 16 mg). At six weeks, the number of patients whose symptoms responded (ie, those with no or trivial analgesic use) was 36 patients (65 percent). The treatment protocol was well tolerated. However, the findings are limited by the retrospective design and the concurrent use of triptans and DHE.

Inpatient settings — For most patients with MOH managed in inpatient settings, we suggest bridge therapy using IV DHE plus adjunctive therapy with metoclopramide based on clinical experience and observational data. Alternative options for patients whose symptoms do not respond or have a contraindication to DHE include prochlorperazine, valproate sodium, or methylprednisolone.

●Dihydroergotamine – DHE appears to be beneficial as bridge therapy for MOH. IV DHE is also used as acute treatment for status migrainosus [31].

•Protocols – DHE can be given intravenously as repetitive or continuous therapy based on institutional protocol.

-Repetitive DHE – Repetitive IV DHE treatment (modified "Raskin protocol") consists of IV metoclopramide pretreatment followed by IV DHE given every eight hours until the headache resolves or up to a maximum of three days.

Treatment is started with metoclopramide 10 mg IV given over 30 minutes, followed by a test dose of IV DHE (0.5 mg) given over one minute [32]. Patients who have clinically significant improvement in headache after the test dose continue with DHE 0.5 mg every eight hours. Those with persistent headaches without severe nausea are given an additional dose of DHE 0.5 mg one hour after the first dose, and then DHE 1 mg every eight hours.

Metoclopramide (10 mg) is administered as needed before each infusion of DHE. For patients who have severe nausea, the metoclopramide dose may be increased to 20 mg, or the next dose of DHE can be decreased to 0.25 mg.

The doses of DHE and metoclopramide are adjusted daily based upon headache severity and side effects. Therapy is continued every eight hours until the patient is headache-free or up to 48 hours. At that point, DHE is tapered to every 12 hours for two doses, then discontinued. Alternative options are used for patients with refractory symptoms.

Therapy is stopped if hypertension, severe nausea, or chest pain occur.

-Continuous DHE – Continuous DHE infusion consists of 3 mg DHE in 1000 mL of normal saline delivered at 42 mL/hr by infusion pump, administered at a constant rate over 24 hours [33]. The dose of continuous IV DHE is then weaned over one to two days. Adjunctive metoclopramide (10 mg IV) is given every eight hours as needed for nausea.

Dose reductions in DHE and/or metoclopramide are made if side effects occur. The delivery of DHE can be decreased or interrupted if significant nausea, vomiting, leg cramps, diarrhea, or other undesirable symptoms occur. Once these subside, the DHE dose can usually be continued at a decreased but more tolerable rate. As headaches began to diminish, the dose of continuous IV DHE is weaned over one to two days.

Venous thromboembolic prophylaxis may be warranted for inpatients patients receiving DHE for MOH. Specific strategies including early ambulation, mechanical thromboprophylaxis, and/or pharmacologic thromboprophylaxis vary according to risk of thromboembolism. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Assess risk'.)

•Adverse effects and contraindications – Significant adverse reactions to DHE include nausea, vomiting, dizziness, and somnolence. Pretreatment with metoclopramide may alleviate nausea and vomiting symptoms.

DHE is contraindicated in patients with ischemic vascular disease and/or vaso-occlusive arterial disease involving the coronary, cerebrovascular, or peripheral circulations due to risk of coronary vasospasm, elevated blood pressure, or cardiac arrhythmias. Other contraindications to DHE include pregnancy, uncontrolled hypertension, hemiplegic migraine, migraine with brainstem aura, sepsis, and severe liver or kidney dysfunction.

•Evidence of efficacy – Repetitive IV DHE (the "Raskin protocol") was evaluated originally in a 1986 study that treated 55 patients with chronic intractable migraine headache (including 36 dependent on ergotamine, analgesics, diazepam, or glucocorticoids) [34]. Patients received IV DHE and metoclopramide every eight hours. A control group consisted of 54 matched patients treated with diazepam every eight hours. Many of the patients in both groups were overusing opioids and aspirin-caffeine-butalbital preparations. The proportion of patients who were headache-free was higher among those treated with DHE (89 percent within two days) than patients treated with diazepam (13 percent within six days). Retrospective studies assessing the efficacy of repetitive DHE as a bridge for patients weaning from medications used for chronic daily headache (eg, analgesics, barbiturates, caffeine, opioids, ergots) have reported similar results, typically withing two to three days [32].

Limited data suggest that continuous IV DHE may be as effective as repetitive IV DHE. In a retrospective study of 171 patients with refractory headache, headache-free rates were similar after treatment with continuous IV DHE or repetitive IV DHE (92.5 versus 86.5 percent) [33]. The average hospital stay for both treatment groups was four days. The average length of time to become headache-free was approximately three days for both groups.

●Alternative options

•Prochlorperazine – Short-term treatment with repetitive IV prochlorperazine may be useful as bridge therapy for patients with MOH based on data for patients with chronic daily headache [35].

Prochlorperazine is typically given at 5 to 10 mg orally up to every eight hours or 2.5 to 10 mg IV up to every four hours, with a maximum total daily dose of 40 mg. The dose is titrated as tolerated and needed to alleviate headache symptoms and then discontinued by tapering over a 24-hour period once patients are headache-free. In addition, pretreatment with diphenhydramine 12.5 to 25 mg IV may be administered to treat akathisia and prevent acute dystonic reactions associated with prochlorperazine.

In a retrospective study, 135 patients with refractory chronic daily headache (including 95 with analgesic overuse) were treated with IV prochlorperazine 5 to 10 mg every eight hours, with the dose adjusted up to a maximum of 10 mg every six hours (for no longer than two to three days at the maximum dose) according to efficacy and side effects [35]. After IV prochlorperazine treatment, the response rate (≥50 percent reduction of headache intensity) was noted by 90 percent, and 85 percent were headache-free. Efficacy among patients with analgesic overuse was 70 percent. The mean inpatient stay was six days (range 3 to 20), and the mean total prochlorperazine used was 98 mg (range 15 to 255 mg).

•Valproate sodium – IV valproate sodium may be an option in patients who have contraindications to or have not improved with DHE [36]. Valproate may be given at a loading dose of 15 mg/kg given over 30 minutes followed by maintenance dosing of 5 mg/kg given over 15 minutes every eight hours until headache resolves or a maximum of 48 hours.

In an uncontrolled study, eight patients with chronic daily headache and MOH were treated with IV valproate sodium every eight hours for 12 to 48 hours [36]. All analgesics and triptans were discontinued prior to treatment with valproate sodium, and preventive medications for migraine were begun or continued. Total or near total resolution of headache was reported by four of the eight patients with MOH, while significant improvement in headache was reported by six such patients.

•Methylprednisolone – The benefit of IV glucocorticoid infusion as bridge therapy was assessed in a retrospective study with a five-day protocol consisting of methylprednisolone 250 mg, along with both diazepam 10 mg and esomeprazole 40 mg [37]. The proportion of patients who were pain-free after treatment was 82 percent, and the reduction in monthly headache days at three-month follow-up was 9.4 days.

•Intravenous aspirin – A single retrospective chart review from the United Kingdom reported that open-label IV aspirin (lysine acetylsalicylate) was effective for short-term pain relief, assessed one to three hours after administration [38]. The study evaluated a series of 168 hospitalized adults with various forms of headache, including 165 with chronic daily headache, 159 who were overusing headache medication at admission, and 129 with a primary headache diagnosis of migraine. IV aspirin (1 g) was given from 1 to 50 doses (median five). Among 113 patients with available outcome information, the subjective effect of aspirin was considered good, moderate, or absent for 27, 58, and 14 percent of patients, respectively. The treatment was well-tolerated, and no serious adverse events were reported.

IV aspirin is available in Europe and Japan but is not available in the United States.

Patients who prefer to avoid acute therapy — Some patients may avoid acute or bridge therapy during MOH treatment, due to past intolerances to available options or a preference to reduce the risk of adverse effects of medications. This strategy may be appropriate for select highly motivated patients in the outpatient setting. Foregoing acute therapy may improve headache burden over the long-term but is difficult to pursue because headaches may temporarily worsen during the acute period of discontinuing the overused medication. We do not commonly use this strategy because it may be painful, and it is difficult to adhere to protocols. In addition, most patients being treated for MOH warrant continued use of acute treatment for the underlying headache disorder.

In an open-label controlled trial, 72 patients with MOH undergoing detoxification over two months were randomly assigned to receive either no acute headache medication or acute medication restricted to two days per week [39]. Of 58 patients who completed six-month follow-up, patients assigned to no acute treatment had a greater reduction in headache days per month (46 versus 22 percent) and a higher rate of reversion to episodic headache (70 versus 42 percent) compared with patients assigned to limited acute treatment two days per week. The number of patients who initiated preventive treatment was similar in both groups. Detoxification without acute treatment was assessed to be the most effective detoxification strategy.

Some observational data suggest that discontinuing acute headache medications alone may result in a responsive state amenable to preventive intervention [2]. In an uncontrolled prospective study of 175 patients with probable MOH who discontinued acute headache medications and complied with a two-month medication-free period before starting preventive treatment, approximately one-half had a significant reduction in headache frequency [40]. The remaining 50 percent of patients who showed no initial response at two months improved after onset of preventive therapy with a reported 26 percent reduction in headache frequency. However, in several randomized trials, concomitant preventive therapy was similarly effective for patients who were overusing medications and those who were not [41-48].

Start preventive therapy — Preventive therapy is an important element to help support treatment of MOH as well as the underlying headache disorder. Patients with MOH typically report a high burden of headache attacks warranting preventive therapy for long-term benefit and to reduce the risk of ongoing or future episodes of MOH precipitated by excess use of acute headache medications.

Most patients — For most patients with MOH, we suggest starting preventive treatment at the time the overused medication is discontinued or even before, in agreement with available guidelines and data from clinical trials as well as a 2016 systematic review [26,49,50].

●Selection of therapy – Pharmacotherapy is the mainstay of headache preventive therapy. Preventive medications should be chosen according to the suspected underlying primary headache disorder (eg, migraine, tension-type headache). Preventive pharmacotherapy is discussed in detail separately for the major types of primary headache that underlie MOH.

•(See "Preventive treatment of episodic migraine in adults".)

•(See "Chronic migraine".)

•(See "Tension-type headache in adults: Preventive treatment".)

•(See "Cluster headache: Treatment and prognosis", section on 'Preventive interventions'.)

•(See "Hemicrania continua".)

•(See "New daily persistent headache".)

When presenting features are suggestive of MOH and the underlying primary headache disorder is unknown, we typically start with an agent effective for migraine prevention and, ideally, other forms of primary headache as well, due to the high overall prevalence of migraine and prevalence of migraine amongst patients with MOH. Common initial options in this setting include topiramate or amitriptyline. Alternative preventive options may be identified when the primary headache disorder is identified following MOH treatment and/or guided by response to initial options.

The role of behavioral therapies in long-term management of patients with MOH is uncertain. However, a small randomized, controlled, single-blind trial found that patients treated with frontal electromyographic biofeedback combined with preventive pharmacologic therapy were likelier to experience a decrease in headache frequency compared with those getting pharmacologic treatment alone [51]. Other preventive options that have shown promise for patients with MOH include mindfulness and cognitive-behavioral therapy [52,53].

●Efficacy – Several open-label studies and randomized trials on preventive therapy for primary headache syndrome have reported efficacy in the setting of medication overuse [49,54-64]. In a placebo-controlled trial assessing erenumab in 584 patients with chronic migraine who developed MOH, the rate of MOH remission at six months was higher for those assigned erenumab at 140 and 70 mg doses than those assigned to placebo (69 and 60 versus 53 percent) [65]. Patients assigned to erenumab also used less acute therapy for breakthrough attacks.

Some data have shown that adding preventive therapy provides additional benefit in MOH treatment strategies. One trial of 102 MOH patients evaluated strategies of withdrawing the overused agent, adding a preventive agent, or withdrawing the overused agent plus adding a preventive agent [50]. The reduction in number of monthly headache days was similar across groups at six months. However, remission from chronic to episodic headaches was more likely in patients in the withdraw-plus-prevention group than those in the withdrawal-only group (74 versus 42 percent) [50]. In a prospective, open-label investigation of 56 adults with MOH who were assigned to prophylactic treatment without instructions to stop the overused medication (the prophylaxis group), discontinuation of the overused medication without prophylactic treatment (the withdrawal group), or no specific treatment (the control group), headache burden was reduced in both the prophylaxis and withdrawal groups at three-month follow-up [66]. The prophylaxis group averaged 7.2 fewer headache days per month (95% CI -2.7 to -11.8), and the withdrawal group averaged 4.2 fewer headache days per month (95% CI -3.3 to -7.4), while the control group averaged 1.6 fewer headache days per month (95% CI 1.8 to -5.1).

Preventive therapy may also improve headache burden even for patients who initially continue the overused medication [13,41-48,67-69]. As an example, a secondary analysis of two trials of onabotulinumtoxinA for the treatment of chronic migraine focused on the subgroup of 904 subjects who were overusing medications at baseline [47]. Among patients overusing acute medications at baseline, those who received onabotulinumtoxinA had greater reductions in headache days, migraine days, days with moderate to severe headache, headache episodes, number of hours with headache, and the percentage of participants with severe headache-related disability than those assigned to placebo. In a prospective, open-label randomized trial of 720 participants with MOH, similar reductions in frequency of moderate to severe headache days during weeks 9 to 12 after randomization were reported for groups assigned preventive medication plus discontinuation of the overused medication as for those assigned preventive medication alone [13].

Patients who prefer to avoid preventive therapy — Stopping the overused medication without adding preventive medication is an alternative strategy that has been observed to improve headache burden [70]. Some patients may prefer this approach to limit risk of adverse effects from pharmacotherapy. However, we do not use this strategy for most patients because patients may have worsening headaches after acutely stopping the overused medication and may be unable to adhere to the protocol. In addition, identifying effective preventive treatment during MOH treatment may be warranted to help manage underlying headache disorder.

FOLLOW-UP AND RELAPSE PREVENTION — 

It is important to establish or maintain follow-up after the overused medications have been stopped [11]. Patients who successfully complete treatment for MOH frequently return to a pattern of intermittent headaches that may require ongoing monitoring and management to further improve headache burden and reduce the risk of recurrent MOH.

●Maintain effective preventive therapy – Effective preventive therapy guided by the underlying headache condition should be optimized. Adjunctive therapies may need to be added for patients with suboptimal benefit, and ineffective therapies should be substituted. (See "Preventive treatment of episodic migraine in adults" and "Chronic migraine" and "Tension-type headache in adults: Preventive treatment" and "Cluster headache: Treatment and prognosis" and "Hemicrania continua".)

●Guide appropriate use of acute therapies – To prevent the redevelopment of MOH, acute medications should be provided for breakthrough attacks, and education in their use should be provided. The frequency of acute medication usage should be appropriately limited to avoid risk of recurrent MOH, and the rationale for the restriction should be explained to the patient.

To prevent MOH, our preference is to limit the use of triptans, ergotamines/dihydroergotamine (DHE), or combination analgesics to nine or fewer days per month on average, butalbital-containing analgesics should be used sparingly (if at all), and dosing limited to three or fewer days per month, and nonsteroidal anti-inflammatory drugs (NSAIDs) to 14 or fewer days per month (table 2) [71]. The more restrictive limits on butalbital-containing analgesics are due to their high potential for MOH. We generally avoid opioids and/or butalbital for the regular management of primary headache disorders.

Calcitonin gene-related peptide antagonists and noninvasive neuromodulation are acute treatment options that are not likely to be associated with MOH [72].

Ineffective acute therapies should be stopped, and other therapies substituted.

The acute treatment of migraine and tension-type headache is reviewed in detail separately. (See "Acute treatment of migraine in adults" and "Tension-type headache in adults: Acute treatment" and "Cluster headache: Treatment and prognosis", section on 'Acute interventions'.)

●Treat comorbid risk factors – Proper treatment of MOH and relapse prevention requires recognition of the elements that may contribute to and underlie its development and perpetuation. Coexistent anxiety should be properly managed if present. (See "Medication overuse headache: Etiology, clinical features, and diagnosis", section on 'Biobehavioral factors'.)

PROGNOSIS — 

The overall prognosis of patients who complete MOH treatment is variable. The long-term success of withdrawal from MOH depends, in part, on the type of primary headache and the type of overused medication. Most relapses happen in the first year after withdrawal.

A meta-analysis of 17 studies and 1101 patients with MOH found that the success rate for withdrawal therapy at one to six months was 72 percent, where treatment success was defined as either no headaches or a reduction in headache days of >50 percent [12]. In a study with prospective data collected from 240 patients with MOH who were treated with drug withdrawal and preventive therapy, the one-year rate of treatment success (defined as absence of chronic headache and medication overuse) was 57 percent [73].

●Risks for relapse – Factors suggestive of unfavorable treatment outcome include [73-76]:

•Higher frequency of primary headache attacks

•Ergotamine overuse

•Greater severity of headache-related disability at the time of MOH diagnosis

•Tension-type headache at baseline

●Long-term remission – In a prospective study of 96 patients with MOH, complete data sets at four years were available for 75 patients [75]. The relapse rate at six months, one year, and four years was 31, 41, and 45 percent, respectively.

Outcome at one year after MOH treatment may be a reliable predictor of long-term remission and could be an important time to detect those at risk of MOH relapse. In a prospective cohort study at a specialized headache center, 240 patients with MOH were treated and included in a one-year follow-up study and then subsequently followed for up to 10 or more years (median follow-up three years) [77]. At the end of follow-up, approximately 43 percent were in remission. The most important predictors of remission were lower number of headache days per month at one year (hazard ratio [HR] 0.94, 95% CI 0.88-0.99) and efficient initial drug withdrawal (HR 0.14, 95% CI 0.04-0.44).

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Medication overuse headache (The Basics)" and "Patient education: Headaches in adults (The Basics)" and "Patient education: Migraine in adults (The Basics)")

●Beyond the Basics topics (see "Patient education: Headache causes and diagnosis in adults (Beyond the Basics)" and "Patient education: Headache treatment in adults (Beyond the Basics)" and "Patient education: Migraine in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Patient education – Treatment begins with patient education about how the excessive use of some of headache medications has the potential to worsen headache symptoms, leading to MOH, and also may cause medication adverse effects or toxicities (table 2). (See 'Patient education' above.)

●Treatment approach – Our approach to the management of MOH typically involves weaning or discontinuing the overused medication, providing acute treatment for breakthrough pain or short-term preventive (bridge) therapy for patients with severe symptoms, and starting longer-term preventive therapy (table 1). (See 'Initial management' above.)

•Weaning the overused medication – For most patients with MOH, we suggest weaning the overused medication rather than continuing (Grade 2C). Weaning may reduce the risk of adverse effects associated with excessive medication use. However, the selection of a weaning strategies should be individualized based on the class and dose of the overused medication, risk of adverse effects, patient preferences, and available resources. Weaning strategies include discontinuing the overused medication, reducing the frequency of use, or continuing use during initial treatment with subsequent taper. (See 'Wean the overused medication' above.)

The pace at which overused headache medications should be weaned varies by medication pharmacokinetics, dose exposure, and risk of adverse effects associated with weaning. (See 'Weaning protocols' above.)

-For patients discontinuing butalbital, we taper butalbital by 25 to 50 percent every three to seven days. In addition, we add a phenobarbital taper for seizure prophylaxis.

-For patients discontinuing opioids, we taper slowly to minimize the risk of withdrawal symptoms and adverse effects.

-For patients discontinuing benzodiazepines, we taper slowly based on the pharmacokinetics of the specified overused medication, typically reducing by 25 to 50 percent every one to two weeks.

-For patients discontinuing other medications (eg, triptans, nonsteroidal anti-inflammatory drugs [NSAIDs], analgesics), we typically discontinue the overused medication without a taper.

•Acute or bridge therapy – For patients with MOH intermittent headache attacks or milder symptoms, we suggest an acute agent from a different class rather than the overused medication to be used ≤2 days each week (Grade 2C). (See 'Acute therapy for infrequent breakthrough attacks' above.)

Patients with frequent or persistent headaches, severe symptoms, and those treated in inpatient settings typically warrant a short course of daily preventive (bridge) therapy to provide symptom relief during weaning. (See 'Bridge therapy for patients with severe symptoms' above.)

-For patients treated in the outpatient setting, we typically use long-acting NSAIDs or glucocorticoids, using patient preferences and medication risk profiles to select between these options.

-For patients treated in the inpatient setting, we typically use intravenous (IV) dihydroergotamine (DHE) plus adjunctive therapy with metoclopramide to provide symptom relief during weaning. Alternative inpatient treatment options include prochlorperazine, valproate sodium, or methylprednisolone.

•Adding preventive therapy – For most patients with MOH, we suggest starting preventive treatment at the time the overused medication is discontinued (Grade 2C). Preventive therapy is an effective component of MOH treatment in multiple studies. Preventive medications should be chosen according to the suspected underlying primary headache disorder (eg, migraine, tension-type headache). (See 'Start preventive therapy' above.)

●Preventing relapses – Patients who successfully complete treatment for MOH frequently return to a pattern of intermittent headaches that may require ongoing monitoring and management to further improve headache burden and reduce the risk of recurrent MOH. This includes maintaining preventive therapy for long-term benefit, providing acute headache therapies at appropriate doses for breakthrough attacks, and treating comorbid conditions. (See 'Follow-up and relapse prevention' above.)

●Prognosis – The overall prognosis of patients with MOH is variable with long-term treatment success rates approximately 60 to 70 percent. Risks for relapse include high frequency of primary headache, tension-type headache at baseline, presence of headache-related disability, and overuse with ergotamine overuse. (See 'Prognosis' above.)