Breaking the cycle of medication overuse headache

By Tyler Reimschisel, MD

The cause of your patient's chronic headache may be the very thing she is taking for relief. The solution sounds simple but is often challenging—complete discontinuation of headache medication.

A 9-year-old girl has been brought to the pediatric neurology clinic for evaluation of chronic headache. The headaches cause right supraorbital or bifrontal pain that she describes as "throbbing" or "tight." The pain is occasionally associated with nausea and abdominal pain. At their worst, the headaches cause her to cry out in pain. The severe headaches are also associated with phosphenes (visual sensations experienced with the eyes closed and in the absence of light), photophobia, and phonophobia.

The headaches have been slowly increasing in frequency over the last two years. When she was in first grade, the girl had a headache every two or three weeks; in second grade, once a week; and now, in third grade, at least two or three times a week. Her use of over-the-counter medication during the past two years has also increased steadily. For the last seven months she has taken ibuprofen at least two or three days a week.

The headaches have worsened in frequency and severity without any obvious triggers. She has not sustained any head trauma or had any major illness. Despite the intensity of her headaches, she has not missed school. There is a family history of migraine headache. Her physical examination, including a thorough neurologic examination, is entirely normal.

The history of progressively worsening headaches associated with frequent analgesic use is consistent with medication overuse headache. The intermittent, severe headaches that she has are migraines. The pediatric neurologist discusses the diagnoses and the cause of medication overuse headache. He recommends that she stop taking ibuprofen. The ibuprofen is discontinued, and over the next few months her headaches diminish significantly. She now has a migraine headache less than once a month.

This is a typical case of medication overuse headache (MOH). Synonyms for this headache disorder include rebound headache and drug-induced headache. MOH is also known as analgesic rebound headache, but this is a misnomer because the headache can develop from the frequent use of a variety of abortive headache medications, not just analgesics. Possible offending agents include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, caffeine, opiates, benzodiazepines, barbiturates, and ergotamines.¹ The headaches are usually dull, bilateral or unilateral, and daily or almost daily. They recur when the abortive therapy wears off.² Over time, more frequent and larger doses of medication are needed to control the pain.

It is not well established how frequently or how much medication must be used in children or adolescents before MOH develops. Most people with MOH use abortive medication on a daily or near-daily basis. However, in my experience, MOH can develop in children or adolescents who use abortive medications only two or three days a week for multiple weeks to months, as exemplified by the patient in the opening vignette.

People who suffer from MOH have an underlying, primary headache disorder that is exacerbated by the frequent use of abortive medications.³ For example, migraines can "transform" into chronic daily headaches if the migraine medication is overused. Alternatively, a person with infrequent headaches may begin to use analgesics often when an illness or injury causes frequent or severe headaches. After the illness resolves or the injury heals, the person finds that attempts to discontinue the medication precipitate a headache.

Although MOH is common in children, adolescents, and adults, it is under-recognized and under-diagnosed. It is the most common cause of daily or near-daily chronic headaches.⁴ It is also the most common cause of chronic daily headaches in adult patients presenting to headache specialty clinics in the United States.⁵ Failure to address MOH in children could lead to dependence on narcotics or other addictive drugs in adulthood, as patients with MOH may develop tolerance to over-the-counter analgesics.

This article will review the possible pathogenesis of MOH, discuss the evaluation of patients who may suffer from this disorder, and provide recommendations for treatment and prevention.

Pathogenesis

MOH appears to occur only in people with a history of recurrent headaches who use abortive therapies at least two to three days a week for multiple weeks.³ People who overuse abortive medications do not develop MOH unless they have a history of migraines or another headache syndrome. For example, people who do not suffer from migraines or another chronic headache syndrome but who use an analgesic regularly for arthritis do not develop MOH.⁶ These findings suggest that only headache sufferers have a predisposition to developing MOH. There is recent evidence that only migraineurs can develop MOH,⁷ but this has not been well established.

Multiple theories have been proposed to explain the pathogenesis of the disorder. There may be a genuine rebound effect, in which headache severity is inversely correlated with the level of the drug in the blood or the activity of the drug at its receptor site.⁸ In another theory, the pain modulation system in the brain of people with MOH may be impaired. Serotonin is the principle neurotransmitter in this system. It is hypothesized that serotonin enhances the efficacy of enkephalin-mediated analgesia.² When serotonin activity is low, responsiveness to noxious stimuli increases; that is to say, when the serotonin level is low, a noxious stimulus hurts more than when the serotonin level is high. Hering and colleagues showed that people with MOH have a low whole blood serotonin level.⁹ The serotonin level increases as the headache resolves. Furthermore, compared to people with migraines who do not overuse abortive medication, people with MOH have less serotonin in their platelets,¹⁰ and more serotonin receptors on the platelet membranes.¹¹ People with MOH, therefore, have serotonin hypofunction. According to Mathew, these data suggest that medication overuse depletes serotonin and impairs intrinsic pain modulation.⁴

History

Obtaining a comprehensive history is the most important aspect of evaluating a patient with chronic headaches. Keep in mind that the person may suffer from more than one type of headache. For example, he may have intermittent migraines superimposed on a daily, chronic headache that is secondary to medication overuse. The discussion that follows focuses on aspects of the history that are pertinent to diagnosing MOH (Table 1). A review of the components of a comprehensive headache history is beyond the scope of this article.

TABLE 1
Historical features of medication overuse headaches

The character of MOH is usually easy to differentiate from other headache types. It is usually less intense than a typical migraine, dull, bilateral or unilateral, and fronto-occipital or diffuse.¹ The headaches can, however, vary in character, location, and intensity from time to time.¹² The pain threshold in patients with MOH is lowered, and any minor disturbance can trigger a headache.¹²

The frequency of the headaches can also vary. They usually occur two to four times a week, but may become more frequent as use of abortive medication increases.²

Medication overuse headaches may be associated with nausea, irritability, restlessness, memory problems, and difficulty concentrating.¹ They are not associated with focal neurologic symptoms such as phosphenes, scotomas, paresthesias, or weakness.²

It is essential to ask the patient or family member to list all the medications that are used to treat headaches. MOH can occur from overuse of acetaminophen, NSAIDs, triptans, caffeine, opiates, benzodiazepines, barbiturates such as butalbital, and any combination of these drugs. Over time, many people with MOH develop tolerance to medications. Higher and more frequent doses are required to treat the headaches.^2,4 The clinician should, therefore, inquire about the doses and frequency of all medications taken. She should ask specifically about nonprescription medications, because patients and family members may think that use of over-the-counter drugs is unimportant. The clinician should also ask about the patient's caffeine intake.

The headaches typically develop when the abortive medication wears off, usually about three to four hours after the last dose is taken. In addition, people with MOH may get a severe, early morning headache that awakens them from sleep.¹ These headaches can be particularly worrisome because early morning headache is commonly associated with space-occupying lesions in the brain. Headache caused by a brain tumor is, however, frequently associated with other medical problems and focal neurologic abnormalities that help distinguish it from overuse headache.

Studies in adults have shown that there is an increased incidence of depression in individuals who have MOH.^1,4 In adolescents with chronic nonprogressive (tension-type) headaches, the severity of the headaches may be worsened by underlying depression, anxiety, or other psychosocial stressors. Therefore, in an adolescent or adult with chronic headaches, it is essential to inquire about signs or symptoms of psychiatric disorders, such as anxiety, anhedonia, abnormal sleep, poor anger management, feelings of hopelessness or helplessness, and suicidal or homicidal ideation.

If a person with chronic headaches has comorbid MOH and psychiatric abnormalities, it is still important to treat the MOH by discontinuing all abortive therapies (as explained later in the discussion of treatment). It is also important to simultaneously treat the psychiatric disorders. The clinician should refer such patients to a headache clinic and a psychologist or psychiatrist.

Physical examination

A thorough general and neurologic examination is essential in the evaluation of a patient with chronic headache. The physical examination findings are usually normal. The important components of this examination are listed in Table 2.

TABLE 2
Physical examination of the patient with chronic headache

Ophthalmologic evaluation of the retina should be performed to rule out pseudotumor cerebri. The optic disk margins should be assessed. If venous pulsations are present, it is unlikely that the patient has increased intracranial pressure. Venous pulsations may be absent in unaffected patients, however. Visual acuity and visual fields should be tested. Unexplained focal neurologic deficits, such as unilateral weakness, sensory deficit, or lack of coordination, are worrisome. These deficits should prompt further investigation, and the patient should be referred to a pediatric neurologist. If, on the other hand, the neurologic examination is normal, it is very unlikely that an underlying space-occupying lesion is causing the chronic headaches.

Diagnostic studies

Laboratory tests and neuroimaging studies are unnecessary in the evaluation of a patient with chronic headache if two criteria are met:

• The history is consistent with MOH with or without superimposed migraine or tension-type headache

• There are no unexplained neurologic deficits.

Treatment

Treatment of MOH begins with patient and family education. (Table 3 summarizes the treatment of MOH.) Explain the cause of the disorder and review specific features of the patient's history that suggest that the patient has MOH. If the patient has any additional type of headache, such as migraines or tension-type, those disorders should also be reviewed. Investing time in establishing a mutually respectful physician-patient relationship will help the patient and family accept the recommended therapy.

TABLE 3
Treatment of medication overuse headache

May be done on an outpatient basis

Provide ongoing telephone or clinic support during the drug-withdrawal period

Inpatient admission, if necessary

Symptomatic management of side effects

Amitriptyline daily (start at 5–10 mg/day), with or without naproxen

Naproxen daily (10 mg/kg/dose)

IV dihydroergotamine (see protocol in Wasiewski and Rothner¹)

Prednisone taper (begin at 2 mg/kg/day, taper over 7–10 days)

Valproate daily (10–15 mg/kg/day in two or three divided doses)

Maintain headache calendar

Limited abortive therapy (no more than 2 to 3 days per week)

Consider prophylactic medication (indicated for frequent or severe headaches)

Encourage regular exercise and sleep

Review headache diet (list of foods that in some individuals can exacerbate headache severity^2,3)

Treatment for MOH is straightforward, but it can be difficult for the patient and family to adhere to. First, the patient must discontinue all medications that he is taking for the headaches. Be sure to inform the patient that this will precipitate a severe headache. I usually say, "You must stop all of the medicine that you are using to treat your headaches. Unfortunately, it is very likely that this will make your headaches much worse at first." I try to encourage the patient and family by reminding them that if they persevere through this exacerbation, the frequency and severity of the headaches will lessen significantly.

It usually helps to emphasize that all abortive medications must be stopped completely. Using them even once a week can prevent full recovery and make prophylactic headache medication (discussed later) less efficacious.¹³ Also, inform the patient and family about other withdrawal symptoms that may occur, including anxiety, restlessness, disturbed sleep, nausea, and vomiting. These symptoms usually last two to 10 days.³

Caffeine, acetaminophen, NSAIDs, and triptans should be stopped abruptly. This can be done on an outpatient basis. Opiates, benzodiazepines, and barbiturates should be tapered slowly to prevent withdrawal symptoms. An inpatient admission may be necessary if the patient has been using these medications for a prolonged period. Withdrawal symptoms can be minimized with clonidine.⁴ Admission during the period of drug withdrawal, though not usually indicated, should also be considered for any patient who has depression or another medical condition that may impair his ability to discontinue the medication.

Vasconcellos and colleagues published the best study to date of MOH in children.¹⁴ They performed a retrospective chart review of 24 children with overuse headaches to determine the efficacy of abruptly withdrawing medications. Headache frequency decreased by 80%, and headache severity decreased by 47%. The number of days of school that were missed because of headache decreased from 4.7 to 1.2 days per month. On average, it took approximately six weeks to achieve the best results, but some children improved significantly after only one week. Recovery in others took as long as 12 weeks. Adults with MOH usually recover more slowly—from one week to one year¹³—possibly because adults use more medicines, at a higher dosage, for a longer time. I usually tell patients and their families that the headaches should improve within two weeks to two months.

Once abortive therapies are discontinued, withdrawal headaches usually develop. These headaches can be severe and disabling. Therefore, many specialists recommend using a new medication to ease the pain. In the study by Vasconcellos and colleagues, the children were placed on daily amitriptyline.¹⁴ In the Warner study, dihydroergotamine was used to treat severe headaches.¹³ Diener³ has reviewed other possible treatments, including amitriptyline plus naproxen,¹⁵ naproxen alone,¹⁶ prednisone taper,¹⁷ and valproate.¹⁸

There are no definitive data, however, to show that these medications significantly help treat withdrawal headaches. For example, two of the patients in the Vasconcellos study did not take amitriptyline, yet their recovery was indistinguishable from the recovery of the patients who took the prophylactic medication.¹⁴ Furthermore, the other patients in the study remained headache free for months after discontinuing amitriptyline. In a study of 139 inpatients undergoing drug withdrawal therapy for analgesic-induced chronic headache, Diener and colleagues did not use medication to relieve the overuse headache.¹⁹

Most children with MOH are only misusing over-the-counter medications. In such cases, I believe that initiating yet another medication is unwarranted. The potential benefit offered by these medications has not been proved in children, and the risk of side effects is not negligible. Once I explain this to patients and their families, they are usually willing to discontinue the medication without concomitantly starting another one.

Successful treatment of MOH begins and ends with good communication. During the withdrawal period, the clinician should be available to the patient and family as questions and concerns arise. I have received many calls from worried mothers who want to make sure that they should not treat a severe medication overuse headache. In most cases, listening to their concerns and reaffirming the importance of forgoing abortive treatment is sufficient.

Patients with unexplained neurologic deficits should be referred to a neurologist. In my experience, children with underlying psychiatric disorders or other psychosocial stressors can be very difficult to treat. They should be referred to a headache clinic and psychologist or psychiatrist.

Once the patient has recovered from the overuse headache, he should be evaluated for an underlying, primary headache disorder. In many cases, the primary headaches are mild or infrequent. Limited use—no more than two to three days per week—of abortive treatments, including naproxen or one of the triptans, is appropriate in these cases. Patients who have severe headaches or a headache more than a few times a week should probably be placed on prophylactic medication. Ideally, the patient should recover from MOH before prophylactic medication is prescribed. However, if the patient is suffering from particularly severe or frequent migraines during the drug-withdrawal period, then prophylactic medication is indicated at that time.

Prophylactic headache medications are taken daily to prevent the development of a headache. Typical medications used for prophylaxis include b-blockers such as metoprolol and atenolol, tricyclic antidepressants such as amytriptyline and nortriptyline, and anticonvulsants such as valproate, neurontin, and topiramate. Abortive medication is used when necessary for breakthrough headaches. The comprehensive treatment of migraine headaches, including the selection and initiation of abortive and prophylactic medication, is beyond the scope of this article, but the reader is referred to a recent review.²⁰

Prevention

Anticipatory guidance and patient education can help prevent MOH. I tell all my headache patients that they should never take medication for their headache, in any combination, more than two or three days a week. More frequent use can lead to MOH.

Improper management of children with chronic headache can lead to significant health problems in adulthood. An adult headache specialist reminded me recently that failure to address MOH in children could lead to dependence on narcotics or other addictive drugs in adulthood. He sees many patients in whom MOH was unrecognized in childhood. When these patients developed tolerance to over-the-counter medications, they turned to opiates, benzodiazepines, or barbiturates to treat the pain. Treating MOH in patients who use these medications is much more challenging than addressing overuse of over-the-counter medications in childhood. Clinicians who identify and treat MOH in children or adolescents may significantly improve their patient's health in adulthood.

In many cases, children who are brought to a pediatric neurology clinic for evaluation of chronic headache have developed MOH because their primary care clinician was unaware that frequent use of abortive headache medications could, in fact, exacerbate the headaches. Educating clinicians about the cause, evaluation, treatment, and prevention of MOH will help decrease the incidence of this frequently iatrogenic disorder.

REFERENCES

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12. Mathew HT, Kurman R, Perez F: Intractable chronic daily headache. A persistent neurobiobehavioral disorder. Cephalalgia 1989;9(suppl 10):180

13. Warner JS: The outcome of treating patients with suspected rebound headache. Headache 2001;41:685

14. Vasconcellos E, Pina-Garza JE, Millan EJ, et al: Analgesic rebound headache in children and adolescents. Journal of Child Neurology 1998;13:443

15. Hering R, Steiner TJ: Abrupt outpatient withdrawal of medication in analgesic-abusing migraineurs. Lancet 1991;337:1442

16. Mathew NT: Amelioration of ergotamine withdrawal with naproxen. Headache 1987;27:130

17. Krymchantowski AV, Barbosa JS: Prednisone as initial treatment of analgesic-induced daily headache. Cephalalgia 2000;20:107

18. Mathew NT, Ali S: Valproate in the treatment of persistent chronic daily headache. An open label study. Headache 1991;31:71

19. Diener H-C, Dichgans J, Scholz E, et al: Analgesic-induced chronic headache: Long-term results of withdrawal therapy. Journal of Neurology 1989;236:9

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DR. REIMSCHISEL is a pediatric neurologist and a fellow in genetic medicine at The Johns Hopkins Hospital, Baltimore, Md. He has nothing to disclose in regard to affiliations with, or financial interests in, any organization that may have an interest in any part of this article.

Tyler Reimschisel. Breaking the cycle of medication overuse headache.

Contemporary Pediatrics

October 2003;20:101.