Medication-overuse headache: clinical profile and management strategies

Historical background

A report in 1963 of 52 patients who had headaches after taking ergotamine for prolonged periods, showed 71% developed signs and symptoms of toxicity, which reversed when the drug was discontinued.² In 1990, similar observations were made regarding triptans.³ In 1998, the term “drug-induced headache” was introduced by the International Headache Society in the ICHD-1 for the first time. In 2004 in the ICHD-2, the term was changed to “medication-overuse headache” to highlight the impact of regular and longtime use of specific medications resulting in headache, and to differentiate it from headaches as side effects, caused by other headache-triggering medications.^4,5(However, the criteria specified that MOH can only be diagnosed once the headache disappears, after the offending agent is removed Otherwise, it was defined as probable MOH, leading to difficulties in clinical practice. In 2006, the requirement that headache can be definitively diagnosed only once it disappears was eliminated and that criterion was retained in the recent ICHD-3 guideline.^1,6

Epidemiology

Medication-overuse headache occurs in 2% of women, and 1% of men worldwide.^7,8 It is most prevalent in people in their 40s, and about 50% of patients with chronic headaches have associated MOH.^6,8 Medications commonly implicated in MOH are paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), ergots, triptans, and opioids.^6,9

Disease burden

The MOH has a broad impact on physical and psychological health. A recent study assessing the burden of MOH concluded those who overuse acute medications were more likely to have moderate to severe depression, moderate to severe anxiety, moderate to severe headache-related disability, and a higher incidence of emergency department and urgent care use for headache within the past 6 months.^10-13

Pathophysiology

The pathophysiology of MOH is still not fully understood. In animal studies, Green et al¹⁴ observed multiple changes in the physiological process in the central nervous system (CNS) after repetitive administration of analgesics. Data showed using triptans for long durations can result in susceptibility to cortical spreading depression (CSD) due to decreased threshold.^15,16 Long-term exposure to analgesics was found to increase the neuronal excitability in the amygdala’s central nucleus, which may lead to the development of depression or anxiety.^17,18

The serotonergic system was also affected by the use of analgesics for a long time, which leading to neuronal hyperexcitability, trigeminal nociception enhancement, and CSD due to an increase in the expression of serotonin 2A (pro-nociceptive) receptor binding sites and lowering of the production of serotonin in the CNS.¹⁵

Data from a study reported by Cargnin et al¹⁹ showed variations in genes in the dopaminergic gene system (DRD2, DRD4, SLC6A3), and genes related to dependence of drug pathways (ACE, HDAC3, WSF1, BDNF). These genetic traits were considered potential risk factors for susceptibility to MOH with multi-drug consumption.^18-20

Data from Pellesi et al²¹ have reported the detection of high concentrations of different serum bands in patients with MOH in comparison to controls. Those include Hemopexin, alpha-1-acid glycoprotein 1, apolipoprotein A4 and haptoglobin which have been reported previously in an animal model of neuropathic pain. It was suggested that it was consequence of enduring neural damage and sensitization of the trigeminal nociceptive pathways due to over exposure to acute headache medication. Furthermore, additional proteins were isolated in patient with MOH: Alpha-1-antitrypsin, immunoglobulin heavy constant alpha 1, retinol binding protein and transthyretin.²¹

Structural changes have been reported in the CNS

Increased gray matter volume mainly in the periaqueductal grey area, hippocampus, posterior cingulate cortex, thalamus, cerebellum, fusiform gyrus, and ventral striatum. Orbitofrontal cortex (OFC), anterior cingulate cortex, left middle occipital gyrus, anterior cingulate cortex, insula and precuneus had lesser gray matter volume.¹⁸ However, functional changes have been reported as well in the CNS (mesocorticolimbic system, the salience network, the fronto-parietal attention network, the default network, and the memory processing network).²²

Clinical profile

The character of MOH is difficult to differentiate from other forms of chronic daily headache. The headache’s character and associated symptoms of MOH are not defined in ICHD-3 criteria. However, MOH are refractory, daily, severe, have no specific location, are changeable on different days, and are associated with asthenia, nausea, irritability, anxiety, and concentration difficulties.²³ An interaction between susceptible patient and a therapeutic medication used excessively is considered MOH.¹

Diagnosis

A detailed history is essential for headache evaluation, including the medication history. The ICHD-3 diagnostic criteria in Table 1 is used to consider the diagnosis of MOH. The onset of headache usually is gradual, and the nature of the headache is often typical, such as tension or migraine, and can be more frequent and intense.²⁴ Patients with MOH usually report neck pain and headaches in the morning due to poor quality of sleep or overnight drug withdrawal.^25,26 Table 2 compares the different diagnostic criteria of ICHD.

It is important to consider the red flags for secondary headaches — such as cerebral venous thrombosis and idiopathic intracranial hypertension, which can present in chronic headache with medication overuse — when taking a patient’s history and performing the physical examination. Hemicrania continua, giant cell arthritis, and new daily persistent headache can also be presented with chronic headaches. The choice of which appropriate investigation to follow depends on the consideration of secondary headache diagnosis and the strength of suspicion. Computerized tomography and magnetic resonance imaging can be used to rule out tumors, venous thrombosis, high intracranial pressure, and pachymeningitis for most secondary headaches.²⁷ Psychiatric disorders such as anxiety and depression can be associated with MOH; it has been suggested they occur in patients with MOH because of the headaches, not because of personality traits.^6,28,29

Management. Role of counseling

Educating patients, the general population, and healthcare providers about MOH and analgesic overuse — especially when headache sufferers take it for any primary headache disorders — can prevent the development of MOH.⁶ New information campaigns for patients at risk before the onset of MOH have important role in the management of headache.¹⁵ Headache centers in Germany provide a brochure about MOH, which has proved effective in the prevention of developing MOH in those with frequent usage of medications and migraine.¹⁵ Primary health care counselling has a major role in the prevention of MOH as well as the initial treatment, while general practitioners (GP) can educate patients about proper usage of medication and modifiable risk factors, such as physical inactivity, stress, obesity, and smoking.³⁰ Intervention by a GP was found to be effective in the management of MOH, according to the Norwegian Akerhus study.²⁵ They compared those patients who received GP counselling with those who did not; there was a significant decrease in headache and the frequency of medication usage with those who received counseling. Thus, education by a GP is effective, preventing the need for withdrawal from medications, and can be demonstrated after 16 months.^25,31

Strategies

Management strategies for withdrawing from drug overuse can be abrupt or gradual. Abrupt, sudden removal is considered the treatment of choice for triptans, ergots, simple and combination analgesics, and NSAIDs. Gradual withdrawal is best for the overuse of opioids, barbiturates, and benzodiazepines.^32-34 Danish guidelines recommend the total cessation of all medications within 2 months.^6,35 Withdrawal symptoms such as headache, nausea, vomiting, hypotension, sleep disturbance, and tachycardia generally last for 2-10 days.^15,36 Table 3 summarizes treatment strategies for patients with MOH.

Inpatient or outpatient?

Outpatient management, considered more cost effective, is recommended for committed, motivated patients, who are taking non-opioid and non-barbiturate medications, and do not have any physical or psychiatric comorbidities. Inpatient management is considered when outpatient management has failed; barbiturates, opioids or benzodiazepines have been overused, or with the patient has medical or psychiatric comorbidities, or experiences severe withdrawal symptoms such as vomiting. For that reason, inpatient care will ensure compliance and adherence, and the health care provider can decide the most appropriate treatment for withdrawal symptoms including intravenous administration.^33,37,38 Non-pharmacological management, such as behavioral strategies can be applied in inpatient settings for patients with dependence and psychological symptoms.^39-41

Prophylactic management

The European Federation of Neurological Sciences recommends that if prophylactic therapy has started before or at the time of abrupt withdrawal of the overused medication, preventive therapies should be at the lowest doses, then dosage can be titrated up with time. The choice of treatment depends on the medication used, patient preferences, the type of primary headache disorder, comorbidities, and adverse effects.⁴² A meta-analysis of randomized controlled trials (RCTs) on the effects of prophylactic therapies confirmed the efficacy of valproate, nabilone, onabotulinumtoxin A, topiramate, and amitriptyline. The results of RCTs with patients affected by chronic migraine and MOH suggest the use of onabotulinumtoxin A and topiramate without early discontinuation.⁴³ Another RCT in 2020 compared 3 treatment strategies: withdrawal with preventive treatment, preventive without withdrawal treatment, and withdrawal with postponed optional preventive treatment. Study results recommend the use of withdrawal and the preventive treatment strategy for MOH.⁴⁴

New therapy modalities. CGRP and their role

Recent studies looked at the prophylactic effect of anti-calcitonin gene-related peptide receptor (anti-CGRP) monoclonal antibodies (MAB) in MOH. A prospective study in 2021 with 316 patients started anti-CGRP MAB as a migraine prophylaxis for 6 months. They noticed a >50% reduction in headache frequency regardless of the presence of MOH, concluding anti-CGRP MABs are probably an effective prophylactic treatment for migraine patients with MOH; and they were safe and well-tolerated.^45,46 They did not support that one anti-CGRP MAB is better than another for MOH (erenumab vs. galcanezumab). They also did not support dual therapy with concomitant botulinum toxin-A instead of monotherapy. Anti-CGRP MABs were considered safe, facilitate acute medication discontinuation, reduce headache frequency, and reduce usage of acute medication.⁴⁷

Future potential of the new medication

In terms of acute therapy, FDA approval of both small molecule CGRP receptor antagonists, such as ubrogepant, and the serotonin (5-HT) 5-TH1F receptor agonist, such as lasmiditan, for the management of migraine, may have the potential to lower the MOH risk profile, which is supported by preclinical and preliminary clinical data.^47,48

More detailed studies for real-world evidence of the efficacy of these new medications can improve our understanding and management possibilities of using these therapies.

Conclusion

Proper approach for MOH is crucial, as well as the need for appropriate clinical assessment and a treatment strategy for the overused medication. It is equally important that patients be made aware of MOH. Overall, it is a challenging disorder, and appropriate assessment with clinical profile utilizing updated diagnostic criteria will help in the diagnosis and management of MOH. Treatment strategies vary by medication. Abrupt and sudden removal is considered the treatment of choice for triptans, ergots, simple and combination analgesics, and NSAIDs. Gradual withdrawal is best for the overuse of opioids, barbiturates, and benzodiazepines. Further research is needed to evaluate new acute therapy safety and efficacy of new medications in patients with MOH.