Continuing Education Activity

Medication-overuse headaches (MOH), also known as analgesic rebound headaches, drug-induced headaches, or medication-misuse headaches, are a common neurologic disorder that results in enormous disability and suffering and plays a significant role in the transformation from episodic to chronic headache disorders. These headaches typically develop in patients with established primary headache disorders like migraine or tension-type headaches who overuse medication in an attempt to alleviate the symptoms of their primary headache. An unfortunate cycle of medication overuse results in increased headache frequency, whereby the medication indicated for the treatment of the primary headache becomes the cause of headaches. Patients prone to headaches who take analgesics for other conditions can also develop MOH. This activity reviews the presentation, evaluation, and management of medication-overuse headaches and highlights the role of an interprofessional team approach to the care of affected patients.

Objectives:

• Identify the medications typically associated with medication-overuse headaches.
• Describe the exam findings typically seen in patients with medication-overuse headaches.
• Explain the management considerations for medication-overuse headaches.
• Discuss the modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by medication-overuse headaches.

Introduction

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 medication-misuse headache. Patients with established primary headache disorders like migraine or tension-type headaches overuse medication for their acute headaches and inadvertently increase the frequency and intensity of their headaches. 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.[1][2]

Recognition of MOH was as early as in the 1930s when physicians observed prolongation of headaches associated with ergotamine-overuse.[3] 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 evolutive migraine.[4] 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.”[5] MOH was first introduced in the second edition of ICHD (2004) with multiple subtypes dependent on offending medicine, such as ergotamines, triptans, opioids, etc.[6]

Etiology

Medication overuse headache is classified 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.[7] 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 and (2) regular medication overuse for greater than three 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 the headache pattern returns to the 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 class 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 barbiturates, have a two-fold increase in relative risk for MOH. 

Some studies suggest that NSAIDs may have a protective effect from MOH in patients with ten headache days or less per month.[8]

Epidemiology

Medication overuse headache has a true prevalence that is unknown, partly resulting from various changes in diagnostic criteria, but estimates are in the range of 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.[9] 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 aged 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 the 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.[10]

Main Risk Factors for MOH with Odds Ratio (OR):[11][12][13]

• Demographic
  • Age (less than 50 years)--1.8
  • Female--1.9
  • Low educational level--1.9
• Self-reported complaints
  • Chronic musculoskeletal complaints--1.9
  • Gastrointestinal complaints--1.6
  • Anxiety or depression--4.7
• Lifestyle
  • Smoking--1.8
  • Physical inactivity--2.7
  • Metabolic syndrome--5.3
  • High daily caffeine intake (greater than 540mg versus less than 240mg)--1.4
• Medication
  • Tranquilizers--5.2
  • Aspirin--0.5
  • Ibuprofen--0.7
  • Opioids--2.3

Of those patients with MOH, dependency-like behavior presented more often in those who overuse opioids and triptans than aspirin or ibuprofen. MOH can be associated with the substance-related disorder spectrum as it is believed they share common neurobiological pathways.[14] 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.[15] 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 attacks are more prone to MOH. Another study found a threefold risk of MOH if there is a family history of MOH or substance abuse (drug or alcohol).[16] Several trials have demonstrated that frequent and often multiple psychiatric mood disorders such as anxiety and depression exist in patients with MOH.[17] Some trials interestingly found that 40% of MOH patients actually met the criteria for depression and upwards of 58% for anxiety.[18] 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 to drug dependency and obsessive-compulsive disorder (OCD).[16]

In general, the following medicines can cause medication overuse headache, listed in highest to lowest incidence:

• Opioids, butalbital-containing combination analgesics, and acetaminophen-aspirin-caffeine combinations[19]
• Triptans
• NSAIDs
• Calcitonin gene-related peptide antagonists

Pathophysiology

The pathophysiology of MOH is not well understood, but studies have demonstrated that central sensitization likely plays a major role.[20] Since patients with migraines 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, and orbitofrontal cortex (OFC), and the mesocorticolimbic reward system.[21][22] Also found were changes in the serotonergic neuromodulatory system, upregulation of vasoactive and pro-inflammatory mediators, increased susceptibility to cortical spreading depression, central sensitization, and an increase in nociceptive sensory fields.[23] Some studies have theorized a potential genetic risk as to the etiology of the development of MOH. One such model is the renin-angiotensin system, known to have an active role in regulating neural plasticity.[24]

The thinking is that the insertion/deletion polymorphism in the gene that encodes an 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 a brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT), and serotonin transporter (SERT).[25][26][27] 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 serotoninergic and endocannabinoid systems.[28] 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 a lack of habituation after further stimulation.[29] 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 seems 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.

History and Physical

As always, detailed history with particular emphasis on evaluating headaches 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 three 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 headaches (27%), and mixed/other headaches (8%).[30] 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.[30] Patients often report morning headaches and neck pain resulting from overnight drug withdrawal or poor sleep quality.[31]

The central sensitization caused 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.

Evaluation

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 diagnose MOH.

Diagnosis of Medication-overuse Headache (MOH) According to ICHD-3 Must Meet Criteria A-C for the Diagnosis of MOH

• Headache on 15 or more days per month AND a pre-existing headache disorder
• Overuse of acute and/or symptomatic headache drugs for over three months (Regular intake of drugs on greater than or equal to 10 days/month for ergotamines, triptans, opioids, and combination analgesics and on greater than or equal to 15 days per month for acetaminophen, ASA and NSAIDs)
• No better explanation by another ICHD-3 diagnosis  

Medication Overuse Headache by Drug Class and Duration of Headache[32]

• Ergotamine-->10 days/month for over 3 months
• Triptan-->10 days/month for over 3 months
• ASA-->15 days/month for over 3 months
• NSAIDs-->15 days/month for >3 months
• Acetaminophen/paracetamol-->15 days/month for over 3 months
• Opioids-->10 days/month for over 3 months
• Combination analgesics-->10 days/month for over 3 months
• Multiple drug classes-->10 days/month for over 3 months

Treatment / Management

The management approach includes patient education, effective prophylaxis, discontinuation of the overused analgesic, and follow-up to prevent a recurrence.

Prevention

MOH is felt to be a preventable disease; therefore, the emphasis should be 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 headaches with excessive medication use is essential.[33] Several small studies have emphasized the need for MOH patient education to reduce the incidents of MOH.[34] About 75% of all the patients discontinued overused medication in one such study.[35] 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.

Specific transitional strategies can be used to help discontinue the overused medication and hence reduce MOH.

Replacing the overused medication with an alternative symptomatic therapy: The overused magic medication is stopped,  preventive therapy is started or optimized, and alternative symptomatic medication is used for less than or equal to 2 days a week. This is particularly helpful for patients who have a higher risk of drug toxicity from overused medication than experiencing withdrawal symptoms. This approach is supported by evidence from open-labeled clinical trials.[36] 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.[37] To date, therapy with beta-blockers, calcium channel blockers, tricyclic antidepressants, and anticonvulsants have all been utilized.[38] In studies, topiramate in studies was beneficial in patients with MOH but is more effective in patients with chronic migraine.[39][40] In the PREEMPT trials for chronic migraines, 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.[41][42][43] The COMOESTAS project demonstrated that the combination of detoxification and prophylaxis of MOH patients decreased disability, depression, and anxiety.[18] 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.[44] Not surprisingly when comparing inpatient versus outpatient programs, the dropout rate was higher in the outpatient setting.

Continuing overused medication during initial treatment: This approach is particularly beneficial for patients who are reluctant to stop the medication and are not at risk of toxicity.

Using bridge therapy (temporary medication): A transitional therapy is advised for the patients with severe or frequent headaches and who are more likely to experience headaches while discontinuing the overused medication with start of symptomatic and preventive therapy.

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.[45][38] Tizanidine is beneficial as an adjunct to NSAID therapy.[46] Steroid therapy, in several currents studies, has demonstrated minimal to no effect on MOH withdrawal symptoms including fewer headache hours.[47][48][49] Several antiemetics and neuroleptics have proven useful during this phase including prochlorperazine, diphenhydramine, promethazine, metoclopramide, and chlorpromazine.[38] 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.[31] Lidocaine infusions may be helpful in those with vascular disease.[50] 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.[51] Intravenous hydration, antiemetics, NSAIDs, and magnesium are also helpful during the withdrawal phase.[52]

Discontinuing the overused medication before starting prophylactic therapy:  And alternative strategy includes stopping the overused medication for two months prior to the start of preventive medication.  However, patients may not tolerate this approach. Therefore,  this route is usually not advised.

Treatment approach based on discontinuation of the specific offending drug:

1. Discontinuation of the drugs other than opioids, barbiturates, or benzodiazepines:
   1. Start or optimize preventive therapy
   2. Switch from overused medication to an alternative medication from a different class. The use of acute medication should be limited don’t know more than two days per week.OR Slowly taper the acute medication as the frequency of headaches decreases in response to preventive therapy. However, for patients who still experience headaches, bridge therapy with a long acting NSAID or steroid should be added.
2. Discontinuation of opioids, barbiturates, or benzodiazepines: Drugs are gradually tapered (in 2-4 weeks) if used at higher dosages. However, they may be withdrawn abruptly if lesser dosages are taken.
   1. Treatment with once a week transdermal clonidine patch (0.1 to 0.2 mg/24 hours) may be advised for one to two weeks to manage opioid withdrawal symptoms.
   2. Phenobarbital is particularly recommended for patients discontinuing butalbital. A 30 mg of phenobarbital is equivalent to 100 mg of butalbital. Therefore, it corresponds with maximum dose of 90 mg of phenobarbitol with 300 mg of butabital.

Differential Diagnosis

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 headache, cluster headache, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), hypnic headache, nummular headache, and chronic paroxysmal hemicrania. 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.

Prognosis

Overuse of acute therapy can lead to a poor prognosis of chronic headache and lower quality of life by itself.[53] The key to MOH treatment is patient motivation.[38] 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.[54] A good predictor of long-term success is retaining withdrawal after 1 year.[55][56] Relapse rates after 6 years range between 40 to 50%.[57] A successful withdrawal phase leads to a better response for prophylactic treatment even in those patients with little to no improvement in headache frequency.[58] 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.[59][60][61] Triptan overuse has a lower relapse rate while combined drug therapy has a higher relapse rate.[62] Finally, codeine-containing drugs and patient-reported poor sleep quality, and high body pain are probable predictors for poor 1-year outcomes.[63] 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.[64]

Complications

Side effects from the medication, including dependence and toxicity. Use of NSAIDs can cause upper gastrointestinal bleeding.

Consultations

Patients are initially managed by internists and general physicians. Neurology and or psychiatry consultations can be sought when necessary.

Deterrence and Patient Education

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.[65]

Enhancing Healthcare Team Outcomes

MOH is a common and worldwide problem with a prevalence of 1% in the general population but accounts for approximately 11 to 70% of 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 treatment success, it is essential that the primary care provider, nurse practitioner, pharmacist, and internist openly communicate with the neurologist when MOH is suspected.