Article Topic: Medication Overuse Headache (MOH)
Author: Nurhan Al-Hroub
Editors: Ainaa A.Alzamari, Hamid Ghanem
Reviewer: Ethar Hazaimeh

 

Keywords: headache, drugs, chronic headache syndrome, secondary headache, medication overuse.

Abstract

Introduction: Medication overuse headache (MOH) is a headache caused by abuse of acute headache medications for more than 15 days per month in patients who have preexisting primary headaches. There are no significant laboratory tests, images, or specific features to diagnose it. So, it will be preventable by education and awareness.

Methods: A systematic review search was done which studied primarily medication overuse headache (MOH) through the research database.

Conclusion: MOH is a result of excessive use of acute headache treatments with a history of primary headache. Numerous people increase their analgesic consumption without being aware of the long-term consequences. Education is therefore the most essential technique to avoid MOH.

Overview

The International Headache Society defines MOH as a headache that occurs for at least 15 days each month for more than three months in a patient with a pre-existing primary headache disorder and develops as a result of repeated overuse of symptomatic headache medications or when the symptoms are not better described by other diagnoses [1]. MOH is treated and preventive; hence, it merits more attention [2]. 

Pathogenesis

MOH is classified as a chronic headache or secondary headache in (ICHD-3) [3]. The most important risk factor for the development of MOH is chronic medication usage, with varying risk profiles for different classes of analgesics [4]. The lowest-risk analgesics include combination analgesics comprising opiates or barbiturates, triptans/ergotamine, and single analgesic drugs (NSAIDs, acetaminophen) [4]. However, it has been discovered that using combination analgesics, especially those that contain opioids and/or barbiturates, results in markedly increased relative risk for developing MOH [4].

Although the pathophysiology of MOH is still poorly understood [5], it has been discovered that MOH is intimately linked to alterations in various brain networks and areas [6]. Thus, it is associated with abnormal gray matter in a number of areas, including subcortical nuclei, the brain stem, and the cerebellum [6]. Therefore, MOH reversibly affects the reward system, the prefrontal cortex, and the pain network, as shown in Figure (1) [6].

MOH also demonstrates the interaction between brain networks involved in the response to socioeconomic stressors and specific psychosocial disorders[7]. This may be due to neuronal hyper-excitability in the trigeminal nervous system and the cerebral cortex [8]. The trigeminal nerve system’s hyper-excitability promotes central and peripheral sensitization, which is key in the development of chronic pain. While cortical neuron hyper-excitability resulted from increased inhibition across the neuronal cell, this is comparable to the aura of a migraine [7]. 

 So, chronic acute care medication use compromises the function of diffuse noxious inhibitory control and the central 5-HT-dependent modulating system [9], leading to an increase in neuronal excitability in brain areas, which facilitates the development of cortical spreading depression more easily [9]. Increased activity of trigeminal neurons promotes the process of nociception, causing hyperalgesia and allodynia [9]. Derangement of the 5-HT-dependent modulating system additionally upregulates the calcitonin gene-related peptide (CGRP) system, resulting in trigeminal nociceptive facilitation, as Figure (2) illustrates [9].

The clinical success of anti-CGRP in the treatment of MOH raises the possibility that acute migraine treatments may promote MOH in susceptible individuals, Figure (3). [10].

It has recently been approved that acute-care migraine therapies may also shed some light on MOH and its treatment, as the discovery of the small molecule CGRP receptor antagonists, the ‘Gepants’, for both acute and preventive migraine therapy is particularly patient. It seems unlikely that the Gepants will be connected with MOH given their preventive effect when used frequently [9]. Preclinical data indicate that Ubrogepant is not likely to cause early or latent trigeminal sensory sensitization when used repeatedly [11]. A migraine prevention strategy is being developed for Rimegepant, which the FDA approved in February 2020 for the acute treatment of migraines [9]. Preclinical animal models indicate that the recently FDA-approved Ditan, lasmiditan, a selective 5-HT1F receptor agonist with a mechanism of action more similar to triptans than CGRP inhibition, has the ability to produce MOH through persistent latent peripheral and central sensitization processes [12]. We excitedly anticipate new clinical trials examining these drugs in relation to MOH or its progression [9].

Genetic variation has been implicated in playing a role in the pathogenesis of such susceptibility [13]. According to one study, the clinical signs of MOH are related to Val66Met gene polymorphism, which is a brain-derived neurotrophic factor [14]. Another study found that additional polymorphisms, including the dopamine D2 receptor (DRD2) C939T (rs6275) and the methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), have an effect on the onset of MOH in patients with migraine [15].

There are many similarities between MOH and drug addiction [16]. New research in neuroimaging shows that changes in the orbitofrontal cortex and the mesocorticolimbic dopamine circuit are associated with the pathophysiological mechanisms of MOH and substance-related disorders [17]. As a result, it has been hypothesized that MOH represents a kind of dependency behavior [18]. Codeine, opioids, and caffeine are psychotropic drugs, that are widely available as over-the-counter medications in several countries, so abuse and dependence may occur if they are used with some headache medications, which may accentuate the presence of MOH [19,20].

Accordingly, histone deacetylase 3 (HDAC3) seems to be involved in the memory processes that lead to the disappearance of drug-seeking behavior in animal models. Sodium valproate, a medication that has been demonstrated to work in MOH, inhibits HDAC3 [21].

Contrary to drug abusers, MOH patients were more concerned about the drug’s effects than its type [22]. Even after a successful medication withdrawal and an improvement in the headache situation, a high rate of drug usage has been identified as a “drive” for medication [23]. 

Given what is known at this time, it is impossible to tell whether the dependency-like behavior seen in MOH patients constitutes a true dependence or if it is only a “pseudoaddiction” brought on by recurrent headaches [24]. However, further research will be required in the future.

Risk Factors

The actual prevalence of MOH is unknown, however, estimates for the general population range from 0.5 to 2.6% [25], and for those who experience persistent daily headaches, up to 11-70% [26].

The primary cause of MOH is migraine, followed by tension-type headaches, and rarely cluster headaches. The effects will worsen for those who abuse medication while suffering from headaches [27, 28].

MOH most frequently affects those aged thirty to fifty years, with a peak incidence in the fourth decade [25, 29]. This disorder has a high prevalence among females, as it affects them three to four times more than males [29]. Also, MOH patients have a high prevalence of smoking, sleeping problems, and an elevated BMI [37].

Although the name of MOH seems to reflect the role of overuse in developing it, on the other hand, it is challenging to confirm it because not everyone who suffers from daily headaches and takes painkillers frequently develops this type of chronic headache [30]. 

Any analgesic has the potential to cause MOH from medication overuse, but opioids and triptans seem to have the greatest risk of developing it in a very short period of time [31]. Other medications that can cause MOH are NSAIDs, acetaminophen-aspirin-caffeine combinations, butalbital-containing combination analgesics, and calcitonin gene-related peptide antagonists [32, 25].

Many socioeconomic and psychosocial factors have an effect on MOH [29]. There is a relationship between MOH, mood, and subclinical obsessive-compulsive disorders [34]. Moreover, people who have psychiatric comorbidities, such as depression and anxiety, appear most susceptible to developing this headache [33]. In addition, more than half of patients with MOH exhibit dependence-type behaviors, such as tolerance [26]. Also, patients who have low education, low income, and low socioeconomic status develop MOH more than other people, although it is not obvious if this contributes to or worsens the headache [38].

Family history suggests a possible underlying genetic predisposition and hereditary susceptibility to develop this disorder [35]. This theory is supported by the fact that people with primary headaches are more likely to develop MOH than people who take medications for other conditions [36]. 

Other risk factors include chronic gastrointestinal or musculoskeletal disorders, tranquilizer use, high caffeine intake, and physical inactivity [39].

Clinical picture

An episodic headache disease that has been treated with frequent use of acute medicines, frequently in excess doses, is typically present before the onset of medication-overuse headache. Medication-overuse headache commonly appears as a morning headache when you first wake up, and symptomatic headache treatments typically only offer temporary relief [40]. 

The patient will notice a change in his typical headache, including an increase in intensity and frequency, greater sensitivity to triggers of these episodes, and resistance to conventional treatment [41].

Table (1) summarizes the main clinical characteristics of MOH [41].

Diagnosis

The diagnosis is not based on particular physical examination findings or certain laboratory tests [42]. The criteria for diagnosis according to (ICHD-3) are an alteration in the baseline headache in people with a pre-existing headache disorder who routinely take acute symptomatic drugs for more than ten to fifteen days per month for longer than three months [43], as shown in Figure (4) [44]. As mentioned before, opioids, triptans, and ergotamines have the greatest and fastest effect on developing MOH, as they can develop it by taking them for more than 10 days per month, unlike other medications, which may develop it after taking them for more than 15 days per month [42].

The patient is most likely to have a primary headache and present with a change in his underlying headache after abusing the offending medications, as mentioned earlier [42]. 

Before the diagnosis, it is important to exclude other causes of chronic daily headaches, such as; hypertension, obstructive sleep apnea, pituitary disease, depression vasculitis, medications, increased intracranial hypertension, or malignancy. So, further investigations are required to exclude other causes [45].

Treatment

It is challenging to treat medication overuse headaches and requires individualized care [42]. Prevention, patient counseling, and detoxification are the backbone of treatment. Patients who are suspected of abusing medications, such as those with a history of substance abuse, as well as psychiatric patients who overlap with MOH, may need to be referred to a specialized headache center as part of treatment [46].

Educate patients

MOH management is a long-term process that may take weeks or months [47]. So, it is important to manage expectations and adequately prepare the patient before attempting drug withdrawal or adding a migraine preventative [42]. 

The patient should understand that the frequent use of analgesics can cause MOH, and the headache is likely to improve when the overused medication is removed [47]. Furthermore, using migraine preventatives and treating psychiatric comorbidities may reduce MOH. In addition, re-exposure to medication overuse will result in MOH recurrence [47]. 

Withdrawal from the drug

Patients are instructed to withdraw their analgesics to an acceptable level [48]. The speed of drug withdrawal is determined by the class of drug being overused [48]; this takes no more than fifteen days for simple analgesics and, no more than ten days for opioid/triptans. 

Abrupt withdrawal is preferable for triptans and analgesics, which can induce some unfavorable symptoms, such as nausea, vomiting, sleep disturbance, and anxiety [42]. Patients who overuse triptans typically improve over seven–ten days, whereas those overusing simple analgesics improve over two–three weeks [49]. As a result, simple analgesic and triptan overuse can often be treated as an outpatient [42]. 

Opioid medication overuse, on the other hand, is more disturbing and may require inpatient supervision. Withdrawal tends to be more gradual and takes longer time [42]. Individuals with substantial opiate overuse may benefit from inpatient detoxification and intravenous lidocaine infusions [50].

Prevention of migraine

Adding migraine preventatives to the management of MOH; once established, may make it easier to withdraw from the acute headache medications in the future [42]. Topiramate and botulinum toxin appear to be beneficial in some patients to treat MOH [51].  

Moreover, particular transitional approaches can be employed to assist in discontinuing the overused medicine and reducing MOH [25]. One of them is to replace the overused drug with an alternative symptomatic therapy for less than or equal to two days per week with preventive therapy [52]. This approach may be beneficial for patients who are more likely to experience drug toxicity from overuse than withdrawal symptoms [52]. 

Continuing overused medication during initial treatment is beneficial for patients who are hesitant to discontinue the medication but are not at risk of toxicity [25]. 

Transitional therapy (bridge therapy) is advised for individuals with severe or regular headaches who are more prone to have headaches while quitting the overused medication with the commencement of symptomatic and preventative therapy [25]. Many NSAIDs, including naproxen, indomethacin, and ketorolac, have been studied and proven to be beneficial [25]. Tizanidine is sometimes utilized as a supplement to NSAID therapy [53]. Several antiemetics and neuroleptics, such as prochlorperazine, diphenhydramine, promethazine, metoclopramide, and chlorpromazine have been beneficial during this phase [41]. 

Consequently, multiple general aspects should be considered in the treatment of MOH. The correct diagnosis, stopping the offending drug(s), preventive treatment, using medications during the withdrawal period, aside with education to the patient, the partner, and the family, psychological treatment, and physician support for the patient all play an important role in the management [41]. 

Follow-up and relapse rate

The majority of follow-up studies are conducted in tertiary care centers [29]. However, few studies support that follow-up can be done by the general practitioner [54].

According to studies, the relapse rate is 20%-40% within the first year of withdrawal [29], with some claiming that the majority of patients relapse within the first six months and others between six and twelve months [55]. However, the results on relapse should be evaluated with some care given that the studies varied in their use of headache classification systems, withdrawal, and prophylaxis, as well as follow-up periods and the criteria employed to determine improvement [29].

Prevention

Education is the most crucial factor in preventing MOH [42]. It is important to counsel patients who experience episodic attacks of primary headaches to stay away from some medications, especially simple over-the-counter painkillers [42].

Prognosis

A poor prognosis for persistent headaches and a worse quality of life can result from using acute treatment excessively [56]. 

Numerous studies show that MOH patients who stop using acute drug overdose successfully recover, with a success rate of more than 50% compared to baseline headache frequency [25]. Relapse rates after six years vary from 40 to 50% [57]. Even in patients with little to no improvement in headache frequency, a successful withdrawal phase improves response to prophylactic treatment [58]. 

Patient motivation is essential in MOH treatment [41]. Although the quality of the treatment has a significant impact on the outcome, patient motivation has a greater impact [41]. Even the most successful treatment programs will fail if patient motivation and discipline are absent [41].

Conclusion

MOH is a secondary headache disorder that is caused by the overuse of acute headache medications by a person with an underlying headache disorder. The underlying mechanisms of the MOH are poorly understood, but they are thought to be closely related to chronic migraine. 

A standard neurological examination and the patient’s medical history help to determine the diagnosis. Treating this disorder is complex and must be individualized to the person, and the single most important strategy to prevent medication-overuse headaches is education.

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