Medication-overuse headache (MOH) is a common neurologic disorder with enormous disability and suffering and plays a significant role in the transformation from episodic to chronic headache disorders. Multiple terms have been used to describe MOH such as analgesic rebound headache, drug-induced headache or a medication-misuse headache. Patients with established primary headache disorders like migraine or tension-type headaches excessively overuse medication for their acute headache and inadvertently increase the frequency and intensity of their headache. In this manner, a vicious cycle of further drug consumption and increased headache frequency develops transforming the treatment for their headache to the actual cause of their disease (MOH). Patients prone to headaches who take analgesics for other conditions can also develop MOH.
Recognition of MOH was as early as in the 1930s when physicians observed prolongation of headache associated with ergotamine-overuse. In the 1970s and 1980s, physicians observed its association with analgesics such as barbiturates, codeine, and combination analgesics as well and also noticed a reduction in headache frequency with stopping drugs. For a short time, it was referred to as transformed or an evolutive migraine. The first edition of the International Classification of Headache Disorders (ICHD) in 1988 first defined the disorder calling it a drug-induced headache that was a “headache induced by chronic substance use or exposure.” MOH was first introduced in the second edition of ICHD (2004) with multiple subtypes dependent on offending medicine, such as ergotamines, triptans, opioids, etc.
Medication overuse headache currently classifies as a secondary headache or chronic headache syndrome in the latest version of ICHD-3 (2018) under subsection 8.2 as a chronic headache disorder secondary to a pre-existing headache syndrome. The specific subtype of MOH is dependent upon the medicine involved. Overarching criteria are that (1) a headache is occurring on greater than or equal to 15 days per month for a patient with a pre-existing headache disorder (2) regular medication overuse for greater than 3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of a headache and (3) Not better accounted for by another ICHD-3 diagnosis. If multiple drugs are overused, all applicable/multiple codes should be used. There are no clinical characteristics defined as the headache typically resembles the pre-existing headache syndrome. The general rule is that the MOH resolves upon cessation of the medication. In this manner, two diagnoses are made, first the primary headache syndrome and second the MOH. It is no longer a requirement for the diagnosis that headache pattern returns to previous within two months of stopping the offending drug.
As the name implies, chronic medication overuse is the most significant risk factor for the development of MOH with each of the classes of analgesics carrying a different risk profile. The risk from lowest to highest is: triptans/ergotamine, single analgesic agents (NSAIDs, acetaminophen), and combination analgesics containing opiates or barbiturates. There have been observations that combination analgesics particularly those containing opioids and/or barbituates have a two-fold increase relative risk for MOH.
NSAIDs may have a protective effect from MOH in patients with ten headache days or less per month.
Medication overuse headache has a true prevalence that is unknown partly resulting from various changes in diagnostic criteria, but estimates are in the range from 0.5% to 2.6% in the general population. Higher rates have been reported in Russia (7.6%) and Iran (4.6%), places where it is felt that medication overuse is more prevalent. In some studies from specialized headache centers, the prevalence of MOH in patients with chronic daily headaches has been reported anywhere from 11% to 70%, much higher than the general population. In approximately 80% of MOH patients, migraine is the underlying primary headache disorder with the overwhelming remaining having tension-type or post-traumatic headaches. MOH most commonly affects those age 30 to 50 years with a female to male predominance of 3 to 4 to 1. Interestingly enough, between 21% and 52% of pediatric patients and 35% of the elderly over the age of 64 met criteria for MOH. Some studies in Europe have reported increased prevalence in first-generation migrants, and the feeling was that a potential explanation for this was multi-factorial but likely included socioeconomic class, genetic predisposition, and cultural reasons. As MOH is a worldwide problem, experts surmise that economic, psychological and physical disability all factor into the etiology of this disease. In 2016 Global Burden of Disease (GBD) listed migraine as the second largest cause of disability likely because MOH was considered an emanation of migraine and tension headache.
Of those patients with MOH, dependency-like behavior presented more often in those that overuse opioids and triptans than aspirin or ibuprofen. MOH can be associated with substance-related disorder spectrum as it is believed they share common neurobiological pathways. Data like these support a biological predisposition as another significant risk factor for MOH. Of all headache types, migraine is the one most commonly associated with MOH and occurs in approximately 80% of patients. Patients with higher headache frequency at baseline are also at higher risk for MOH. It is unknown if the high headache frequency leads to more drug consumption and thus MOH or if patients with higher frequency attack are more prone to MOH. Another study found a threefold risk of MOH if family history of MOH or substance abuse (drug or alcohol). Several trials have demonstrated that frequent and often multiple psychiatric mood disorders such as anxiety and depression exist in patients with MOH. Some trials interestingly found that 40% of MOH patients actually met criteria for depression and upwards of 58% for anxiety. It remains unclear if psychiatric comorbidities are risk factors or just the consequences of MOH. The 2011 Hagen longitudinal study found that patients with a tension-type headache had the highest incidence of psychiatric comorbidities. Another study found patients with MOH have a higher susceptibility towards drug dependency and obsessive-compulsive disorder (OCD).
The pathophysiology of MOH is not well understood, but studies have demonstrated that central sensitization likely plays a major role. Since patients with migraine or tension-like headaches are prone to developing MOH, the theory is that similar physiological mechanisms may be involved. The condition exhibits both functional and structural changes in the central nervous system (CNS) particularly the hippocampal periaqueductal gray area, posterior cingulate cortex thalamus, cerebellum, orbitofrontal cortex (OFC) and the mesocorticolimbic reward system. Also found were changes in the serotonergic neuromodulatory system, upregulation of vasoactive and pro-inflammatory mediators increases susceptibility to cortical spreading depression, central sensitization and an increase in nociceptive sensory fields. Some studies have theorized a potential genetic risk as the etiology for the development of MOH. One such model is the renin-angiotensin system known to have an active role in regulating neural plasticity.
The thinking is that the insertion/deletion polymorphism in the gene that encodes angiotensin-converting enzyme (ACE) increases an individual’s susceptibility to MOH. ACE is a key enzyme in regulating blood pressure, but in the brain, it interacts with monoaminergic synaptic transmission thereby contributing to dependence behavior. ACE polymorphisms seen in MOH patients have been demonstrated to influence sensitization and habituation patterns. Other potential polymorphisms are brain-derived neurotrophic factor (BDNF), catechol-O—methyltransferase (COMT) and serotonin transporter (SERT). All of these lead to disturbances in the normal brain pathway neurotransmitters making patients more susceptible to dependence, behavioral disorders, substance abuse, pain disorders, and several neuropsychiatric disorders.
Animal studies have also demonstrated that pain medications alone can cause altered neurotransmitter metabolism especially the serotoninergic and endocannabinoid systems. Several human studies have shown hypersensitization and hyperresponsiveness of the cerebral cortex suggesting that the brain of those suffering from MOH are “locked” in a pre-excitation state. In fact, all MOH patients exhibited increased somatosensory evoked potential (SEP) amplitude after stimulation as well as lack of habituation after further stimulation. After drug discontinuation, a slow progression back to normal sensory processing was observed in most patients and within most areas of the brain. The primary force leading to MOH related structural and functional properties of the brain seem to be prolonged exposure to pain medications. All pain medications can cause MOH, but some drug classes can cause it faster or with shorter overuse. Therefore it is believed from evidence from multiple studies that MOH causes changes in the central nervous system specifically in pain processing and dependence networks, sensitization and receptor density all of which help to explain the clinical features of the disease.
As always, detailed history with particular emphasis on evaluating headache is essential. Equally important is the detailed medication history and history of substance abuse. To be considered for a diagnosis of MOH, a patient must have a headache for 15 or more days monthly in a patient with an established diagnosis of a headache disorder such as migraine or tension-type. Additionally, they must be utilizing one or more symptomatic medications regularly (10 to 15 days per month depending on the type of drug consumed) for over 3 months. The headache characteristics are usually typical for their primary headache types such as migraine or tension although they are often more intense and frequent. Evolution towards MOH is substance-specific occurring faster in those that overuse triptans, opiates, and combination analgesics than those that overuse simple analgesics.
The most common headache diagnoses before the evolution of MOH are migraines (65%), tension-type headache (27%) and mixed/other headaches (8%). Note that the transition from episodic to MOH is typically gradual in onset with patients noting an increase in their headache intensity and frequency. Patients typically describe their usual headache but caution is advisable as features of their headache can change over time. Most patients with MOH (90%) utilize multiple different medications for relief. Patients often report morning headaches and neck pain which may be the result of overnight drug withdrawal or poor sleep quality.
The central sensitization causes by MOH can lead to skin hypersensitivity and the expansion of their headache. Autonomic and gastrointestinal symptoms such as a runny nose, tearing, nausea, vomiting and diarrhea can accompany their headache. Physical examination is typically nonfocal with no neurologic deficits. A false-positive diagnosis must be excluded by obtaining a detailed history and physical examination including headache type, frequency and drug use to rule out any secondary headache syndromes that may require different management.
Remember it is the frequency of a headache and not the quality or intensity that makes the diagnosis of MOH. Unless there are concerning clinical features in the patient's history or physical examination, there are no confirmatory nor necessary laboratory, radiographic or other tests required to make the diagnosis of MOH.
Diagnosis of medication-overuse headache (MOH) according to ICHD-3, must meet criteria A-C for the diagnosis of MOH:
Medication overuse headache by drug class and duration of headache:
Prevention: MOH is felt to be a preventable disease; therefore, the emphasis should is on educating patients on the importance of appropriate medication administration and the risks not only of its side effects but also the potential development of chronic headache with excessive medication use is essential. The thinking is that only 8% of patients demonstrate knowledge that overuse of all types of headache medication, including those readily available over the counter, could lead to the development of MOH.
MOH requires a multi-step treatment approach but typically entails (1) withdrawal of the overused medication, (2) treatment of withdrawal symptoms or rescue therapy, and (3) initiation of preventative therapy if desired and (4) finally alternative symptomatic medication for future headaches. There currently is not enough high powered evidence from randomized trials to indicate which is the best or most effective method of treatment for MOH to date.
Drug Withdrawal Phase: The clinician must first determine if the patient can be managed safely as an outpatient or if they require inpatient hospitalization for close monitoring during the drug withdrawal phase. Several studies have demonstrated that advice alone might be appropriate for those patients who do not have major psychiatric comorbidities and overuse triptans or simple analgesics. Fortunately, this can be managed by the patient’s primary care provider in most cases. The Brief Intervention for Medication-Overuse Headache (BIMOH) study found that brief intervention by patient’s own physician on the education of medication overuse had lasting and impactful results with 50% of headaches resolved within 3 months and 63% in 6 months.
A classification system for MOH was created by Saper and Lake to help stratify these patients. MOH Type I are those patients who do not have behavioral conditions and do not overuse opioids or barbiturates. These patients are more simple and are manageable in the outpatient setting with a clear rescue medication program. MOH Type 2 patients may need inpatient therapy. They are more complex and suffer from behavioral conditions and because they chronically use opioids and barbiturates are more likely to have withdrawal symptoms, emotional and sleep problems and experience more pain during the withdrawal phase. The 2011 European Federation of Neurological Societies (EFNS) state that withdrawal therapy is the best treatment for MOH. The rate of removal of the drug, whether it is rapid or tapered, has not been studied to determine the most effective method, but the consensus is that a rapid withdrawal leads to a more rapid resolution. Drugs that are known to have potentially significant and life-threatening withdrawal symptoms, such as barbiturates, opioids or benzodiazepines, should have a tapered withdrawal. Typical withdrawal symptoms are worsening headache, restlessness, anxiety, insomnia, nervousness, nausea, vomiting, tachycardia or hypotension. Some symptoms may last up to 4 weeks but typically last 2 to 10 days. These patients do not necessarily require management by a neurologist during the withdrawal phase as a study from 2009 demonstrated similar outcomes with primary care provider management.
Withdrawal Treatment or Rescue Medication Phase: To help minimize a patient's withdrawal symptoms and maximize comfort during this phase several medication therapies have demonstrated usefulness. Keep in mind that the offending drug should not be an option. Several NSAIDs have been trialed and demonstrated effective such as naproxen, indomethacin, and ketorolac. Tizanidine is beneficial as an adjunct to NSAID therapy. Steroid therapy, in several currents studies, has demonstrated minimal to no effect on MOH withdrawal symptoms including fewer headache hours. Several antiemetics and neuroleptics have proven useful during this phase including prochlorperazine, diphenhydramine, promethazine, metoclopramide, and chlorpromazine. Infusions with dihydroergotamine (DHE) may be necessary in more complex cases.
The "Raskin protocol" is one such regimen that compared intravenous DHE and metoclopramide every 8 hours versus diazepam in patients with MOH and it demonstrated that DHE was beneficial (89% headache free in 48 hours and 71% at 16 months) during the detoxification phase of MOH, however it should not be utilized in patients with vascular disease. Lidocaine infusions may be helpful in those with vascular disease.. A retrospective study by Williams demonstrated 90% of MOH patients with a history of analgesic abuse including opioids had headache improvement, 97% withdrew the overused drug, and 70% had sustained benefits at 6 months. Valproate showed improvement in 80% of patients with MOH in a small study with good patient tolerance. Intravenous hydration, antiemetics, NSAIDs, and magnesium are also helpful during the withdrawal phase. During detoxification, those Type 2 MOH more complex patients that have overused narcotics, barbiturates, and tranquilizers may require long-acting opioids, phenobarbital, and clonidine while in transition.
Prophylaxis Therapy Phase: Consensus agrees that the most appropriate and effective choice for treatment of MOH is the acute withdrawal of painkilling drugs, but debate exists as to when and whether preventative medications should be utilized. A guideline from the European Federation of Neurological Sciences recommends the abrupt discontinuation of the overused medication and if started prophylactic therapy initiation just before or at the time of drug discontinuation with close regular follow-up. If used, preventive therapies are started at low doses when MOH treatment begins, then titrated up with time with the choice of treatment depends upon previous drugs used, patient preferences, the type of primary headache disorder, comorbidities and the side effect profile. To date, therapy with beta-blockers, calcium channel blockers, tricyclic antidepressants, and anticonvulsants have all been utilized. In studies, topiramate in studies was beneficial in patients with MOH but is more effective in patients with chronic migraine. In the PREEMPT trials for chronic migraine, onabotulinumtoxinA was studied. A number of the patients in the trial had MOH, and subgroup analysis performed on those patients reported benefit in reducing headache days, frequency and severity but this study did not include patients who overused opioids. The COMOESTAS project demonstrated that the combination of detoxification and prophylaxis of MOH patients decreased disability, depression, and anxiety. This group developed an evidence-based treatment protocol and at the end of their trial, 66% of MOH patients no longer overused medications and 47% reverted back to episodic headaches. Not surprisingly when comparing inpatient versus outpatient programs, the dropout rate was higher in the outpatient setting.
The Consensus protocol for the treatment of MOH from Tassorelli et al. is as follows:
Use a headache diary
Prevention of relapse in MOH is not well studied, but withdrawal strategies and preventative therapies do not appear to affect prognosis or relapse rates. According to a recent review of the treatment of MOH by Chiang et al. in 2016, the authors felt that considering the current evidence on the treatment of MOH and taking into account the systemic toxicity of overusing headache medications, that discontinuation of the medication was the recommendation, with the addition of preventative medication. This approach led to a better outcome than discontinuation alone, but more studies are necessary to choose the best treatment strategy.
The differential diagnosis of MOH would include any form of chronic daily headache whether it is a primary or secondary headache diagnosis including migraine, tension-type, and cluster. Always ask patients about a history of head trauma, and if a patient’s history or physical examination causes concern, then appropriate diagnostic testing should be performed to rule out the possibility of a severe medical or neurologic condition. Some differentials that should be under consideration are venous sinus thrombosis, subdural hematoma, carbon monoxide poisoning, brain tumors, hydrocephalus, and idiopathic intracranial hypertension.
Overuse of acute therapy can lead to a poor prognosis of chronic headache and lower quality of life by itself. The key to MOH treatment is patient motivation. Outcomes for MOH patients withdrawing from acute drug overuse have had reports in multiple studies with a generally accepted success rate of greater than 50% reduction from baseline headache frequency. Rates of successful withdrawal have been reported in around 50 to 70% of MOH patients after 1 year. A good predictor for long-term success is retaining withdrawal after 1 year. Relapse rates after 6 years range between 40 to 50%. A successful withdrawal phase leads to a better response for prophylactic treatment even in those patients with little to no improvement in headache frequency. Several predictors for relapse have been documented such as tension-type headache, longer duration of regular intake, a high number of acute treatments, no improvement after 2 months of withdrawal, smoking, and alcohol use and return to overused drugs Triptan overuse has a lower relapse rate while combined drug therapy has a higher relapse rate. Finally, codeine-containing drugs and patient-reported poor sleep quality, and high body pain are probable predictors for poor 1-year outcomes. Adding behavioral therapy to the treatment algorithm can greatly reduce the relapse rates for MOH. In this particular study, 42% of patients had a relapse of headache at 3 years, but only 12.5% reverted when coupled with behavioral therapy.
Side effects from the medication including dependence and toxicity as well.
Neurology and or psychiatry consultations can be sought when necessary.
Patients with MOH will fair better if their comorbidities such as mood disorders, obesity, smoking or inactivity are also addressed and continual support is offered in the form of education, patient monitoring, and behavioral therapies. MOH awareness in the general public should be a goal as a study from 2014 demonstrated that 77% of undergraduate students were not aware of the existence of MOH, and after learning about MOH, 83% of the students felt there should be warnings about MOH on medication bottles and 80% after learning about MOH would reduce analgesic consumption.
MOH is a common and worldwide problem with a prevalence of 1% in the general population but accounts for approximately 11 to 70% in those with chronic daily headaches, often under-recognized and unfortunately correlate with a significant negative impact on the patient's quality of life. That opiates and combination analgesics carry an increased risk for MOH needs to be recognized. Among the multiple risk factors for the development of MOH, some are modifiable and require attention and action. Anxiety and depression are common comorbidities, and up to 50% of patients show dependence-type behaviors like tolerance or inability to control pain medication utilization.
Treatment trials are still needed to determine the best evidence-based approach for helping these patients break their vicious headache cycle, but intervention will require patient counseling, detoxification, and prevention therapy. The future needs to include a focus on increased awareness of MOH for the general population and primary prevention strategies for patients and providers. To achieve success in treatment, it is essential that the primary care provider, nurse practitioner, pharmacist, and internist openly communicate with the neurologist when MOH is suspected.
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