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Medication Overuse Headache
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315981
Keywords: Analgesic overuse, chronic headache, drug withdrawal, education, opioids, medication overuse, secondary headache, triptans
Headache disorders are common worldwide including in India and associated with significant morbidity.[1],[2] They are classified as primary (headache itself is the disease) and secondary (where the headache is due to other conditions manifesting with a headache with or without associated symptoms) disorders. Although commonly episodic, some conditions may be associated with a headache of more than 15 days per month for more than three months, when they are called as chronic headache disorders.[3] The International Classification of Headache Disorders-3 (ICHD-3) classifies medication overuse headache (MOH) as a secondary headache disorder. In MOH headache occurs due to the consumption of a drug used for the symptomatic relief of the headache episodes, in a patient with a primary headache disorder. Migraine and tension-type headache (TTH) are the common primary headache disorders prevalent all over the world, and some patients consuming acute pain-relieving medicines develop paradoxical increase in the headache.[4] Rarely MOH can develop in a patient with cluster headache also.[5] The type of drug overused depends on the availability of over the counter medications, affordability, prescription pattern, and cultural beliefs of the patient and it varies from region to region. The usual agents are analgesics, ergots, triptans, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids.[4] The worsening or development of the headache in a patient who uses these agents to reduce the pain itself is interesting and various risk factors and pathogenetic mechanisms have been put forward. The treatment comprises of explaining to the patients about the condition, removing the offending agent, and preventing the recurrence. There are many reviews on MOH in the literature.[6],[7],[8],[9],[10],[11],[12] In this article we present an update of this disorder with an emphasis on pathophysiology, treatment, and controversies. We performed the, literature search in the PubMed/MEDLINE and Cochrane database from the years 2000 to October 2020. Relevant full-text articles were downloaded and were reviewed. The search terms used were chronic headache, medication overuse headache, withdrawal headache, and each term was also searched using words: history, epidemiology, diagnosis, treatment, and prognosis.
The MOH is defined when a headache occurs on 15 or more days/month in a patient with a pre-existing primary headache disorder and developing as a consequence of regular overuse of acute or symptomatic headache medication (on 10–15 or more days/month, depending on the class of medication) for more than three months. It usually, but not invariably, resolves after the overuse is stopped. It may manifest as a new type of headache or as a worsening of preexisting headache. In a patient with a preexisting headache when MOH develops patient receives a diagnosis of both conditions.[3] The duration of exposure required for diagnosis depends on the medication use per month. It may be ten days (ergotamine, opioids, combination analgesics, multiple drugs) to 15 days (triptans and non-opioid analgesics).[3] Medication overuse headache develops due to interaction between a susceptible patient with primary headache disorder and the medication administered. The usual primary headache disorders associated are migraine, TTH, or both. The various subtypes of MOH are given in [Table 1]
Diagnostic Criteria ICHD3 (international classification of headache disorders 8.2)[3]
Peters and Horton described 52 patients who developed headaches after intake of ergotamine which subsided after withdrawal and also published the withdrawal regimen.[13] Similar observations were made after the introduction of triptans in early 1990. The International Headache Society (IHS) in ICHD-1 classification for the first time, introduced the term “Drug-induced Headache” in 1998.[14] During 2004 in ICHD-2 classification, it was changed to “Medication overuse Headache” to stress the importance of regular and prolonged use of specific medications resulting in headache and to separate it from headaches caused by other headache-causing medications as adverse effects.[15] But the criteria required that MOH can only be diagnosed once the headache disappears after the offending agent is removed; otherwise it was defined as probable MOH. This led to difficulty in clinical practice, and in 2006 the requirement of improvement in headache was done away with and the same criterion has been followed in the recent ICHD-3 criteria.[3] The worldwide prevalence of MOH is 1–2% in the general population with a range of 0.5 to 7.2%. It affects around 63 million people around the world. About 50% of patients with chronic headaches have associated MOH. The male-to-female ratio in MOH is 1:3–4. The prevalence is maximum in the middle ages especially in the fourth and fifth decades of life.[16],[17] In specialized headache clinics the prevalence ranges from 30% to 50%. The common medications implicated in MOH are paracetamol, NSAIDs, ergots, triptans, and opioids. The pattern of used drugs differs based on local availability and varies with the region and country. The pattern of drug usage may even change over time and more than one drug may be involved. Over-the-counter (OTC) drugs are the most common in primary care, while more potent centrally acting drugs like opioids are common in secondary and tertiary care settings.[17],[18] OTC remedies containing brain stimulatory essential oils from camphor and eucalyptus, may be an unrecognized cause of medication overuse headache.[19] The burden of the MOH is due to its physical and psychological disability. In the global burden disease, 2016 study migraine became the second leading cause of disability worldwide because MOH was considered a sequela of highly prevalent migraine and TTH.[1]
It is very intriguing to know that the agent used for the headache relief itself can be the reason behind the development of MOH. It develops as a result of interaction between a susceptible individual and a therapeutic agent. There is a vicious cycle between the occurrence of headaches and the intake of acute medications with the interplay of various mechanisms [Figure 1]. The medications for acute pain relief are taken more and more without adequate symptomatic relief. The exact mechanism behind the occurrence of MOH in patients with primary headache disorders is not known. MOH does not occur in patients taking analgesics with cancer pain or arthritic pain. The presence of a primary headache disorder is a pre-requisite for the development of MOH. As MOH can occur with different classes of acute medications, there may be an unrecognized final common pathway leading to the origin of MOH. Improvement of headache in about 60-75% of patients after removal of the agent, suggests a cause and effect association. The various risk factors associated with the development of MOH are female sex, regular use of tranquilizer, chronic musculoskeletal complaints, hospital anxiety depression scale score of 10 or more, physical inactivity, lower socioeconomic status, lower education level, higher prevalence of smoking, sleep disorders, a family history of MOH or substance abuse and higher body mass index.[18],[20],[21],[22],[23] Genetic factors in the form of candidate polymorphic variants in the dopaminergic, angiotensin-converting enzyme, Brain-derived neurotrophic factor pathway have been implicated.[11] Cortical neuronal hyperexcitability secondary to medication overuse may be a potential mechanism of MOH. In rat models, chronic administration of paracetamol resulted in an increased frequency of cortical spreading depression (CSD) and cortical hyperexcitability. Low serotonin (5-HT) levels may also play a role in the generation of MOH. In animal models low 5-HT results in upregulation of pronociceptive 5 HT 2A receptor and a higher frequency of CSD.[24] MOH has many similarities to drug abuse and dependence. Preparations containing codeine, opioids, and caffeine cause both MOH and drug dependence. Functional neuroimaging studies suggest changes in the orbitofrontal cortex and mesocorticolimbic dopaminergic pathways.[25] Alteration in endocannabinoid systems is also thought to be important in the pathogenesis of MOH. Increased expression of calcitonin gene-related peptide (CGRP) has been demonstrated in cultured dorsal root ganglion (DRG) neurons after chronic exposure to opiates.[26] Sustained or repeated administration of triptans to rats resulted in increased labeling for CGRP in identified trigeminal dural afferents that persisted long after discontinuation of triptan exposure. Two weeks after triptan exposure rats showed enhanced cutaneous allodynia and increased CGRP in the blood.[27] Chronic morphine infusion may alter the diffuse noxious inhibitory controls (DNICs) and impaired DNICs are found in MOH.[28] Increased levels of orexin-A and corticotrophin-releasing hormone are found in the cerebrospinal fluid of patients with MOH compared with patients with chronic migraine. These levels correlated with monthly drug intake.[29] Thus, persistent pronociceptive neural circuitry and neurochemical changes and central sensitization may underlie the development of MOH. A recent study on the identification of candidate proteomic markers suggests that serum of patients with MOH share common markers with chronic painful conditions.[30]
The MOH is usually seen in the age group of 40–45 years and women are affected more than men. The mean duration of intake for triptan (1.7 years) is shortest compared to ergots (2.7 years) and simple analgesics (4.8 years) and also at lower doses.[6] The character of headache in MOH depends on the underlying primary headache disorder and also overused medicine. It may be indistinguishable from the earlier headache character with increased severity and number of attacks, a new type of headache, or an earlier headache with reduced associated symptoms. The headaches are refractory, daily, severe in type, and may change in location during different days. It may be associated with asthenia, nausea, irritability, anxiety, and difficulty in concentration.[4],[6] Patients with ergot overuse, also, may have cold extremities, tachycardia, muscle pain, and hypertension.[6] While eliciting history details of preexisting and current headache, the use of headache medications with an emphasis on duration, frequency and dose, and negative history of features of secondary headache disorders should be enquired. If a patient is maintaining a headache diary it will give detailed information. The examination should be directed to rule out secondary causes of headache by looking for papilledema and focal deficits. Investigations if planned are usually done to rule out secondary causes. The ICHD-3 criteria for MOH should be applied and diagnosis can be done.[3]
The presence of medication overuse should not stop a physician from looking for 'red flags' for the secondary headaches in the history and examination. Idiopathic intracranial hypertension and cerebral venous thrombosis can present as a chronic headache with medication overuse. Medication overuse must be carefully enquired for, in patients with chronic migraine and chronic TTH which also present as chronic daily headache. Hemicrania continua, new daily persistent headache, and giant cell arteritis can also present in some patients as chronic headaches.[4],[6] The choice of investigations depend on the secondary headache diagnosis considered, and the strength of suspicion. Imaging with computerized tomography (CT) and magnetic resonance imaging (MRI) will rule out most of the disorders (tumors, venous thrombosis, raised intracranial pressure, and pachymeningitis) Depression and anxiety may co-exist with chronic migraine and MOH.[31] Psychiatric co-morbidities should not only be diagnosed but also be addressed appropriately. It has been suggested that the depression and anxiety in patients with MOH are due to headaches and not due to personality traits.[32]
Management of MOH is challenging and requires patience and commitment from the physician as well as the patient. Besides, patients also benefit from a comprehensive team comprising apart from physician, psychiatrists, psychiatric social workers, and nursing staff. The management is varied and complex due to different drugs causing the disease and paucity of good randomized controlled studies. Providing education (physician, patient, pharmacist, and to the general public), withdrawal of the responsible drug, supporting patients at outpatient or inpatient setting during withdrawal, and preventing recurrence by prophylaxis and other measures for the underlying primary headache disorder, form the cornerstones of the treatment options available [Figure 2]. The associated comorbidities like anxiety, depression, obesity, and metabolic disorders need to be treated. Healthy lifestyle habits need to be developed in form of quitting smoking and alcoholism and undertaking regular exercises. Nevertheless, successful management is very rewarding for doctors, patients as well as for society. The direct health care costs reduced by more than 50% and productivity increased significantly with the successful management of MOH.[33] There are very few guidelines for the treatment of MOH. The European guidelines by Diener et al. and the consensus guidelines followed by the Danish Headache center can provide a framework with the key points based on which the treatment can be tailored for a given patient.[34],[35],[36]
Patient education Educating patients, pharmacists, and the general public through various modalities of communication to prevent the overuse of analgesics, when they start using for migraine or other primary headache disorders can prevent the development of MOH.[37],[38] In a patient of MOH due to triptan or simple analgesic, education of the patient (regarding mechanism and treatment of MOH) is the first and very often, the only step required for the treatment.[8],[9],[10],[11],[12],[39] During follow-up at 18 months, around 76% of the patients with MOH were found to have no overuse in a study of 109 patients done in Norway.[40] The use of headache dairy provides the clinician with an important guide for making treatment decisions. The patient education comprises of making them aware that the analgesic use is the cause for headache, its removal may be curative even though it may not be complete. The patient may need treatment for an underlying primary headache disorder and comorbidities and it may be a long-drawn process with the involvement multidisciplinary team.[41] The patient needs to be made aware of the symptoms of withdrawal headache. Patients should be counseled and the use of anticipatory medication use must be discouraged.[35] Withdrawal or detoxification Withdrawal of the overused drug can be abrupt or gradual. For triptans, ergots, combination analgesics, simple analgesics, and NSAID's abrupt withdrawal is the treatment of choice and in case of medication overuse with opioids, barbiturates, and benzodiazepines, tapered withdrawal is suggested[34],[36] Danish guidelines suggest the total cessation of all abortive drugs in two months.[35] This abrupt withdrawal resulted in a better reduction in headache days/month after 6 months, as compared to a restricted intake of acute medications (2 days per week).[42] In terms of disability, depression, and anxiety abrupt withdrawal fared better than restricted withdrawal.[32],[43] Management of the withdrawal symptoms Withdrawal of the overused drug can lead to symptoms such as worsening of the headache, nausea, vomiting, irritability, hypotension, sleep disturbances, restlessness, and anxiety. The duration can vary from two to ten days but can last up to four weeks.[44] Treatment is tailored as per the patient's symptoms. The overused medication must be avoided at all costs. Support is the key feature in the management of withdrawal symptoms. Both psychological as well as medical support may be required. Round the clock availability of doctor/nurse, advice, and motivation are needed. The headache which occurs during the withdrawal period can be treated with acute medications ensuring that the medication which has been overused is avoided. Observational and retrospective studies have found steroids to be beneficial for withdrawal symptoms.[45],[46] In a randomized controlled trial (RCT) it was shown that the severity and duration of headache remained unchanged with the use of prednisone 100 mg every day for five days for the treatment of withdrawal headache. But a secondary endpoint, the demand for rescue medication during withdrawal was significantly reduced by the steroid use (p-0.021).[47] In the case of opioid withdrawal, oral clonidine, and intravenous lidocaine may help in relieving symptoms.[48] The drugs used in the treatment of withdrawal headache are given in [Table 2].
In-Patient or Outpatient Treatment? Outpatient withdrawal is recommended in patients who are motivated, taking non-opioid, and non-barbiturate medications with no comorbidities. Inpatient care is usually considered due to failed outpatient withdrawal in the past, overuse of barbiturates, opioids, or benzodiazepines, psychiatric or medical comorbidities, severe withdrawal symptoms such as vomiting.[34],[36] Inpatient care will ensure adherence and compliance, the most appropriate treatment including intravenous administration of drugs for the withdrawal symptoms can be decided by the doctor. Physical, psychological, and emotional support can be ensured during the in-patient treatment of MOH. For committed patients, outpatient care is more cost-effective. Nevertheless, in terms of improvement in headache and disability alleviation, both outpatient and inpatient treatment are similar.[39],[49] Outpatient treatment are the most preferred in the Indian context.[50] Prophylactic Medication- What, When, and Why?? Initiation and timing of prophylactic medication in MOH is decided based on the primary headache that the patient has, the possible side effects of the drugs, the comorbidities, the patient's preference, and history of response to medication. Some patients may not require prophylaxis after the successful withdrawal of the overused medication.[35] Avoiding starting prophylaxis therapy at the time of withdrawal gives a chance of disappearance of the headache if the current headache is purely MOH, the nature of the underlying primary headache disorder may be revealed if it starts again and it may restore the effectiveness of prophylactic medication efficacy due to drug holiday.[51] European guidelines state that topiramate, onabotulinum toxin A, and monoclonal antibodies targeting CGRP are effective prophylactic medications in patients with chronic migraine and MOH, though the strength of recommendation is weak.[34] The initiation of prophylactic therapy at the time of withdrawal resulted in a 60% reduction of headache frequency in 6 months.[32] A recent RCT showed that the introduction of the prophylactic along with the withdrawal was more beneficial than withdrawal alone (with the option of starting prophylactic after 2 months) or prophylactic therapy alone in patients with MOH.[52]
Studies on MOH in India are scarce. The prevalence of MOH is much lower in India as compared to the West, which may be due to the common use of complementary and alternative medicine rather than routine drugs used, which may not be defined scientifically.[50] Among the drugs, a combination of caffeine 100 mg, ergotamine 1 mg, paracetamol 250 mg, prochlorperazine 2.5 mg, which contains ergot is the common drug that is overused. Amitriptyline, sodium valproate, botulinum toxin, and steroids are used for prophylaxis and treatment of withdrawal symptoms. Education of the primary health care physicians regarding the entity of MOH and steps to prevent MOH will go a long way in the prevention and management of MOH in India.[50]
Overuse could be eliminated in more than 60% of the patients with optimum management of MOH. In many patients, the chronic headache becomes episodic. The relapse rate can be as high as 41% irrespective of the mode of treatment.[53] Predictors of relapse are the long duration of migraine before the medication overuse, a higher frequency of migraine after withdrawal therapy, and a greater number of previous prophylactic treatments, male sex, intake of combination analgesics after withdrawal therapy, nicotine and alcohol consumption, and taking the former medication again after withdrawal therapy.[54],[55],[56] A long follow-up study of nine years by Boe et al. found a relapse rate of 32%.[57] Most of the relapses occur in the first year following treatment.[58],[59] Can we prevent relapse? Identifying the risk factors for relapse, maintaining a headache diary, behavioral intervention, treatment with onabotulinum toxin, and regular follow-up are the 'good practice statements' suggested in the European guidelines.[34] Psychotherapy with pre-specified protocol resulted in a much greater reduction in relapse rate in MOH as compared to patients without psychotherapy.[60] Counseling, biofeedback, and cognitive behavioral therapy help in treatment compliance.[61]
Even though the MOH is a recognized entity in literature as well as established in clinical practice, there are several scientific arguments regarding its genesis and naming. As with the majority of headache disorders, there is no specific imaging and biological marker, the duration of headache days and number of medication days required for diagnosis are not from randomized studies but from observational studies, not all patients on medication develop MOH and many may not improve after removing the drug, in some patients few of the painful conditions without headache with the use of analgesics, never develop MOH.[62],[63] Few authors argue that the frequent use of symptomatic medicines should be viewed as poorly controlled headache disorder in the patient, or the cyclical phase of the primary headache disorder which has become unresponsive to treatment. The term MOH has the potential for self-stigmatization, self-blame for the patient and caregivers, and some authors have suggested alternative terms like 'medication adaptation headache'.[63]
Medication Overuse headache is one of the secondary causes of headache, developing in a patient with the use of symptomatic medications for pain relief which is associated with significant disability worldwide. Though exact pathophysiology is not known, a combination of factors in a susceptible individual will lead to the disorder. The clinical approach involves ruling out other secondary headache disorders and planning for outpatient or inpatient treatment. Simple education, withdrawal, and in some patient's prophylaxis with drugs are the mainstays of the treatment with the involvement of a multidisciplinary team of caregivers. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2]
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