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12 Articles in Volume 12, Issue #5
A-Delta Pain Fiber Nerve Conduction Study Benefits Patients With Spinal Pain
Chronic Pain Management of the Noncompliant Patient
Clinical Applications of Radiofrequency Lesioning for Back and Neck Pain
Current Understanding and Management Of Medication-overuse Headache
Fibromyalgia: An Overview of Etiology and Non-pharmaceutical Treatment Options
June 2012 Pain Research Updates
Junk The Term Narcotics—Call Them Opioids
Managing Adverse Drug Effects in Pain: Focus on Muscle Relaxants
Music Therapy for Pain Management
Perioperative Pain Management in the Opioid-tolerant Elderly Patient: Case Challenge
Practical Tips in the Treatment Of Osteoarthritis of the Knee
Sudden, Unexpected Death in Chronic Pain Patients

Current Understanding and Management Of Medication-overuse Headache

While the number of patients presenting with medication-overuse headache is growing, the condition is commonly overlooked and difficult to treat.

Medication-overuse headache (MOH) is a chronic disorder that arises from the frequent use of acute (abortive) medications for the treatment of a primary headache. It manifests as almost daily headaches that cause substantial disability and diminish health-related quality of life.

The International Headache Society defines MOH as a condition in which headaches occur on 15 or more days per month when the therapeutic agent is used excessively and on a regular basis for three or more months and when headaches have developed or worsened during the period of medication overuse.1

MOH has become a chronic headache of growing worldwide importance. The World Health Organization Atlas of Headache Disorders reported that in primary and neurology care, a respective 6% and 9% of headache sufferers present with this disorder. In specialized headache clinics the figure is closer to 30%, and more than 50% in the United States.2 Data from a physician survey that included neurologists, headache specialists, and general practitioners suggested that MOH may be the third most frequent type of headache after migraine and tension type headaches (TTHs).3 Yet, while the number of patients presenting with this condition is growing, MOH is commonly overlooked and difficult to treat.4 This review aims to discuss the clinical features, risk factors, and pathophysiology of MOH. It also summarizes current strategies for managing and preventing headache chronicity.

Clinical Features
The primary headache disorders leading to MOH include migraine headache (65%), TTH (27%), or a combination of the two (8%). Interestingly, individuals with cluster headaches generally consume acute medication without developing MOH. Women are more prone to MOH than men. Studies indicate that the average duration of the primary headache is 20.4 years, the mean duration of the excessive medication intake is 10.3 years, and the mean period of daily headaches is 5.9 years in patients with MOH.5

In principle, all acute-care headache medications have the potential to cause MOH. These include over-the-counter drugs like aspirin and acetaminophen, combination medications containing paracetamol and aspirin, non-steroidal anti-inflammatory drugs, anti-migraine abortive drugs (ergots, triptans), barbiturate-containing medications (mainly butalbital), opioids, and opioid agonist/antagonist agents (butorphanol). However, triptans in particular are currently the most frequently overused medication associated with MOH.6

The time until development of MOH and the amount of drug that is sufficient to trigger MOH varies with the individual agent. One prospective study of 96 headache patients who developed MOH revealed that the delay between starting the drug and developing MOH was shortest for triptans (1.7 years), longer for ergots (2.7 years), and longest for analgesics (4.8 years). It was further demonstrated that just 18 single doses of triptans per month were enough to induce MOH, compared with the lowest doses per month of 37 and 114 for ergots and analgesics, respectively.4 Generally, for an episodic condition to transform into a chronic one, medications need to be taken only a modest number of days per month: five to 10, depending on the type of drug.7

Since up to 90% of all patients with MOH consume more than one specific drug for the treatment of acute attacks, it is difficult to differentiate exactly between the features of different MOH subtypes according to the drug overused. Nevertheless, recent studies reveal that patients who intake ergotamine and analgesics tend to develop a daily TTH-like headache, whereas patients with triptan-induced MOH are more likely to report a migraine-like headache or an increase in migraine frequency.6

Irrespective of the offending agent, there are several general clinical characteristics that can help distinguish MOH in patients with primary headache disorders (Table 1). The threshold for head pain is low, with the slightest physical and intellectual exertion being enough to trigger headache. It has been found that simultaneous prophylactic drugs are unsuccessful while the patient is taking excess amounts of the culprit drug. Moreover, withdrawal symptoms are observed when patients are taken off their pain medications abruptly. However, spontaneous improvement of the headache does occur within days of drug discontinuation.4

Pathophysiology
The mechanisms that underlie MOH remain unclear, primarily due to a lack of experimental work and appropriate animal models. Several mechanisms are theorized to play a key role.

Genetic Disposition
Since only patients suffering from migraine or TTH, but not patients with cluster headache, are seen to develop MOH upon chronic analgesic overuse, genetic determination appears to be important. This is supported by the observation that patients with other chronic painful disorders, such as rheumatoid arthritis, take large amounts of analgesics regularly without incidence of increased headache. On the other hand, patients with migraine who consume analgesics for non-headache pain (ie, neck pain) are significantly more prone to develop MOH than those without migraine. The conclusion drawn from this evidence suggests a specific genetic susceptibility for patients with migraine or TTH to develop MOH.8

Altered Receptor and Enzyme Physiology
It has also been postulated that headache medications have a direct inhibitory effect on the pain-regulating capacity of our brain. Repetitive exposure to triptans causes a substantial decrease in serotonin synthesis and downregulation of serotonin receptors in various cortical regions, the extrapyramidal system, and the brainstem. These alterations may occur as soon as 24 to 96 hours after chronic exposure. Similarly, analgesics like aspirin decrease functional cyclooxygenase (COX)-1 and 2 function. This reduction of serotonin receptors and prostaglandin-synthesizing enzymes occurs in brain structures that transmit or modulate nociceptive signals. For example, the periaqueductal gray matter functionally loses serotoninergic pathways that inhibit trigeminal nuclei. The result is impaired antinociceptive activity and the creation of a hyperalgesic state.4

Central Sensitization
Frequent intake of acute medications that are ineffective at terminating the headache may trigger MOH through a “wind-up” phenomenon in which persistent stimulation of nociceptive pathways produces central sensitization. In support of this argument, neurophysiologic studies have shown facilitation of trigeminal and somatic nociceptive systems in MOH primarily mediated at a supraspinal level. Additionally, animal studies have demonstrated that triptans cause reversible cutaneous tactile allodynia associated with facilitation of trigeminal dural afferents. Researchers are hypothesizing that triptans induce pronociceptive neural adaptive changes within the dural afferents of the trigeminal ganglia and augment responses to an established trigger of migraine headache in humans.9

Who Is at Risk?
In addition to drug overuse and a pre-existing primary headache, other risk factors have also been described that may predispose or exacerbate the disorder. Low socioeconomic and educational status, for instance, has been correlated with a higher frequency of MOH. In the Dutch and German populations, chronic headache is respectively threefold and sevenfold more prevalent within first-generation immigrants in comparison to natives. This occurrence may directly be attributed to poorer use of adequate medical care.10

Withdrawal headache is another contributor to medication abuse. Patients attempting to cease or reduce consumption of abortive headache medication experience worsening pain, which reinforces continued drug use. Moreover, many analgesics contain barbiturates and caffeine, which contribute to physiological dependence and/or produce bothersome withdrawal symptoms such as irritability, nervousness, and restlessness that last for days. Caffeine has currently been classified as a modest risk factor for developing chronic headache and for this reason should be removed from ergotamine-containing formulations.11

Finally, psychological factors play a powerful role in MOH development. Patients admit that the apprehension of losing social function due to headache as well as the fear of a looming headache between attacks drives them to use acute medications prophylactically.12 This habit is further promoted by physicians or package instructions that encourage users to take their medication as soon as possible to prevent a headache. Of course, the fact that the drug initially succeeds at relieving pain works as positive conditioning for the patient.12 Obsessive-compulsive disorder, anxiety, and mood disorders have been more frequently detected in patients with MOH. In fact, psychiatric comorbidity has been reported in two-thirds of all patients with MOH. In some cases, MOH is also suggested to be maintained by substance abuse disorders as a large proportion of patients with chronic headache fulfill the DSM-IV criteria for substance dependence. Collectively, these findings highlight that psychology is an important risk factor for medication abuse.13

Awareness and Detection
Timely identification of MOH is necessary not only to properly manage the handicap that daily headache directly imposes on a patient’s quality of life, but also to curtail the complications of MOH, most of which are caused by the side effects of the abused drugs. The use of ergotamine, for example, leads to sensory neuropathy and slowing of central cognitive processing.6

The diagnosis of MOH relies on the history that is provided by the patient. For this reason, physician awareness of this disorder, as well as open and accurate communication between patient and physician, are vital for the recognition and management of MOH. Broadly speaking, MOH needs to be suspected in anyone suffering from chronic headache.10 A careful survey of the course of the disorder and history of drug intake discloses the features that define MOH. History often reveals episodic migraine, perhaps well controlled by triptans at first, that later becomes more frequent or resistant to medication. Some patients may report daily medication use, while others may be reluctant to reveal their true consumption of drugs. Many migraine sufferers report only severe attacks and the medications used for them. Milder headaches and the medications patients use to treat them may not be accounted for. Clinicians should inquire as to how many days in the month the patient takes any type of acute headache-relief medication for any type of headache. Ask patients how they feel and perform in between attacks and whether they are anxious about not being able to function daily. A headache diary could indicate changes in headache frequency and medication use.12

Another helpful indicator for MOH is the number of physicians the patient has consulted and the number of ineffective therapies attempted. One study demonstrated that MOH patients seek advice from an average of 5.5 healthcare providers who prescribe an average of 8.6 therapies.7 Once again, when presented with such a clinical picture, a useful strategy is to assume that daily headache is likely due to medication overuse. It is also crucial for the physician to be aware that concomitant medical problems, stress, sleep disturbance, and depression increase headache frequency and should be assessed for in the presenting patient.4

Reversing MOH
The goal of treatment is to reduce headache frequency and severity by weaning the patient from the abused medication, while creating a sensible regimen of prophylaxis and acute medications—with limits.12 Along with educating the patient about the origin of their condition, withdrawal is usually the initial step in MOH treatment. This phase can be done gradually over the course of 4 to 6 weeks, during which preventative medications are introduced. Or, it may occur abruptly over days with transitional medications used to dull withdrawal symptoms while prophylaxis is being established.14 Even when medications are tapered gradually, withdrawal symptoms such as headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, and anxiety may arise and persist for an average of 3.5 days. Depending on the agent withdrawn, alleviation of these symptoms might include fluid replacement, analgesics, tranquilizers, neuroleptics, amitriptyline, valproic acid (Depakote), IV dihydroergotamine (DHE), oxygen, and electrical stimulation. Corticosteroids are often recommended as another bridge medication to reduce withdrawal headache, but there is still not enough clinical evidence supporting their benefit.15 In addition, the patient may be provided with acute medications such as triptans and DHE for severe headache attacks, but with strict stipulations: the symptomatic drugs many not be used more than 2 days per week and 10 days per month.14

An important issue is whether withdrawal therapy should be carried out in an inpatient or outpatient setting. The consensus recommendation is that highly motivated patients who are not using barbiturates and tranquilizers may be treated on an outpatient basis. Patients who overuse drugs containing codeine, barbiturates, or tranquilizers, and those with severe comorbid medical and psychiatric illnesses are advised to enter an inpatient facility. The latter group of patients might check into a hospital or a “day hospital” to receive multidisciplinary care.15

Discontinuation of the offending agent may be challenging and headache improvement usually takes time. Some studies indicate that patients experience a 51% reduction of migraines and 18% reduction of TTH solely after withdrawal of acute medication. Yet, others see no improvement in headache frequency and/or severity.11 To truly alleviate the underlying headache problem and prevent relapse into overuse, clinicians and patients must be prepared to undertake a long-term treatment strategy; this involves both medical and behavioral prophylaxis.

Preventative medications attempt to decrease the frequency of headache attacks per month and therefore hold promise of decreasing the use of acute medications. Prophylaxis should be initiated prior to or during the weaning phase. Topiramate (Topamax) is one therapeutic option that has been used with some success, but a substantial number of subjects have reported adverse effects of the drug. Valproic acid, and most recently, botulinum toxin A (Botox) have been shown to be effective migraine preventive medications as well.9 Non-pharmacological strategies involve massage and behavioral therapies such as cognitive-behavioral therapy, stress reduction, and biofeedback training.16

The outcome of MOH treatment is good. Most patients improve when weaned and treated with prophylaxis medications. Recovery is defined as at least a 50% reduction of headache days after 3 months. Seventeen studies demonstrated withdrawal therapy to have a success rate of 72.4% within the first 6 months.10 Unfortunately, the initial improvement seen in patients in the first year is often proceeded by preventable relapse: a large prospective study indicated a relapse rate of 38% within the first 12 months.8 Predictors for relapse after successful initial therapy remains difficult to interpret. Two components appear to be important: 1) the type of primary headache-patients with TTH have higher relapse risk; and 2) duration of regular drug intake-longer duration equates to worse prognosis.10 Patient education, continuous support through frequent follow-up visits, and monitoring by means of a headache diary are all critical to long-term treatment success and relapse prevention.

Prevention Is the Best Treatment
The best approach to MOH is to avert it in the first place. Patient education is central in achieving this end. Physicians need to inform patients on the appropriate use of their acute medications and on the phenomenon and symptoms of MOH.10 Healthcare providers must also be vigilant in their surveillance of patients suffering from headache. Migraine patients must be identified and carefully instructed on how to properly use migraine-specific drugs, such as triptans or ergots. Patients who suffer from more than 10 headaches per month have an escalated risk of developing daily headaches. In these individuals, physicians might consider instituting daily preventative medication, such as tricyclic antidepressants and anticonvulsants, to reduce frequency and severity of attacks.14 To avoid dependency in those individuals who do consume acute headache drugs, physicians must restrict intake frequency (ie, analgesics, <15 intake days monthly; triptans, <10 intake days monthly). Physicians should also veer away from mixed analgesics and migraine drugs that contain caffeine, opioids, tranquilizers, or barbiturates.11

Conclusion
Medication overuse is the most common factor leading to the transition from episodic to chronic headache, and MOH is becoming a growing health concern all over the world. Unfortunately, patients with MOH frequently go unrecognized and fail to receive appropriate treatment. For this reason, healthcare providers must become more familiar with this disabling condition and address it with patients through open communications. Physician surveillance and increased public awareness about the need to prevent excessive acute medication intake are paramount in preventing headache chronification in the first place. However, rescuing patients from already-established MOH most commonly begins with withdrawal of the overused medication(s), a strategy that resets the toxic situation induced by frequent use of symptomatic medication and permits preventative pharmacological therapy to become effective. Physicians must be aware that—together with a long-term treatment plan that includes preventative medication, behavioral therapy, headache diaries, and frequent revisits—current management strategy holds great promise in reducing chronic headaches.

Last updated on: September 25, 2012
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