All 3 of us specialize in this area and see these types of patients every day, so the topic of difficult-to-treat migraine is close to each of us. When we receive referrals for treatment-refractory migraine, part of our process is to look into the possibility that something might have gone unrecognized along the way. We want to make sure that there is not another diagnosis in play, or perhaps another condition that might respond better to a different treatment. These are patients who have tried numerous medications and various different therapies, all to no avail. Thus, I will often take a step back to go over their history again and review their imaging and other records, in an attempt to see if we might be missing a different diagnosis. For instance, acute medication overuse headache may be a factor, and it is not obvious from the medical record when the agents being overused are over-the-counter medications.

Patients with certain comorbidities can be especially challenging to treat, particularly those with anxiety, severe depression, posttraumatic stress disorder, and borderline personality disorder. Epilepsy is another comorbidity that may be associated with treatment-refractory headache. Interestingly, the stress and anxiety of the COVID-19 pandemic may be contributory in a number of ways. In some patients, anxiety and bruxism, both of which seem to be on the rise during this stressful time, may trigger or worsen migraine. If these patients are on certain antidepressant therapies, bruxism may develop or worsen as a side effect. All of this illustrates that there are quite a number of considerations that we need to take into account when seeing these patients to get a better sense of the degree to which they may be refractory to past medications.

I agree that many conditions may underlie presumptive treatment-refractory migraine. Sleep dysfunction is one that is very common. It is amazing and gratifying to see a patient with refractory chronic daily headaches improve when previously undiagnosed sleep apnea is addressed. Once that patient is sleeping more soundly, there can be a significant improvement in migraine, mood, fatigue, and cognition. Other conditions that come to mind include occipital neuralgia and temporomandibular disorders (TMD). A 2019 study demonstrated that nearly 25% of patients who presented with a chief complaint of headache at a community hospital–based headache clinic had a diagnosis of occipital neuralgia in addition to a primary headache disorder such as chronic migraine. If left untreated, occipital neuralgia can reduce the efficacy of migraine treatment. Similarly, TMD can interact with the migraine, as studies demonstrated that, as one’s migraine improves, their TMD tends to improve, and vice versa.

In terms of preventive treatment for the truly refractory patient, one approach is to add to the therapeutic foundation. For example, if a patient is taking a medication with improvement of their migraines, but further titration is limited by side effects, I use the analogy of a runner’s momentum. You want to keep that therapeutic momentum going as you consider adding another treatment from a different therapeutic class, which may have a synergistic benefit. This is likely a better strategy than discontinuing an effective treatment prior to starting a new medication trial. Finally, with more complex patients, taking a team approach to treatment and working in concert with other specialists to address other underlying issues can yield the best results. For example, in a patient who has refractory migraine, TMD, and lumbar radiculopathy, the involvement of an orofacial pain specialist and a pain/spine specialist should be considered. 

I agree with my colleagues on the importance of confirming the diagnosis, the management of comorbidities, and the exclusion of trigger factors that could be exacerbating the condition. I would add that cannabis use is also something that we should be asking patients about. Many individuals use cannabis medically or recreationally these days, and it has been shown, at least in preclinical models, to act just like opioids and other acute medications in producing medication overuse headache.

With regard to pharmacotherapy, I would emphasize the importance of the proper use of preventive treatments, allowing for an adequate trial duration and dose. In refractory cases, a combination of preventative medications yields the best results. We have seen improvements occur over the span of several months with the anti–calcitonin gene-related peptide therapies. Still, for some patients who have more challenging disease(s), you are not going to be successful by simply writing a prescription for acute or preventive treatment; a multimodal approach should be employed.

Some patients experience pain continuously, and important components of treatment include improving their ability to function with pain through such modalities as cognitive behavioral therapy, biofeedback-assisted relaxation therapy, and improvement of coping mechanisms. In addition, combining medication with other modalities, such as extracranial nerve blocks and neuromodulation therapy, may be appropriate. A team approach involving multiple specialists, including exercise physiologists, nutritionists, and psychologists, is also effective in complex cases.