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5dodi_cp.inddT h e n e w e n g l a n d j o u r n a l o f m e d i c i n e This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. A 36-year-old woman with a long history of catamenial migraines had had a head-
ache almost every day during the previous year. The background headache was
mild but became severe and incapacitating at least twice a week, interfering with
work and sleep. She took six to eight tablets containing a combination of aspirin,
acetaminophen, and caffeine per day, with minimal relief. She had no fever, weight
loss, diplopia, or tinnitus. Her headaches were not exacerbated by a Valsalva maneuver
or positional change. Her physical examination was normal. How should she be
evaluated and treated?
Chronic daily headache refers to the presence of a headache more than 15 days per Clinic College of Medicine, Scottsdale, month for longer than 3 months. Chronic daily headache is not a diagnosis but a Ariz. Address reprint requests to Dr. Dodick at the Department of Neurology, category that contains many disorders representing primary and secondary head-Mayo Clinic College of Medicine, 13400 aches.1,2 Secondary causes must be ruled out before the diagnosis of a primary E. Shea Blvd., Scottsdale, AZ 85259, or at headache disorder is made. Approximately 3 to 5 percent of the population world- wide3-5 and 70 to 80 percent of patients presenting to headache clinics in the United States6 have daily or near-daily headaches. The disability associated with Copyright 2006 Massachusetts Medical Society. this disorder is substantial and includes a diminished quality of life related to physical and mental health, as well as impaired physical, social, and occupational functioning.7-9 Risk factors for chronic daily headache as identified in population-based and clinic-based studies include obesity, a history of frequent headache (more than one per week), caffeine consumption, and overuse (more than 10 days per month) of acute-headache medications, including analgesics, ergots, and triptans.10-14 Over half of all patients with chronic daily headache have sleep disturbances and mood disorders such as depression or anxiety, and these disorders can exacerbate the underlying headache.
Transformed migraine and medication-overuse headaches are among the most common and challenging of the chronic daily headache disorders and are the focus of this review (Table 1). The clinical features of primary chronic daily headache disorders are summarized in Table 2.15 Primary chronic daily headache disorders are classified on the basis of the usual length of each episode — that is, prolonged (four hours or longer) or brief (less than four hours).1 s t r a t e g i e s a n d e v i d e n c e diagnosis
Before a primary headache can be diagnosed, secondary causes must be considered. The development of progressively frequent and severe headaches within a period Downloaded from cme.nejm.org by TY TY on April 16, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. Table 1. Criteria for Transformed Migraine and Medication-Overuse Headache.
Daily or almost daily (>15 days per month) head pain for >1 mo Average headache lasting >4 hr per day (if untreated) History of any form of episodic migraine meeting IHS criteria† History of increasing headache frequency with decreasing severity of migrainous features over a period Headache at some time meets IHS criteria for migraine other than duration Does not meet criteria for new daily persistent headache or hemicrania continua Medication-overuse headache2
Headache present at least 15 days per month characterized by the development or marked worsening of pain during medication overuse and resolution of pain and reversion to previous episodic pattern (<15 days per month) within 2 mo after discontinuation of medication Definition of overuse of medication
Regular overuse of a headache medication for >3 mo Use of ergotamine, triptans, opioids, and combination analgesics >10 days per month Use of simple analgesics ≥15 days per month Total use of all headache medications ≥15 days per month * The criteria for transformed migraine are those of Silberstein et al.1,2 These criteria have been used in clinical, popula- tion-based, and treatment studies during the past 10 years. The criteria for chronic migraine have not been field-tested or validated.
† The criteria of the International Headache Society (IHS) for migraine without aura2 include at least five attacks that last 4 to 72 hours (untreated or unsuccessfully treated). The headaches must have at least two of the following characteris-tics: unilateral location, pulsating quality, moderate or severe pain intensity, and reason for avoidance of routine physi-cal activity (e.g., walking or climbing stairs). During the headaches, at least one of the following must be present: nau-sea, vomiting, or both; photophobia and phonophobia; and no attribution to another disorder.
of three months, neurologic symptoms, focal or applied to this group of patients.
lateralizing neurologic signs, papil ledema, head- The overuse of acute-headache medications aches aggravated or relieved by assuming an by patients with frequent headache may lead to upright or supine posture, headaches provoked medication-overuse headache, a syndrome of by a Valsalva maneuver such as a cough or sneeze, daily headaches that is induced and maintained systemic symptoms or fever, or a history of head- by the very medications used to relieve the pain.18,19 ache of sudden onset or onset after the age of 50 The prevalence in the population of chronic years should prompt a diagnostic evaluation with daily headache associated with the overuse of appropriate imaging.
acute-headache medication was recently esti- Most patients with transformed migraine and mated to be 1.4 percent overall and was particu- medication-overuse headache are women and larly high among women (2.6 percent), especially have a history of episodic migraine that dates those over the age of 50 years (5 percent).20 Over-back to adolescence or early adulthood.16,17 Pa- use of acute-headache medications is reported tients often report a period of transformation that by approximately 80 percent of the patients with occurs over months or years in which headaches transformed migraine who are seen in head-become more frequent, until a pattern of daily ache clinics,21 but by fewer than a third of those or near-daily headaches develops that clinically with transformed migraine in the general pop-resembles a mixture of tension-type headache ulation.3 Furthermore, in a substantial propor-and migraine. This clinical phenotype explains tion of patients, daily headache may continue why labels such as “mixed headache” and “ten- once they stop overusing acute-headache medi-sion–vascular headache” have been informally cation. Therefore, the overuse of acute-headache Downloaded from cme.nejm.org by TY TY on April 16, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e Table 2. Other Types of Primary Chronic Daily Headache.*
severe; may be preceded by viral infection; may resemble migraine or tension-type headache acerbations of severe headache; cranial autonomic symptoms; “ice-pick” pain; responsive to indomethacin by definition 1–3 times per year; daily head-aches, often nocturnal, occur-ring 1–8 times per day, lasting about 1 hr on average, ex-tremely severe, mostly peri-orbital or temporal, and asso-ciated with motor restlessness and autonomic symptoms (tearing, rhinorrhea) sleep; moderately severe; often bilateral; lasting about 1 hr; not associated with auto-nomic symptoms headaches except that attacks occur more often (>5 and up to 24 times per day) and are briefer (8–25 min); responsive to indomethacin by definition often (30–100 per day) and are much briefer (20–120 sec); may be mistaken for trigemi-nal neuralgia, except pain is strictly periorbital (V1) with cranial autonomic symptoms * Secondary causes require careful consideration and exclusion. These include medication-overuse headache, cervicogenic headache (pain re- ferred from a source in the neck and perceived in one or more regions of the head, face, or both), intracranial hypertension or hypotension, intracranial infection (meningitis or sinusitis), space-occupying lesions, post-traumatic headache, arterial dissection, venous sinus thrombo-sis, and giant-cell arteritis. Prolonged (four hours or longer) chronic daily headache disorders include chronic migraine, chronic tension-type head-ache, hemicrania continua, and new daily persistent headache. Transient (less than four hours) disorders include cluster headache, hypnic head-ache, paroxysmal hemicrania, and the short-lasting, unilateral, neuralgiform headache with conjunctival injection and tearing syndrome.
medications is neither necessary nor sufficient as analgesics (especially analgesics that combine to cause transformed migraine.
aspirin, acetaminophen, and caffeine and those Patients with transformed migraine most of- that contain butalbital), opioids, ergotamine, or ten overuse acute-headache medications such triptans or a combination of these medications. Downloaded from cme.nejm.org by TY TY on April 16, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. The interval from the frequent intake of these headache continues to occur on at least 15 days medications to the development of medication- per month despite the withdrawal of acute-head-overuse headache has been reported to be short- ache medications, a diagnosis of transformed mi-est for triptans (1.7 years), longer for ergots graine is often made. Although this distinction (2.7 years), and longest for analgesics (4.8 years). is obviously arbitrary, the reduction in the fre-It is unclear whether this observation relates to quency of headache after the withdrawal of medi-the pharmacologic characteristics of the medi- cation is often dramatic in patients who have cations.22 Although it is often difficult to be certain whether the overuse of acute-headache medica- treatment
tion is the cause or the consequence of the daily Nonpharmacologic Therapy
headaches, accurate diagnosis and management Although data are lacking from controlled tri-
require the withdrawal of such medications in als, clinical experience suggests that lifestyle mod-
all patients, especially in the light of the obser- ifications such as limiting or eliminating caffeine
vation that their overuse may preclude the efficacy consumption, engaging in regular exercise, and
of preventive medications. If a pattern of episodic establishing regular mealtimes and sleep sched-
headaches (fewer than 15 days per month) re- ules can be beneficial for some patients. Depres-
curs within 2 months after drug withdrawal, sion, anxiety, and sleep disturbances should be ad-
medication-overuse headache is diagnosed.2 If dressed.23 Training in relaxation techniques and
Table 3. Preventive Medications Used in Cases of Transformed Migraine or Medication-Overuse Headache.*
Medication Class and Drug
Target Daily Dose
Common Side Effects
tion, palpitation, drowsiness, dizziness, fatigue Anticonvulsants
normal thinking, peripheral ede-ma, weight gain, incoordination α -Adrenergic agonists
dizziness, constipation, hypo-tension, bradycardia Neurotoxin
* All the listed agents (except divalproex) have been studied in at least one randomized trial involving patients with a primary chronic daily headache (more than 15 days per month). However, these were not studies specifically of patients with transformed migraine or medica-tion-overuse headache. Most of the patients in some studies and all the patients in other studies had a history of migraine; none of the studies evaluating these therapies uniformly used the definition of the International Headache Society for chronic migraine or the criteria of Silberstein et al.1 for transformed migraine. Overuse of acute-headache medications was present in a substantial proportion of patients in several studies. This table is not intended to be exhaustive. No medications are approved by the Food and Drug Administration for the prevention of headache in patients with transformed migraine or medication-overuse headache.
Downloaded from cme.nejm.org by TY TY on April 16, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e biofeedback may be beneficial, although data to overused medications alone will allow the head-support these interventions come from patients ache to revert to an episodic pattern, without the with chronic tension-type headache, rather than need for preventive therapy.35 However, given transformed migraine.24 Patients should be pro- the relatively poor long-term success rates after vided with support and close follow-up, particu- the withdrawal of medication alone, other in-larly during the first eight weeks after treatment vestigators recommend preventive therapy in such is initiated.
patients in an attempt to reduce the frequency and severity of the withdrawal headaches, as well as the potential for relapse, which can oc- Randomized trials of the use of preventive med- cur during or after the withdrawal period.
ications in chronic daily headache are scarce.25-34 The use of daily opioid therapy in patients In a single trial involving the tricyclic amytrip- with chronic daily headache is controversial. A tyline, the reported response rates (the percent- recent prospective study with an initial cohort age of patients whose frequency of headache is of 160 patients who were prescribed daily opi-reduced by more than 50 percent) have exceed- oid therapy reported the outcomes among 70 pa-ed 50 percent. Response rates superior to those tients with medically refractory chronic daily achieved with placebo have also been reported headache who continued this therapy for at least for gabapentin (36 percent, as compared with 11 three years.36 Only 41 of the original 160 pa-percent for placebo), topiramate (71 percent, as tients (26 percent) had greater than 50 percent compared with 11 percent), and botulinum tox- improvement in a headache index that took into in type A (54 percent, as compared with 38 per- account the frequency and severity of headaches cent).25,30,31 However, available studies are lim- each week. Fifty percent of the patients had “prob-ited by small numbers of patients, the failure to lem drug behavior” (defined as “lost” prescrip-account for the overuse of acute-headache med- tions, seeking medication from other sources, ications, the concomitant use of other preventive and most commonly, dose violations). Most of medications, the lack of a specific diagnosis, or a these patients (74 percent) either did not show combination of these factors.
marked improvement or were dropped from the Nonetheless, on the basis of these data and program because of problem drug behavior. These clinical experience, several potential preventive data from a highly specialized center with very
therapies are being used in patients with trans- close follow-up underscore the low efficacy of
formed migraine (Table 3). Given the high rate long-term opioid therapy and the high risk of
of associated sleep and mood disorders in these misuse in this patient population.
patients, sedating antidepressants such as amitrip-
tyline may be particularly useful, although data withdrawal from acute-headache medication
are lacking to compare this category of drugs with No controlled studies have yet assessed the ef-
a placebo or other preventive medications.
ficacy of withdrawal of medication alone. Treat- Preventive medications are generally titrated ment strategies for patients with transformed to the minimal effective or maximal tolerated dose migraine associated with overuse of acute-head-over a period of one or two months. This target ache medication are therefore based on case series, dose is maintained for at least two months; if prospective uncontrolled studies, controlled trials the patient has a response (more than a 50 percent involving patients with unspecified chronic daily reduction in the number of days on which head- headache, and clinical experience. Withdrawal ache occurs), the medication is continued for at studies are confounded by the addition of pre-least three to six months. At that point, clinical ventive medications, behavioral techniques, lifestyle experience suggests that it is reasonable to at- modifications, and acute-headache medications, all tempt to taper and discontinue the medication, of which may influence the frequency and severity after consultation with the patient.
of headaches. Nonsteroidal antiinflammatory The use of preventive medications in patients drugs and dihydroergotamine mesylate (unlike with headaches thought to be due to overuse of ergotamine tartrate) are generally considered to acute-headache medications is more controversial. have a low risk of medication-overuse headache Some investigators believe that most patients who and are often used to treat breakthough head-overuse these medications have medication- aches during the withdrawal period. It is unclear overuse headache and that withdrawal of the whether the rarity of overuse of acute-headache Downloaded from cme.nejm.org by TY TY on April 16, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. medication associated with dihydroergotamine tion-overuse headache.37 There was a significant reflects a pharmacologic mechanism or whether reduction in the number of hours of severe with-the rarity is explained by the more limited use drawal headache in the active-treatment group of this medication, which requires parenteral ad- (18.1 vs. 36.7 hours, P = 0.04), which confirmed ministration, as compared with ergotamine tar- earlier observations from uncontrolled studies. trate, which is taken orally.
In a 12-week open-label study, a single bedtime In general, most patients can be treated on dose of tizanidine ranging from 2 to 16 mg (aver- an outpatient basis (Table 4). Simple analgesics, age, 3.6) in combination with a single morning ergotamine, triptans, and most combination anal- dose of a nonsteroidal antiinflammatory drug gesics can be discontinued abruptly, whereas opi- resolved chronic daily headache in 34 of 55 pa-oids and butalbital-containing analgesics should tients (62 percent).38be tapered over a period of one month. To mini- Inpatient treatment may be necessary if the mize the potential for troublesome or serious patients are not successful in decreasing their withdrawal symptoms from analgesics contain- use of acute-headache medications, if the amount ing barbiturates and opioids, some experts have of barbiturate or opioid makes withdrawal on drawn on clinical experience to recommend a an outpatient basis unsafe, or if there are seri-short (two to six weeks), tapering course of phe- ous coexisting medical or psychiatric conditions.39 nobarbital or clonidine for patients who have Although there is a paucity of controlled trials been using such agents.
to guide inpatient therapy, a meta-analysis of A prospective study demonstrated that with- uncontrolled inpatient studies demonstrated that drawal symptoms and headaches generally re- 81 percent of patients had a decreased severity solved within four days after the cessation of or frequency of headache of at least 50 percent triptan, whereas fewer than 20 percent of patients after two months of follow-up and that 61 per-reported being free of headache within four days cent had such an improvement after one to four after the discontinuation of analgesics.22 With- years of follow-up.39drawal from ergotamine tartrate and combina- However, relapse is common after the with- tion analgesics may cause severe headache, nau- drawal of acute-headache medications, both in sea, vomiting, hypotension, and tachycardia that patients who were no longer experiencing chronic can last several days to weeks.
daily headache after medication withdrawal A recent double-blind, placebo-controlled study and in those who continued to have chronic evaluated the effect of 100 mg of prednisone for daily headache but who were initially success-five days on the duration of severe withdrawal ful in decreasing their intake of acute-headache headache in 20 patients with presumed medica- medications. One large, prospective study indi- Table 4. Suggested Treatment of Transformed Migraine or Medication-Overuse Headache.
Education, support, and close follow-up for 8–12 wk Lifestyle modifications (quitting smoking, eliminating caffeine consumption, exercising, eating regular meals, and establishing regular sleep schedule) Behavioral therapy (relaxation therapy, biofeedback) Abrupt withdrawal of overused medications for acute headache, except barbiturates or opioids* Prednisone (100 mg for 5 days [optional]) Acute-headache treatment (for moderate or severe headache) Nonsteroidal antiinflammatory drugs (e.g., 500 mg of naproxen sodium) Dihydroergotamine (1 mg) intranasally, subcutaneously, or intramuscularly Antiemetics (10–20 mg of metoclopramide, 10 mg of prochlorperazine, or 4–8 mg of ondansetron) * For butalbital overuse, taper the drug over a period of two to four weeks; if there is concern about the possibility of withdrawal syndrome, provide a tapering course of phenobarbital (30 mg twice daily for two weeks, followed by 15 mg twice daily for two weeks). For opioid overuse, taper the drug over a period of two to four weeks; if there is concern about the possibility of withdrawal syndrome, provide clonidine (transdermal therapeutic system patch for one to two weeks).
Downloaded from cme.nejm.org by TY TY on April 16, 2006 . Copyright 2006 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e cated a relapse rate of 38 percent in the first and examination should rule out features sug-year and a rate of 42 percent after four years.40,41 gestive of a secondary cause. The presentation of In another report, 60 percent of the patients con- the patient in the vignette is consistent with a tinued to have chronic daily headache and were diagnosis of transformed migraine resulting from overusing acute-headache medications four years overuse of acute-headache medication. Although, after the initial withdrawal of the medication.42 strictly speaking, the diagnosis of medication-over-use headache requires the withdrawal of the over- used medication and an evaluation of the frequen-cy of headache after two months of follow-up, The mechanisms by which headache becomes dai- patients tend to tolerate this approach poorly. ly and sometimes continuous remain unclear. Re- Thus, in this case, in combination with abrupt-peated attacks of migraine in susceptible persons ly discontinuing the patient’s overused medica-may lead to a state of chronic central sensitization tions, I would treat her with 60 mg of prednisone of trigeminal-pain pathways, resulting in continu- for five days to minimize withdrawal headaches ous headache. The overuse of analgesics, espe- and other symptoms, even though only limited data cially opioids, may also sensitize central-pain path- are available to support the use of this approach. ways. Randomized, controlled trials of different Although data are lacking from randomized treatment strategies that can be used to inform trials of patients with transformed migraine or therapy for patients with transformed migraine medication-overuse headache to guide the use of or medication-overuse headache are lacking. The preventive therapy, I would also recommend start-role of novel treatments for certain subtypes of ing therapy with amitriptyline (10 mg) at bed-chronic daily headache also remains uncertain. time and increasing the dose in increments of Occipital-nerve stimulation has shown some prom- 10 mg until the frequency of the headaches be-ise in individual patients with chronic migraine, gins to decline or dose-limiting side effects occur, but controlled trials are needed.43 with monthly follow-up for the first three months. On the basis of clinical experience, I would also encourage the patient to limit or eliminate caffeine consumption, exercise regularly, and maintain There are no formal recommendations from the a regular sleep schedule. Moderate or severe head-American Academy of Neurology or the American aches that occur after the withdrawal of overused Headache Society for the management of trans- acute-headache medication could be treated with formed migraine or medication-overuse headache. a nonsteroidal antiinflammatory agent or intra-However, consensus guidelines of the American nasal or parenteral dihydroergotamine; antiemet-Academy of Neurology for the management of ics are helpful for headache-induced or drug-chronic migraine recommend “guarding against induced nausea. If the patient were to make good medication overuse headache by avoiding acute progress and have a marked reduction in the headache medication escalation and initiating pre- frequency of headache for three to six months, ventive medication in patients with frequent head- it would be reasonable to try to taper the dose ache or in those who overuse acute therapies.” 42 of amitriptyline gradually. However, she should be reminded that the need to use acute-head-ache medications for more than two days per week indicates the need to resume a preventive Most patients with chronic daily headache have Dr. Dodick reports receiving research funding from Allergan.
a history of episodic migraine and overuse acute- No other potential conflict of interest relevant to this article headache medications. A careful history-taking r e fe r enc e s
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Use of Antiviral Drugs for Influenza Recommended Guidelines for Practitioners Dr. Upton D. Allen University of Toronto Dr. Fred Y. Aoki University of Manitoba Dr. H. Grant Stiver University of British Columbia For the Canadian Pediatric Society and the Association for Medical Microbiology and Infectious Diseases Introduction and Background Influenza A