Medication-Overuse Headache

The prevalence of chronic daily headache, defined as headache on 15 or more days per month, is 2% to 5%.¹ People with this condition experience a disproportionate amount of disability, expense, high medical resource use, and stigma,^2-6 and often have comorbid conditions that can affect the headache care needed.⁷ Chronic daily headache is often precipitated by overuse of acute treatment for headache disorders in which case it is defined as medication-overuse headache (MOH). People with migraine who use over the counter and prescription medications for acute treatment of migraine attacks are at higher risk for MOH,⁹ which has been recognized since the overuse of early anti-inflammatories around the turn of the 19th to 20th century, seen with ergotamine withdrawal headache in the 1950s, and continues to evolve as newer treatments become available.^1,8 The current definition of MOH is headache on 15 or more days/month in a person with a pre-existing headache disorder who has used 1 or more acute headache treatments on 10 to 15 days/month (depending on the medication) for a period of over 3 months.¹

Chronic migraine, defined as 15 or more headache days per month with at least 8 headache days with migraine features for a period of more than 3 months, can occur with or without medication overuse.¹ Approximately 50% of patients with chronic migraine revert to an episodic pattern (<15 migraine attacks/month) after the precipitating agent is withdrawn.¹⁰

Risk Factors for MOH

All acute treatments have known risk of MOH except the recently approved ubrogepant and rimegepant, for which no risk of MOH has yet been observed. Risk of MOH varies with in-person characteristics including comorbid medical conditions, class of drug used, and frequency of use. Pathophysiology and variable risk of different agents is, however, still poorly understood, and few prospective studies have been done. With the limited data available—mostly retrospective and descriptive—it appears the frequency of use that puts an individual at risk varies among drug classes. This may help determine which acute medications may be reasonable options given the individual characteristics of the person with migraine and the care that they should receive. The most associated medications are opioids, triptans, and combination analgesics.¹¹

A groundbreaking study matched 206 people with chronic daily headache with 507 people with episodic headache conditions. Baseline characteristics showed individuals with chronic daily headache were more likely to use over the counter caffeine-analgesic combinations, triptans, opioids, and other prescription pain medications. Use of aspirin and ibuprofen were negatively associated with chronic daily headache (odds ratio [OR], 0.5 for aspirin and 0.7 for ibuprofen).¹²

Opiates appear to increase risk of chronic daily headache, in part, depending on dose and frequency of use. Use on more than 8 days/month correlates with higher frequency of MOH, especially among men.¹² Barbiturates also appear to have a dose-dependent risk; use on more than 5 days/month correlates with chronic daily headache, particularly in women.¹³ Triptans, including sumatriptan, seem to require higher frequency of use to correlate with chronic daily headache.

Caffeine-containing compounds have unclear risk but are often mixed with nonsteroidal medications that have frequency limitations. Many caffeine-containing compounds have an equivalent dose to a small cup of coffee, and total caffeine dosage in beverages and foods should be added when calculating total caffeine use. The risk with nonsteroidal anti-inflammatory drugs (NSAIDs) is also controversial, because a wide variety of drugs are included in this umbrella term. NSAID use on less than 10 days/month may be protective, but more frequent use may increase risk of MOH. It is unknown if this would vary with medication half-life.¹³ A general rule of thumb has been to limit use of any acute medications less than 10 days/month to avoid MOH and offer preventive treatment to anyone with migraine or other headache conditions on 10 or more days/month.^1,11,13

Treatment

A randomized clinical trial compared 3 strategies for treatment of MOH. Individuals were randomly assigned to have discontinuation of precipitating agent(s) with concurrent addition of preventive treatment, addition of preventive treatment without discontinuation, or discontinuation alone for 2 months followed by optional preventive treatment. Those who had discontinuation and preventive medication had a higher mean reduction in headache days/month (-12.3; 95% CI, 9.3-15.3) compared with those who had added preventive medication alone (9.9; 95% CI, 7.2-12.6) or discontinuation alone (8.5; 95% CI, 5.6-11.5). There was a 30% increase in resolution of MOH in those who had discontinuation plus prevention (P=.03). Of 483 individuals referred to the trial, 120 agreed to participate.¹⁴ See Table for preventive treatments.¹⁵

Discontinuation

When trying to discontinue acute medications, it is critical to establish the goals of treatment early with the patient. It is essential that they be engaged in their care and understand the reason and methodology behind the treatment. It is often difficult to help even the most willing of participants, but nearly impossible to treat someone who is not motivated to change behavior that they may have participated in for decades.¹⁶ The process is organized to eliminate each potentially precipitating agent to improve long-term outcomes. Although an individual may have depended on a particular agent for short-term symptomatic relief, continued use may further impair ability for long term success.¹⁷

It is essential to maintain patients’ comfort through the process and avoid physiologic symptoms from discontinuing medication. Depending on the substance being withdrawn, monitor vital signs and symptoms (eg, tremulousness, akathisia, piloerection, insomnia, anorexia, mood change including suicidality, diarrhea, or other neuropsychiatric and physiologic signs). To know precisely what symptoms to watch for, it is important to be aware of what medications were used at what dosages.¹⁸ Only some agents used for migraine bear significant medical dangers during acute discontinuation. Benzodiazepine or barbiturate withdrawal, however, has a very real risk of withdrawal shakes, seizures, and cognitive changes. Many do not realize combination medications (eg, butalbital/acetaminophen with or without caffeine) can cause physical dependency, and many people underestimate the true number of doses they take across a full day. Overestimating the amount an individual may use is a conservative approach, but accurate pill counts can help improve the discontinuation experience.

Depending on the agent(s) overused, several general processes may be followed to facilitate a comfortable, efficient, and effective discontinuation. When multiple agents are concurrently overused, aspects of several protocols can be combined. It is important to have open dialogue with the patient to ensure they are progressing appropriately or if the protocol needs further regular adjustment.¹⁹ For opioid discontinuation, refer to Chronic Pain: Opioid Tapering in the March 2021 issue.

Barbiturate Containing Compounds. Depending on the combination analgesic, butalbital is often combined with caffeine, and both drugs should be considered in the detoxification. Because butalbital is a short-acting barbiturate, it can successfully be switched with a longer-acting barbiturate, such as phenobarbital, to allow a slower gradual detoxification. In other circumstances, consider clonazepam, lorazepam, diazepam, or oxazepam (in patients with liver dysfunction.)

Other Caffeine-Containing Compounds. There is no well-established caffeine withdrawal protocol given the lack of other established adenosine receptor agonists. Caffeine may be standardized by use of an established dose of coffee, a tablet of caffeine or other dosage form and provided in gradually reducing amounts over time. While some may prefer to use an abrupt “cold turkey” approach, gradual cessation appears to be more successful with long term discontinuation or reduction.

Triptan or Ergots. Although discontinuation of these compounds may not have physiologic withdrawal, it can be coupled with acute exacerbation of the headache condition. It is unclear whether the long-term modulation of calcitonin gene-related peptide (CGRP) or serotonin receptors (5HT_1B,D), where these agents act, have other physiologic effects as well. Discontinuation of triptans or ergotamines can be facilitated with use of intravenous, intramuscular, or intranasal dihydroergotamine (DHE) as per protocols described below.

Bridge Treatments

Even if preventive medication (Table) is added during discontinuation, it may take time to take effect, and break through migraine attacks can occur even when preventive treatment is effective. In the short term, patients may need a more potent treatment to help suppress headache, myalgias, or neck pain during that period.²⁰

Bridge treatments may be provided in a hospital setting or infusion suite, if intravenous, or arranged at home for oral or nasal regimens. Ensure patients understand bridge therapy as transitional care and the role it plays in long-term treatment of the headache condition. These are generally off-label treatments without clear instructions for this use that can be confusing for patients to understand. Success can be enhanced by regularly checking with the patient and modifying treatment based upon tolerability, efficacy, and side effects.²¹

Oral or intravenous steroids (eg, dexamethasone, prednisone, methylprednisone) may be used as bridge therapy, although the dose is not well established. Declining tapering with glucose monitoring and prophylactic treatment of gastrointestinal side effects is recommended. NSAIDs (eg, diclofenac or indomethacin) combined with antiemetics (eg, metoclopramide, chlorpromazine, and prochlorperazine) can address inflammatory pain mechanisms and gastric symptoms often found in migraine and are often more effective in combination.

DHE has been used intravenously (the Raskin protocol)²² intramuscularly, and as a nasal spray (nasal burst protocol) but should not be used within 24 hours of triptans or other serotonergics. Contraindications and potential side effects should be considered beforehand, and prophylactic treatment of gastrointestinal side effects with ondansetron or dromperidone should be given before each DHE dose. For intravenous treatment, a starting dose of 0.5 mg in 100 mL Is given intravenously over 1 hour. If tolerated, a dose of .75 mg in 250 mL is given 8 hours later and then repeated every 8 hours for 3 to 5 days. With nasal spray, 2 doses are given 15 minutes apart (0.5 mg in each nostril twice for full dose of 2.0 mg) every 8 hours for 3 days.

Long-Term Treatment

After medications have been discontinued, they should be replaced with effective preventive treatment if that was not started during discontinuation. It is essential not to return to use of the precipitating medications. This can be difficult for patients who may be tempted to return to a medication that they once found effective. It is exceedingly hard to limit the use of a medication when someone had free access to it previously. It is far better switch to an alternative class or agent to avoid repeating previous behavior.²³

Summary

Acute medications are essential in the management of a migraine or headache disorder but are double-edged swords because gradual increase in use may cause MOH and these agents can be difficult to discontinue. By discontinuing the precipitating acute agent, we seek to improve the effectiveness of both preventive and acute medications. Preliminary evidence suggests that discontinuation with concurrent preventive medication may be the most effective treatment. Bridge treatments may be needed as medication regimens are adjusted.