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Medication overuse headache
Prim Care Clin Office Pract 31 (2004) 369–380
Medication overuse headache Thomas N. Ward, MD Section of Neurology, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Hanover, NH 03756, USA
Medication overuse headache is a common but often under-recognized problem in clinical practice. It may be iatrogenic, caused by a failure to set reasonable limits on acute medication use, or may occur because the headache sufferer has access to multiple prescribers or uses excessive overthe-counter/off-the-shelf remedies [1]. Failure to recognize and effectively deal with this situation may result in treatment refractoriness and serious medical complications for the patient. Medication overuse may confound the clinical course of any headache patient with any type of headache. This has been recognized by the International Headache Society (IHS) [2]. It particularly seems to plague migraineurs. Since the 1950s it has been recognized as a significant clinical problem. This condition is especially relevant for patients with chronic daily headache (headache more than 15 days/month, more than 180 days per year) [3]. Chronic daily headache may be divided into those entities lasting less than 4 hours per day and those headache types lasting more than 4 hours per day. The latter category includes transformed migraine (also known as chronic migraine, frequent headache with migrainous features, evolutive migraine), chronic tension-type headache (CTTH), new daily persistent headache (NDPH), and hemicrania continua (HC) [3,4]. ‘‘Medication misuse’’ headache was identified during the 1940s and 1950s by clinicians at the Mayo Clinic [5]. By the 1980s, reports from Kudrow and Mathew among others led to its increasing recognition, at least among headache experts [4,6]. The phenomenon of analgesic rebound headache was invoked to explain a vicious cycle of increasing medication consumption, followed by withdrawal headache, leading to further medication consumption, and a worsening headache pattern [5]. Peters and Horton at the Mayo Clinic in 1951 described adverse consequences of overuse of ergotamine tartrate, including ergotamineE-mail address: [email protected] 0095-4543/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2004.02.008
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dependency headaches, invoking a rebound phenomenon of vasodilation following vasoconstriction, necessitating further use of the agent to achieve relief. Later they described a program of detoxification during which withdrawal headache was followed eventually by improvement [5]. A landmark article by Kudrow in 1982 described the ‘‘paradoxical effects of frequent analgesic use’’ [6]. Not only did he note that frequent headaches caused by analgesic overuse improved with reduction in acute medication use, but he also reported that amitriptyline used as prophylaxis in these patients was less than half as likely to be effective if the offending analgesics were not stopped. Mathew has reported extensively on transformed migraine and analgesic rebound headache [4,7]. He confirmed there was often a prior history of episodic migraine that changed in pattern of time, often in association with acute medication overuse. Many patients developed a pattern that evolved over time into a nearly constant headache resembling CTTH, with exacerbations reminiscent of their previous migraine attacks. Many patients (65%) were overusing more than one acute medication. Depression and sleep disturbances were common, with patients often awakening between 2 AM and 6 AM with a severe headache and then consuming even more acute medication. Mathew confirmed that many patients suffered severe withdrawal headaches on stopping their symptomatic remedies, but soon manifested significant improvement. He also demonstrated that preventative medications are ineffective if patients continued to overuse acute medications, but became effective once the offending drugs were stopped. The concept of medication-induced headache/analgesic rebound headache has been questioned, because it does not occur in most patients [8]. Indeed, it seems primarily to occur in ‘‘headache-prone’’ patients, especially in those with a personal or family history of migraine. The City of London Migraine Clinic reported that arthritis sufferers who were not migraineprone seemed to be able to use significant quantities of analgesics without developing rebound headache [9]. Analgesic rebound headache seems to be particularly prevalent in the United States, accounting for as many as 70%–80% of patients in specialized headache centers. Far lower numbers are reported from European centers (5%–10%) [10]. In the United States, CDH occurs in approximately 4% of the general population, whereas transformed migraine occurs in 1.3% (‘‘frequent headache with migrainous features’’) [11,12]. The female to male gender ratio for CDH is approximately 2:1 [10]. It occurs in childhood and adolescence and sometimes seems to continue into old age. The natural history is not well understood, however. CDH in the general population seems to be mostly CTTH. In specialized headache centers, it seems to be mostly transformed migraine. This difference is likely because patients with transformed migraine have higher disability and therefore are more likely to consult [11]. Of interest, few clinic patients have CTTH, whereas somewhat more patients with primary
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headaches have NDPH (a new headache of acute onset that persists as a chronic daily headache). The vast majority of these clinic patients overuses symptomatic medications and is depressed, and most regain an episodic headache pattern after treatment. Silberstein and Silberstein took this as evidence that other headaches besides chronic migraine may be perpetuated by medication overuse [13]. The 1988 IHS criteria for migraine diagnosis have been shown to be inadequate for classifying many cases of chronic daily headache. Silberstein et al have proposed revised criteria for chronic migraine. These criteria require headache >15 days per month >4 hours per day, a history of episodic migraine or gradual increasing headache frequency with lessening migrainous features, or headache that meets IHS criteria for migraine at some times save for duration [3]. The natural history of transformed migraine usually seems to begin in otherwise typical migraineurs, often as young adults. In the setting of escalating medication use, the headache pattern changes, acquiring features suggesting CTTH with superimposed exacerbations simulating their prior migraine attacks. This pattern may occur in children and adolescents, but often with a shorter period of transformation [14,15]. Untreated, this chronic headache may persist into old age. It is important to note that transformation sometimes occurs in the absence of medication overuse. The following cases serve to demonstrate part of the spectrum of chronic migraine/transformed migraine. Case 1 This 62-year-old woman was sent to the clinic with chronic daily headache. The referring physician pointedly told the consultant that ‘‘this isn’t analgesic rebound’’ headache as ‘‘she isn’t taking any medication at all.’’ Of note, she had a history of intermittent migraine headaches since her teenage years, beginning with her menarche. She treated these with over-thecounter medications that had poor efficacy. She noted that in her 40s the headache pattern changed. Initially, during the consultation, she reported only 3–4 headaches per month. When asked how many headache-free days she had per month, however, she replied ‘‘none.’’ It turned out she had gradually developed a new pattern over many years for her headaches. She eventually came to have a daily headache that was mild to moderate in severity, bilateral, and more tight and pressing in character than anything else. This background headache was not associated with nausea or vomiting, and there was neither light nor sound sensitivity. It was not disabling. The 3–4 ‘‘headaches’’ she reported occurring monthly were reminiscent of her prior migraine. When asked about medication use, she said she wasn’t taking any. Further specific questioning revealed she was taking approximately 740
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acetaminophen tablets per month (500 mg each). She didn’t consider this ‘‘medication’’ as she purchased it from her local grocery store. She did report that a prior attempt to do without this agent for a day resulted in a severe withdrawal headache. Her neurologic examination was entirely normal, as was an erythrocyte sedimentation rate (ESR) (14 mm/hr). She brought a brain MRI that was normal. After discussion, she was placed on a week of a prednisone taper, with famotidine (Pepcid) to protect her stomach and hydroxyzine (Vistaril) for anxiety, nausea, or mild headache. Subsequent to that, she was allowed the use of hydroxyzine and naproxen sodium 550 mg (Anaprox DS) twice daily as needed. When seen for follow-up in 6 weeks, she was headache-free, not using acetaminophen, and did not need to use any medication at all. She has remained in this essentially headache-free state for more than 3 years, save for 1–2 tension-type headaches per month that resolve in 1–2 hours with the naproxen sodium. This case is typical of transformed migraine. There was a prior history of episodic migraine, which in the setting of frequent use of acute medication, in this case nothing more than acetaminophen, evolved into a chronic daily headache looking like CTTH with superimposed migrainous exacerbations. Of note, because no prescription is required, many patients don’t consider these medications and specific inquiries need to be made. The same point may be made regarding herbal remedies and alternative therapies. Also, notably, this patient initially did not disclose her milder background headaches, focusing instead on the exacerbations. Such under-reporting by patients is common, revealing the need to inquire specifically as to how many types of headaches the patient actually has and whether or not there are any headache-free days. There is no substitute for a careful history and keeping an open mind. Case 2 This 46-year-old man had never suffered from disabling headaches until he was involved as a passenger in a serious motor vehicle accident. He sustained a concussion and was unconscious for more than 3 hours. The clinical course was complicated by a femur fracture, and it was only after he attempted to reduce his oxycodone with acetaminophen (Percocet) intake, that he noticed the occurrence of severe headaches. His lower extremity injury resolved within 2 months, but his need for narcotic pain medication continued. He had frequent headache that seemed to be migraine, occurring 3–4 days per week. Most other days he had milder headache resembling CTTH. A neurologist diagnosed ‘‘post-traumatic headaches’’ with whiplash, but seemed perplexed when they persisted beyond 12 months and even after his litigation was settled. When seen in the headache clinic 7 years after the accident, he was complaining of daily headache, usually severe and disabling. He had trouble
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sleeping and seemed depressed. His examination was normal save for tight posterior paraspinal cervical muscles. He brought normal brain and cervical spine MRIs. He was consuming 2–6 narcotic analgesic pills per day and 4– 10 over-the-counter mixed analgesic pills per day (Excedrin). He reported that his number of pills per day had increased concordant with his overall headache pattern worsening (more frequent, more severe headaches). Often, 3–4 hours after falling asleep, he would awaken with a severe headache, only finding relief by taking more pills. As he had reported that prior attempts to reduce his medication use had resulted in severe headaches with vomiting, he was admitted to the hospital. His narcotic and mixed analgesics were stopped and he was begun on a three times per day regimen of intravenous metoclopramide followed by dihydroergotamine. Within 48 hours he became headache-free. Amitriptyline was begun at 25 mg at bedtime. He was discharged on amitriptyline regularly and naproxen sodium and hydroxyzine on an as-needed basis for headaches. When seen for follow-up 4 weeks later, he was headache-free. Post-traumatic headaches may mimic any type of headache, including any of the primary headaches. Typically they resolve within 12 months [16]. Their perpetuation by medication overuse has been reported [17]. In some cases post-traumatic headache that has continued for many years has improved after stopping medications that may have been causing analgesic rebound. Notably, analgesic rebound headaches may occur when headacheprone patients are put on pain medications for non-headache conditions [18]. Recognition of medication overuse offers the potential for effective clinical intervention. Case 3 This 57-year-old woman had a history of episodic migraine since her teenage years, which worsened after her second pregnancy at age 26 years. At that time, because of severe vomiting with the attacks, her physician prescribed ergotamine tartrate with caffeine (Cafergot) suppositories. Although highly effective for her attacks, she found she required them 4–5 days per week. Less use resulted in even more severe attacks than she had been experiencing. Over time she found that one third to one half of a suppository each night at bedtime effectively prevented the severe attacks. If she neglected this ritual for even a single night, her reward the next morning (early) would be a severe disabling migraine with vomiting that would remit only with the administration of another portion of a suppository. On further questioning she admitted to daily mild headaches also. When seen in the clinic she was distressed, because ergotamine suppositories had become hard to obtain in the United States and she had to import them from Canada. Neurologic examination was normal. She was admitted to the hospital and treated with intravenous chlorpromazine and hydrocortisone. She experienced a withdrawal headache for
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5 days, lessened with the intravenous medications, which soon after discharge became minimal and vanished entirely by 4 weeks. Since that time she has had only mild headaches, no more than 3–4 per month, easily controlled with hydroxyzine and naproxen sodium. Ergotamine-dependency headaches are seen infrequently now, as ergotamine has been replaced largely by the triptans in acute headache treatment. Ergotamine tartrate has a long duration of action but is suspected of causing rebound headaches, as noted. Overuse may lead to the well known complications of ergotism and fibrosis. Many experts limit their use to 2 days per week to avoid generating ergotamine-dependency headaches [1]. This patient was unable to cease using this ‘‘remedy’’ for more than 30 years, yet once she was detoxified from this agent she had dramatic clinical improvement. The mechanism by which analgesic rebound/medication overuse occurs is not known. There has been much speculation, especially noting that it tends to occur in ‘‘headache-prone’’ patients, particularly migraineurs. Medication overuse also has been reported to perpetuate other headache types, including NDPH, HC, and post-traumatic headache [13,17–19]. Continuing peripheral input into the trigeminal nucleus caudalis, with increased activity of ‘‘on cells’’ and decreased activity of ‘‘off cells’’ in the medulla, with central sensitization has been invoked [20,21]. Analogies with the proposed epileptic phenomenon of kindling have been advanced [12]. Given the hereditary nature of migraine, receptor changes (serotonin, NMDA) have been described, as has a suppression of ascending/descending central anticonceptive serotonergic systems [1,20,22,23]. Welch, using sophisticated MRI techniques, has demonstrated increased iron deposition in the periaqueductal gray in chronic daily headache patients and hyperoxia in the red nucleus and substantia nigra. The amount of iron deposition correlates with the duration of illness [24]. The possibility of free radical generation and tissue damage is of concern. Clinically, in some patients it seems that rebound headache happens because of the occurrence of withdrawal headache leading to further medication use, to be followed by further withdrawal headache in a selfperpetuating cycle. Frequency of use therefore may be more important than actual amount of drug taken [1]. There are likely to be individual differences in susceptibility to this phenomenon. It is not certain, but many experts suspect that analgesic combinations are more likely to trigger rebound [25–27]. Caffeine’s role is controversial. It is added to many products to enhance absorption and as an adjunct analgesic. Although it is of low dependence potential by itself, its presence may be synergistic with other components of pain remedies in promoting rebound. Caffeine has been reported to cause withdrawal headaches as a single agent [12,28]. The treatment of medication overuse headache involves several fundamental principles. The first involves recognition of the condition. Especially for patients with transformed migraine, there is usually a prior history of intermittent migraine that evolves over time, with an increase in
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frequency to a chronic daily headache pattern and the appearance of two main headache types. The more frequent background headache resembles CTTH. Superimposed on this background headache pattern are exacerbations with many characteristics of the patient’s prior migraine headaches. The patient usually answers affirmatively the question, ‘‘Over the past few months or years have you been taking more pills yet having more headaches?’’ The acute medications, despite being used in ever-increasing amounts, work less and less well, and the patients often experience side effects from chronic use, such as esophagitis and ulcers. Preventative medications fail to offer relief and are often poorly tolerated [7,10]. These are the headache patients who come in to the clinic and have been tried on ‘‘everything’’ yet ‘‘nothing works.’’ If the patient is not able to stop overusing the offending medications, it is unlikely the chronic headaches will improve. The natural history of untreated frequent migraine/transformed migraine is not understood fully, but certainly many patients develop worsening patterns that may persist for years, even into old age. Education of the patient as to the nature of the problem, the role of medication overuse, and the possibility of future improvement is mandatory. Unless the patient is an active participant in the treatment plan, the likelihood of success is low. Outpatient and inpatient treatment strategies have been proposed and compared [27,29,30]. Outpatient detoxification can be attempted in many highly motivated, cooperative patients. A withdrawal headache occurring as the offending medications are tapered or stopped should be anticipated [7,25]. Many medications, such as simple analgesics, ergotamine, and triptans, can be stopped abruptly. Other agents, such as butalbital, benzodiazepines, and narcotics, are best tapered to avoid the risk for seizures, delirium, or severe withdrawal syndromes. Some clinicians advocate instituting a steroid taper, such as using prednisone for a week with measures to protect the stomach [31–33]. Hydroxyzine (Vistaril) may be used for nausea and jitteriness caused by the steroid and at bedtime for sleep. Promethazine (Phenergan) or other antiemetic suppositories should be available. After the week of steroid, longer-acting agents, such as dihydroergotamine intranasally (Migranal) or subcutaneously or intramuscularly (DHE-45), naratriptan (Amerge), or frovatriptan (Frova) might be used for severe headache exacerbations, and longer-acting NSAIDs such as naproxen sodium, 550 mg twice daily [34]. Ideally even these agents should be used no more than 2–3 times weekly to avoid rebound. At the same time, effective prophylaxis should be initiated. The choice of drug needs to be made in light of which comorbid/coexistent medical conditions the patient has. Even prophylactic agents that were ineffective or poorly tolerated when the patient was in the rebound state may be dramatically effective once the patient is no longer misusing medications. The patient should be alerted to the likelihood of short-term worsening of the headaches (withdrawal) as the price to pay for potential long-term benefit. Although there is often rapid
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improvement in the headache pattern soon after the withdrawal headache, the analgesic washout period (the time it takes for the system to reset and normalize) actually seems to last approximately 8 weeks and occasionally as long as 12 weeks (Box 1) [1]. Smith recently has published a protocol using low-dose tizanidine (Zanaflex) at bedtime in conjunction with long-acting NSAIDs [34]. Most patients responded to a low bedtime dose of tizanidine (average dose, 3.6 mg). The success rate defined as needing four or fewer acute medication doses in a 2-week period was approximately 65%. Although this rate is not as high as some of the inpatient protocols (up to approximately 90%), this may be a cost-effective option. Patients who fail outpatient attempts to treat analgesic rebound are candidates for inpatient therapy. This is also true for those with confounding medical or psychiatric conditions that render outpatient treatment impractical. An example might be a patient with long-standing ergotaminedependency headaches who has begun to develop angina provoked by the ergotamine (an urgent situation requiring immediate action). Numerous protocols have been advocated (Box 2). Such therapy is best used by those physicians experienced in managing intractable headaches in a multidisciplinary setting. The repetitive intravenous metoclopramide/dihydroergotamine protocol popularized by Raskin is often useful [40]. Meticulous attention to detail is
Box 1. Outpatient treatment regimens for medication-overuse headache Stop offending medications Taper butalbital, benzodiazepines, narcotics Anticipate withdrawal headache Antiemetic suppositories for vomiting Course of prednisone 60 mg daily for 3 days, 40 mg for 2 days, 20 mg for 2 days Initiate prophylaxis such as amitriptyline 25 mg at bedtime [31,32] Limit subsequent use of analgesics to 2–3 days per week –or– Initiate tizanidine 2 mg at bedtime; escalate dose by 2 mg every 3–5 days until therapeutic effect is achieved or sedation occurs Patients may use long-acting NSAID daily (such as rofecoxib, naproxen, piroxicam, ketoprofen SR, celecoxib) Treat severe headaches with dihydroergotamine (subcutaneously, intramuscularly, or intranasally) or with a triptan [34]
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essential. The offending medication must be stopped. Ten milligrams of metoclopramide is administered first. If dystonia or akathisia (restlessness, jitteriness) occurs, diphenhydramine (Benadryl) or benztropine mesylate (Cogentin) is given as the antidote. After the metoclopramide, a dose of 0.5 mg dihydroergotamine follows. The essential therapeutic maneuver is to adjust the dihydroergotamine to the effective subnauseating dose (up to 1 mg) then given on a three times daily basis (not every 8 hours, to allow the patient to sleep). Side effects of leg cramps and nausea respond to dose reduction. Diarrhea may be treated with diphenoxylate and atropine (Lomotil) or loperamide (Imodium). Dihydroergotamine should be avoided in patients with coronary artery disease or vasospastic conditions. Other inpatient treatment regimens have been advocated. The author and others have used intravenous chlorpromazine, titrating the dose until the patient is asleep and continuing for several days until the withdrawal headache has subsided [36]. Again, if akathisia or dystonia occurs, diphenhydramine or benztropine is administered. The patient needs to be
Box 2. Inpatient treatment regimens for medication overuse headache Admit to hospital Stop offending medications (taper those that might cause withdrawal seizures or delirium, as noted in Box 1) May substitute 30 mg phenobarbital at bedtime per 100 mg of butalbital patient has been using [35] Repetitive metoclopramide/dihydroergotamine regimen (Raskin protocol) Titrate dosage to the effective subnauseating dose (see text) [36] Manage side effects Most patients improve in 2–3 days; some require a few days longer –or– Intravenous chlorpromazine (see text) Titrate the dose to achieve sleep [36] –or– Intravenous valproate [37] or Intravenous lignocaine (lidocaine) [38] or Intravenous propofol [39] Order appropriate consultations Education Initiate prophylaxis Appropriate follow-up with plan to treat subsequent headaches while avoiding relapse
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maintained at bedrest, as orthostatic hypotension is common. Measures are taken to prevent deep venous thrombosis. Hypotension often responds to dose reduction or intravenous fluid boluses. Intravenous valproate (Depacon), lignocaine (lidocaine), or propofol (Diprivan) are other therapeutic choices [37–39]. The main goal of the inpatient regimens is to allow the removal of the offending medications and prevent/treat the withdrawal headache. Brief 2–3 day admissions can be sufficient for many patients, but some require longer stays. Appropriate education and consultation (psychiatry, behavioral medicine, pain management) should be undertaken before discharge. Effective prophylaxis should be initiated to ensure the patient can tolerate the new agent. A plan for controlling the headaches without relapsing into medication overuse needs to be made, together with clinician availability before the follow-up visit after discharge in case of clinical deterioration. Relapse rates following treatment for medication overuse headache have been reported to be as high as 50% but generally are lower [26,27]. Risk factors for relapse seem to be male sex, use of combination analgesics and ergots, and perhaps administration of ineffective therapies, such as naturopathy/homeopathy [27]. Relapse was defined generally as a resumption of medication overuse with a worsening of the headache pattern. Relapse does not seem to correlate with whether the initial treatment regimen was outpatient or inpatient, although inpatient regimens seem to have a higher initial success rate [34,40]. The literature regarding the various treatment strategies is not of high quality, with few randomized trials, small studies, and much anecdotal evidence presented [29]. Often more than one treatment is manipulated at once, and it has been suggested that perhaps some of the ‘‘improvement’’ reported may represent little more than ‘‘regression to the mean’’ [12]. Medication overuse may be a consequence of headache or a cause of it. Recognition of this diagnosis is important, so a high degree of clinical suspicion must be maintained. Accurate diagnosis of the headache types the patient is suffering allows institution of appropriate therapy. If medication overuse is suspected, the offending drugs should be discontinued either in the outpatient or inpatient settings. If analgesic rebound indeed has been occurring, there may be dramatic clinical improvement. Additionally, preventative therapies may be more likely to work, and side effects from overused, ineffective medications may be lessened or avoided. After an early withdrawal headache, the headache pattern may revert to an intermittent one or headaches may cease entirely. The analgesic washout period may last up to 3 months or longer, but improvement if it is going to occur usually is seen in days to weeks [1]. Transformed migraine seems to occur in all age groups, although in adolescents there may be a brief period of transformation, if any at all, and drug overuse is seen less often [14]. Medication overuse headache may persist into old age, especially if not recognized and addressed, as patients
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have easy access to analgesics without a prescription. The best situation is to prevent this condition from occurring through education of the public and setting limits on medication use so this cycle of pain never develops.
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[22] Price DD, Mao J, Mayer DJ. Central neural mechanisms of normal and abnormal pain states. In: Fields HL, Liebeskind JC, editors. Progress in pain research and management. Seattle: IASP Press; 1994. p. 61–84. [23] Srikiatkachorn A, Maneesri S, Govitrapong P, Kasantikul V. Derangement of serotonin system in migrainous patients with analgesic abuse headache: clues from platelets. Headache 1998;38(1):43–9. [24] Welch KM, Nagesh V, Aurora SK, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 2001;41(7):629–37. [25] Katsarava Z, Fritsche G, Muessig M, Diener HC, Limmroth V. Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Neurology 2001;57(9):1694–8. [26] Fritsche G, Eberl A, Katsarava Z, Limmroth V, Diener HC. Drug-induced headache: long-term follow-up of withdrawal therapy and persistence of drug misuse. Eur Neurol 2001;45(4):229–35. [27] Suhr B, Evers S, Bauer B, Gralow I, Grotmeyer KH, Husstedt IW. Drug-induced headache: long-term results of stationary versus ambulatory withdrawal therapy. Cephalalgia 1999;19(1):44–9. [28] Feinstein AR, Heinemann LA, Dalessio D, Fox JM, Goldstein J, Haag G, et al. Do caffeinecontaining analgesics promote dependence? A review and evaluation. Clin Pharmacol Ther 2000;68(5):457–67. [29] Zed PJ, Loewen PS, Robinson G. Medication-induced headache: overview and systematic review of therapeutic approaches. Ann Pharmacother 1999;33(1):61–72. [30] Ford RG, Ford KT. Continuous intravenous dihydroergotamine in the treatment of intractable headache. Headache 1997;37:129–36. [31] Krymchantowski AV, Barbosa JS. Prednisone as initial treatment of analgesic-induced daily headache. Cephalalgia 2000;20:107–13. [32] Spierings EHL, Krymchantowski AV. Prednisone as initial treatment of drug-induced daily headache [letter]. Cephalalgia 2000;20:748. [33] Bonuccelli U, Nuti A, Lucetti C, Pavese N, Dell’Agnello G, Muratorio A. Amitriptyline and dexamethasone combined treatment in drug-induced headache. Cephalalgia 1996; 16(3):198–200. [34] Smith TR. Low-dose tizanidine with nonsteroidal anti-inflammatory drugs for detoxification from analgesic rebound headache. Headache 2002;42:175–7. [35] Rapoport AM, Sheftell FD. Inpatient treatment of primary headache disorders. In: Rapoport AM, Sheftell FD, editors. Headache diorders. A management guide for practioners. Philadelphia: WB Saunders; 1996. p. 148. [36] Ashkenazi A, Levin M, Ward TN. Treatment of chronic daily headache with intravenous chlorpromazine [abstract S135]. Presented at the 44th Annual Scientific Meeting of the American Headache Society. Seattle, Washington, June 2002. [37] Mathew NT, Kailsam J, Meadors L, Chernyschev O, Gentry P. Intravenous valproate sodium (Depacon) aborts migraine rapidly: a preliminary report. Headache 2000;40(9): 720–3. [38] Hand PJ, Stark RJ. Intravenous lignocaine infusions for severe chronic daily headache. Med J Aust 2000;172(4):157–9. [39] Krusz JC, Scott V, Belanger J. Intravenous propofol: unique effectiveness in treating intractable migraine. Headache 2000;40(3):2224–30. [40] Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology 1986;36:995–7.
Medication overuse headache Thomas N. Ward, MD Section of Neurology, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Hanover, NH 03756, USA
Medication overuse headache is a common but often under-recognized problem in clinical practice. It may be iatrogenic, caused by a failure to set reasonable limits on acute medication use, or may occur because the headache sufferer has access to multiple prescribers or uses excessive overthe-counter/off-the-shelf remedies [1]. Failure to recognize and effectively deal with this situation may result in treatment refractoriness and serious medical complications for the patient. Medication overuse may confound the clinical course of any headache patient with any type of headache. This has been recognized by the International Headache Society (IHS) [2]. It particularly seems to plague migraineurs. Since the 1950s it has been recognized as a significant clinical problem. This condition is especially relevant for patients with chronic daily headache (headache more than 15 days/month, more than 180 days per year) [3]. Chronic daily headache may be divided into those entities lasting less than 4 hours per day and those headache types lasting more than 4 hours per day. The latter category includes transformed migraine (also known as chronic migraine, frequent headache with migrainous features, evolutive migraine), chronic tension-type headache (CTTH), new daily persistent headache (NDPH), and hemicrania continua (HC) [3,4]. ‘‘Medication misuse’’ headache was identified during the 1940s and 1950s by clinicians at the Mayo Clinic [5]. By the 1980s, reports from Kudrow and Mathew among others led to its increasing recognition, at least among headache experts [4,6]. The phenomenon of analgesic rebound headache was invoked to explain a vicious cycle of increasing medication consumption, followed by withdrawal headache, leading to further medication consumption, and a worsening headache pattern [5]. Peters and Horton at the Mayo Clinic in 1951 described adverse consequences of overuse of ergotamine tartrate, including ergotamineE-mail address: [email protected] 0095-4543/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2004.02.008
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dependency headaches, invoking a rebound phenomenon of vasodilation following vasoconstriction, necessitating further use of the agent to achieve relief. Later they described a program of detoxification during which withdrawal headache was followed eventually by improvement [5]. A landmark article by Kudrow in 1982 described the ‘‘paradoxical effects of frequent analgesic use’’ [6]. Not only did he note that frequent headaches caused by analgesic overuse improved with reduction in acute medication use, but he also reported that amitriptyline used as prophylaxis in these patients was less than half as likely to be effective if the offending analgesics were not stopped. Mathew has reported extensively on transformed migraine and analgesic rebound headache [4,7]. He confirmed there was often a prior history of episodic migraine that changed in pattern of time, often in association with acute medication overuse. Many patients developed a pattern that evolved over time into a nearly constant headache resembling CTTH, with exacerbations reminiscent of their previous migraine attacks. Many patients (65%) were overusing more than one acute medication. Depression and sleep disturbances were common, with patients often awakening between 2 AM and 6 AM with a severe headache and then consuming even more acute medication. Mathew confirmed that many patients suffered severe withdrawal headaches on stopping their symptomatic remedies, but soon manifested significant improvement. He also demonstrated that preventative medications are ineffective if patients continued to overuse acute medications, but became effective once the offending drugs were stopped. The concept of medication-induced headache/analgesic rebound headache has been questioned, because it does not occur in most patients [8]. Indeed, it seems primarily to occur in ‘‘headache-prone’’ patients, especially in those with a personal or family history of migraine. The City of London Migraine Clinic reported that arthritis sufferers who were not migraineprone seemed to be able to use significant quantities of analgesics without developing rebound headache [9]. Analgesic rebound headache seems to be particularly prevalent in the United States, accounting for as many as 70%–80% of patients in specialized headache centers. Far lower numbers are reported from European centers (5%–10%) [10]. In the United States, CDH occurs in approximately 4% of the general population, whereas transformed migraine occurs in 1.3% (‘‘frequent headache with migrainous features’’) [11,12]. The female to male gender ratio for CDH is approximately 2:1 [10]. It occurs in childhood and adolescence and sometimes seems to continue into old age. The natural history is not well understood, however. CDH in the general population seems to be mostly CTTH. In specialized headache centers, it seems to be mostly transformed migraine. This difference is likely because patients with transformed migraine have higher disability and therefore are more likely to consult [11]. Of interest, few clinic patients have CTTH, whereas somewhat more patients with primary
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headaches have NDPH (a new headache of acute onset that persists as a chronic daily headache). The vast majority of these clinic patients overuses symptomatic medications and is depressed, and most regain an episodic headache pattern after treatment. Silberstein and Silberstein took this as evidence that other headaches besides chronic migraine may be perpetuated by medication overuse [13]. The 1988 IHS criteria for migraine diagnosis have been shown to be inadequate for classifying many cases of chronic daily headache. Silberstein et al have proposed revised criteria for chronic migraine. These criteria require headache >15 days per month >4 hours per day, a history of episodic migraine or gradual increasing headache frequency with lessening migrainous features, or headache that meets IHS criteria for migraine at some times save for duration [3]. The natural history of transformed migraine usually seems to begin in otherwise typical migraineurs, often as young adults. In the setting of escalating medication use, the headache pattern changes, acquiring features suggesting CTTH with superimposed exacerbations simulating their prior migraine attacks. This pattern may occur in children and adolescents, but often with a shorter period of transformation [14,15]. Untreated, this chronic headache may persist into old age. It is important to note that transformation sometimes occurs in the absence of medication overuse. The following cases serve to demonstrate part of the spectrum of chronic migraine/transformed migraine. Case 1 This 62-year-old woman was sent to the clinic with chronic daily headache. The referring physician pointedly told the consultant that ‘‘this isn’t analgesic rebound’’ headache as ‘‘she isn’t taking any medication at all.’’ Of note, she had a history of intermittent migraine headaches since her teenage years, beginning with her menarche. She treated these with over-thecounter medications that had poor efficacy. She noted that in her 40s the headache pattern changed. Initially, during the consultation, she reported only 3–4 headaches per month. When asked how many headache-free days she had per month, however, she replied ‘‘none.’’ It turned out she had gradually developed a new pattern over many years for her headaches. She eventually came to have a daily headache that was mild to moderate in severity, bilateral, and more tight and pressing in character than anything else. This background headache was not associated with nausea or vomiting, and there was neither light nor sound sensitivity. It was not disabling. The 3–4 ‘‘headaches’’ she reported occurring monthly were reminiscent of her prior migraine. When asked about medication use, she said she wasn’t taking any. Further specific questioning revealed she was taking approximately 740
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acetaminophen tablets per month (500 mg each). She didn’t consider this ‘‘medication’’ as she purchased it from her local grocery store. She did report that a prior attempt to do without this agent for a day resulted in a severe withdrawal headache. Her neurologic examination was entirely normal, as was an erythrocyte sedimentation rate (ESR) (14 mm/hr). She brought a brain MRI that was normal. After discussion, she was placed on a week of a prednisone taper, with famotidine (Pepcid) to protect her stomach and hydroxyzine (Vistaril) for anxiety, nausea, or mild headache. Subsequent to that, she was allowed the use of hydroxyzine and naproxen sodium 550 mg (Anaprox DS) twice daily as needed. When seen for follow-up in 6 weeks, she was headache-free, not using acetaminophen, and did not need to use any medication at all. She has remained in this essentially headache-free state for more than 3 years, save for 1–2 tension-type headaches per month that resolve in 1–2 hours with the naproxen sodium. This case is typical of transformed migraine. There was a prior history of episodic migraine, which in the setting of frequent use of acute medication, in this case nothing more than acetaminophen, evolved into a chronic daily headache looking like CTTH with superimposed migrainous exacerbations. Of note, because no prescription is required, many patients don’t consider these medications and specific inquiries need to be made. The same point may be made regarding herbal remedies and alternative therapies. Also, notably, this patient initially did not disclose her milder background headaches, focusing instead on the exacerbations. Such under-reporting by patients is common, revealing the need to inquire specifically as to how many types of headaches the patient actually has and whether or not there are any headache-free days. There is no substitute for a careful history and keeping an open mind. Case 2 This 46-year-old man had never suffered from disabling headaches until he was involved as a passenger in a serious motor vehicle accident. He sustained a concussion and was unconscious for more than 3 hours. The clinical course was complicated by a femur fracture, and it was only after he attempted to reduce his oxycodone with acetaminophen (Percocet) intake, that he noticed the occurrence of severe headaches. His lower extremity injury resolved within 2 months, but his need for narcotic pain medication continued. He had frequent headache that seemed to be migraine, occurring 3–4 days per week. Most other days he had milder headache resembling CTTH. A neurologist diagnosed ‘‘post-traumatic headaches’’ with whiplash, but seemed perplexed when they persisted beyond 12 months and even after his litigation was settled. When seen in the headache clinic 7 years after the accident, he was complaining of daily headache, usually severe and disabling. He had trouble
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sleeping and seemed depressed. His examination was normal save for tight posterior paraspinal cervical muscles. He brought normal brain and cervical spine MRIs. He was consuming 2–6 narcotic analgesic pills per day and 4– 10 over-the-counter mixed analgesic pills per day (Excedrin). He reported that his number of pills per day had increased concordant with his overall headache pattern worsening (more frequent, more severe headaches). Often, 3–4 hours after falling asleep, he would awaken with a severe headache, only finding relief by taking more pills. As he had reported that prior attempts to reduce his medication use had resulted in severe headaches with vomiting, he was admitted to the hospital. His narcotic and mixed analgesics were stopped and he was begun on a three times per day regimen of intravenous metoclopramide followed by dihydroergotamine. Within 48 hours he became headache-free. Amitriptyline was begun at 25 mg at bedtime. He was discharged on amitriptyline regularly and naproxen sodium and hydroxyzine on an as-needed basis for headaches. When seen for follow-up 4 weeks later, he was headache-free. Post-traumatic headaches may mimic any type of headache, including any of the primary headaches. Typically they resolve within 12 months [16]. Their perpetuation by medication overuse has been reported [17]. In some cases post-traumatic headache that has continued for many years has improved after stopping medications that may have been causing analgesic rebound. Notably, analgesic rebound headaches may occur when headacheprone patients are put on pain medications for non-headache conditions [18]. Recognition of medication overuse offers the potential for effective clinical intervention. Case 3 This 57-year-old woman had a history of episodic migraine since her teenage years, which worsened after her second pregnancy at age 26 years. At that time, because of severe vomiting with the attacks, her physician prescribed ergotamine tartrate with caffeine (Cafergot) suppositories. Although highly effective for her attacks, she found she required them 4–5 days per week. Less use resulted in even more severe attacks than she had been experiencing. Over time she found that one third to one half of a suppository each night at bedtime effectively prevented the severe attacks. If she neglected this ritual for even a single night, her reward the next morning (early) would be a severe disabling migraine with vomiting that would remit only with the administration of another portion of a suppository. On further questioning she admitted to daily mild headaches also. When seen in the clinic she was distressed, because ergotamine suppositories had become hard to obtain in the United States and she had to import them from Canada. Neurologic examination was normal. She was admitted to the hospital and treated with intravenous chlorpromazine and hydrocortisone. She experienced a withdrawal headache for
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5 days, lessened with the intravenous medications, which soon after discharge became minimal and vanished entirely by 4 weeks. Since that time she has had only mild headaches, no more than 3–4 per month, easily controlled with hydroxyzine and naproxen sodium. Ergotamine-dependency headaches are seen infrequently now, as ergotamine has been replaced largely by the triptans in acute headache treatment. Ergotamine tartrate has a long duration of action but is suspected of causing rebound headaches, as noted. Overuse may lead to the well known complications of ergotism and fibrosis. Many experts limit their use to 2 days per week to avoid generating ergotamine-dependency headaches [1]. This patient was unable to cease using this ‘‘remedy’’ for more than 30 years, yet once she was detoxified from this agent she had dramatic clinical improvement. The mechanism by which analgesic rebound/medication overuse occurs is not known. There has been much speculation, especially noting that it tends to occur in ‘‘headache-prone’’ patients, particularly migraineurs. Medication overuse also has been reported to perpetuate other headache types, including NDPH, HC, and post-traumatic headache [13,17–19]. Continuing peripheral input into the trigeminal nucleus caudalis, with increased activity of ‘‘on cells’’ and decreased activity of ‘‘off cells’’ in the medulla, with central sensitization has been invoked [20,21]. Analogies with the proposed epileptic phenomenon of kindling have been advanced [12]. Given the hereditary nature of migraine, receptor changes (serotonin, NMDA) have been described, as has a suppression of ascending/descending central anticonceptive serotonergic systems [1,20,22,23]. Welch, using sophisticated MRI techniques, has demonstrated increased iron deposition in the periaqueductal gray in chronic daily headache patients and hyperoxia in the red nucleus and substantia nigra. The amount of iron deposition correlates with the duration of illness [24]. The possibility of free radical generation and tissue damage is of concern. Clinically, in some patients it seems that rebound headache happens because of the occurrence of withdrawal headache leading to further medication use, to be followed by further withdrawal headache in a selfperpetuating cycle. Frequency of use therefore may be more important than actual amount of drug taken [1]. There are likely to be individual differences in susceptibility to this phenomenon. It is not certain, but many experts suspect that analgesic combinations are more likely to trigger rebound [25–27]. Caffeine’s role is controversial. It is added to many products to enhance absorption and as an adjunct analgesic. Although it is of low dependence potential by itself, its presence may be synergistic with other components of pain remedies in promoting rebound. Caffeine has been reported to cause withdrawal headaches as a single agent [12,28]. The treatment of medication overuse headache involves several fundamental principles. The first involves recognition of the condition. Especially for patients with transformed migraine, there is usually a prior history of intermittent migraine that evolves over time, with an increase in
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frequency to a chronic daily headache pattern and the appearance of two main headache types. The more frequent background headache resembles CTTH. Superimposed on this background headache pattern are exacerbations with many characteristics of the patient’s prior migraine headaches. The patient usually answers affirmatively the question, ‘‘Over the past few months or years have you been taking more pills yet having more headaches?’’ The acute medications, despite being used in ever-increasing amounts, work less and less well, and the patients often experience side effects from chronic use, such as esophagitis and ulcers. Preventative medications fail to offer relief and are often poorly tolerated [7,10]. These are the headache patients who come in to the clinic and have been tried on ‘‘everything’’ yet ‘‘nothing works.’’ If the patient is not able to stop overusing the offending medications, it is unlikely the chronic headaches will improve. The natural history of untreated frequent migraine/transformed migraine is not understood fully, but certainly many patients develop worsening patterns that may persist for years, even into old age. Education of the patient as to the nature of the problem, the role of medication overuse, and the possibility of future improvement is mandatory. Unless the patient is an active participant in the treatment plan, the likelihood of success is low. Outpatient and inpatient treatment strategies have been proposed and compared [27,29,30]. Outpatient detoxification can be attempted in many highly motivated, cooperative patients. A withdrawal headache occurring as the offending medications are tapered or stopped should be anticipated [7,25]. Many medications, such as simple analgesics, ergotamine, and triptans, can be stopped abruptly. Other agents, such as butalbital, benzodiazepines, and narcotics, are best tapered to avoid the risk for seizures, delirium, or severe withdrawal syndromes. Some clinicians advocate instituting a steroid taper, such as using prednisone for a week with measures to protect the stomach [31–33]. Hydroxyzine (Vistaril) may be used for nausea and jitteriness caused by the steroid and at bedtime for sleep. Promethazine (Phenergan) or other antiemetic suppositories should be available. After the week of steroid, longer-acting agents, such as dihydroergotamine intranasally (Migranal) or subcutaneously or intramuscularly (DHE-45), naratriptan (Amerge), or frovatriptan (Frova) might be used for severe headache exacerbations, and longer-acting NSAIDs such as naproxen sodium, 550 mg twice daily [34]. Ideally even these agents should be used no more than 2–3 times weekly to avoid rebound. At the same time, effective prophylaxis should be initiated. The choice of drug needs to be made in light of which comorbid/coexistent medical conditions the patient has. Even prophylactic agents that were ineffective or poorly tolerated when the patient was in the rebound state may be dramatically effective once the patient is no longer misusing medications. The patient should be alerted to the likelihood of short-term worsening of the headaches (withdrawal) as the price to pay for potential long-term benefit. Although there is often rapid
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improvement in the headache pattern soon after the withdrawal headache, the analgesic washout period (the time it takes for the system to reset and normalize) actually seems to last approximately 8 weeks and occasionally as long as 12 weeks (Box 1) [1]. Smith recently has published a protocol using low-dose tizanidine (Zanaflex) at bedtime in conjunction with long-acting NSAIDs [34]. Most patients responded to a low bedtime dose of tizanidine (average dose, 3.6 mg). The success rate defined as needing four or fewer acute medication doses in a 2-week period was approximately 65%. Although this rate is not as high as some of the inpatient protocols (up to approximately 90%), this may be a cost-effective option. Patients who fail outpatient attempts to treat analgesic rebound are candidates for inpatient therapy. This is also true for those with confounding medical or psychiatric conditions that render outpatient treatment impractical. An example might be a patient with long-standing ergotaminedependency headaches who has begun to develop angina provoked by the ergotamine (an urgent situation requiring immediate action). Numerous protocols have been advocated (Box 2). Such therapy is best used by those physicians experienced in managing intractable headaches in a multidisciplinary setting. The repetitive intravenous metoclopramide/dihydroergotamine protocol popularized by Raskin is often useful [40]. Meticulous attention to detail is
Box 1. Outpatient treatment regimens for medication-overuse headache Stop offending medications Taper butalbital, benzodiazepines, narcotics Anticipate withdrawal headache Antiemetic suppositories for vomiting Course of prednisone 60 mg daily for 3 days, 40 mg for 2 days, 20 mg for 2 days Initiate prophylaxis such as amitriptyline 25 mg at bedtime [31,32] Limit subsequent use of analgesics to 2–3 days per week –or– Initiate tizanidine 2 mg at bedtime; escalate dose by 2 mg every 3–5 days until therapeutic effect is achieved or sedation occurs Patients may use long-acting NSAID daily (such as rofecoxib, naproxen, piroxicam, ketoprofen SR, celecoxib) Treat severe headaches with dihydroergotamine (subcutaneously, intramuscularly, or intranasally) or with a triptan [34]
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essential. The offending medication must be stopped. Ten milligrams of metoclopramide is administered first. If dystonia or akathisia (restlessness, jitteriness) occurs, diphenhydramine (Benadryl) or benztropine mesylate (Cogentin) is given as the antidote. After the metoclopramide, a dose of 0.5 mg dihydroergotamine follows. The essential therapeutic maneuver is to adjust the dihydroergotamine to the effective subnauseating dose (up to 1 mg) then given on a three times daily basis (not every 8 hours, to allow the patient to sleep). Side effects of leg cramps and nausea respond to dose reduction. Diarrhea may be treated with diphenoxylate and atropine (Lomotil) or loperamide (Imodium). Dihydroergotamine should be avoided in patients with coronary artery disease or vasospastic conditions. Other inpatient treatment regimens have been advocated. The author and others have used intravenous chlorpromazine, titrating the dose until the patient is asleep and continuing for several days until the withdrawal headache has subsided [36]. Again, if akathisia or dystonia occurs, diphenhydramine or benztropine is administered. The patient needs to be
Box 2. Inpatient treatment regimens for medication overuse headache Admit to hospital Stop offending medications (taper those that might cause withdrawal seizures or delirium, as noted in Box 1) May substitute 30 mg phenobarbital at bedtime per 100 mg of butalbital patient has been using [35] Repetitive metoclopramide/dihydroergotamine regimen (Raskin protocol) Titrate dosage to the effective subnauseating dose (see text) [36] Manage side effects Most patients improve in 2–3 days; some require a few days longer –or– Intravenous chlorpromazine (see text) Titrate the dose to achieve sleep [36] –or– Intravenous valproate [37] or Intravenous lignocaine (lidocaine) [38] or Intravenous propofol [39] Order appropriate consultations Education Initiate prophylaxis Appropriate follow-up with plan to treat subsequent headaches while avoiding relapse
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maintained at bedrest, as orthostatic hypotension is common. Measures are taken to prevent deep venous thrombosis. Hypotension often responds to dose reduction or intravenous fluid boluses. Intravenous valproate (Depacon), lignocaine (lidocaine), or propofol (Diprivan) are other therapeutic choices [37–39]. The main goal of the inpatient regimens is to allow the removal of the offending medications and prevent/treat the withdrawal headache. Brief 2–3 day admissions can be sufficient for many patients, but some require longer stays. Appropriate education and consultation (psychiatry, behavioral medicine, pain management) should be undertaken before discharge. Effective prophylaxis should be initiated to ensure the patient can tolerate the new agent. A plan for controlling the headaches without relapsing into medication overuse needs to be made, together with clinician availability before the follow-up visit after discharge in case of clinical deterioration. Relapse rates following treatment for medication overuse headache have been reported to be as high as 50% but generally are lower [26,27]. Risk factors for relapse seem to be male sex, use of combination analgesics and ergots, and perhaps administration of ineffective therapies, such as naturopathy/homeopathy [27]. Relapse was defined generally as a resumption of medication overuse with a worsening of the headache pattern. Relapse does not seem to correlate with whether the initial treatment regimen was outpatient or inpatient, although inpatient regimens seem to have a higher initial success rate [34,40]. The literature regarding the various treatment strategies is not of high quality, with few randomized trials, small studies, and much anecdotal evidence presented [29]. Often more than one treatment is manipulated at once, and it has been suggested that perhaps some of the ‘‘improvement’’ reported may represent little more than ‘‘regression to the mean’’ [12]. Medication overuse may be a consequence of headache or a cause of it. Recognition of this diagnosis is important, so a high degree of clinical suspicion must be maintained. Accurate diagnosis of the headache types the patient is suffering allows institution of appropriate therapy. If medication overuse is suspected, the offending drugs should be discontinued either in the outpatient or inpatient settings. If analgesic rebound indeed has been occurring, there may be dramatic clinical improvement. Additionally, preventative therapies may be more likely to work, and side effects from overused, ineffective medications may be lessened or avoided. After an early withdrawal headache, the headache pattern may revert to an intermittent one or headaches may cease entirely. The analgesic washout period may last up to 3 months or longer, but improvement if it is going to occur usually is seen in days to weeks [1]. Transformed migraine seems to occur in all age groups, although in adolescents there may be a brief period of transformation, if any at all, and drug overuse is seen less often [14]. Medication overuse headache may persist into old age, especially if not recognized and addressed, as patients
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have easy access to analgesics without a prescription. The best situation is to prevent this condition from occurring through education of the public and setting limits on medication use so this cycle of pain never develops.
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