Intractable and Refractory Headaches: Diagnosis and Management

Educational Objectives

The goal of this program is to improve the diagnosis and management of intractable and refractory headache. After hearing and assimilating this program, the clinician will be better able to:

1. Distinguish between intractable and refractory migraines.
2. Apply therapeutic algorithms for managing refractory migraine.

Summary

Patient management during referrals: when referring patients outside for assistance, reassurance that they are not being abandoned is critical; “intractable” means unstoppable, whereas “refractory” means it is extremely resistant to a process or stimulus; help the patient understand that this is not their fault; definition is important for research and for the patient, as a cue to begin aggressive therapies early (eg, inpatient management, psychologic behavioral therapy, multidisciplinary approach and control of comorbid conditions); evaluation of compliance is crucial because lack of compliance can lead to a refractory state

Evaluation: to determine whether a headache is intractable or refractory, assess response to medications, number of medications, and other preventive therapies, disability, medication overuse, and frequency; chronic migraine is often easily misconstrued as refractory; patients may have episodic disease that does not respond to any therapy; in studies, untreated episodic migraines have disability rates comparable to chronic migraines; disability is an important factor to consider when beginning preventive therapies; if a patient is functioning normally but has a persistent headache that is not responding to therapy, the diagnosis should be reconsidered; presence of disability despite lifestyle changes, trigger management, and optimization of mood and sleep, and stress and weight management may indicate refractory disease

Medications: side effects are a sign that the medicine worked; when a patient reports no response to medications, including side effects, consider a mismatch in the mechanism of action of the drug chosen vs the migraine pathway or an incorrect diagnosis; in general, a patient must have tried 2 to 4 medications for migraine, and 4 medications for cluster headache, before being considered as refractory; the concept of medication overuse (MOU) headache is debatable; current treatment regimens that do not require cessation of overused medication are available as over-the-counter agents (eg, triptans); in the United States (US), it is believed that patients with MOU should be considered refractory, whereas in Europe, it is believed that MOU patients should not be considered refractory

Opinion of clinicians: many members of the American Headache Society believe that refractory migraine, along with insufficient response to multiple acute and preventive medications, headaches lasting ≥15 day/mo, and disability, should be included in international classification

Refractory migraine: in the US, the patient must have tried ≥2 of 4 medications (ie, a triptan and dihydroergotamine, and either a nonsteroidal anti-inflammatory drug or a combination analgesic) and had an inadequate response; this does not include requirement to discontinue excessive medication use; disability is defined using the Migraine Disability Assessment; in Europe, the patient must have tried ≥3 drugs at specific doses, been adequately treated for comorbid conditions, with no findings on magnetic resonance imaging, and detoxified from medication overuse; refractory cluster headache is a failure of ≥4 drug classes

Classification for referral: initially was based on availability of specialists, ie, refer, even if a patient has tried 2 to 3 preventatives or an acute inpatient infusion; referrals occur now after failure of one medication

Refractory headache in practice: study by Irima et al (2011) — 5.1% of patients reporting to a headache clinic were refractory; majority of these patients were women with chronic migraine, with ≈36% having MOU headache; those with MOU headache were more disabled than those without; study by Robbins et al (2012) — followed patients for 10 yr with a refractory reading scale; pain and quality of life improved in all patients with refractory migraine; however, the most severe group showed the least improvement

Ketamine infusions: can be tried for refractory chronic migraine, with comorbid sleep apnea and diabetes, that showed no response to previous treatments; headaches may recur, and repeat infusions might be needed; a side effect of repeat infusions is elevations on liver function test; ketamine acts on N-methyl-D-aspartate system; refractory patients who do not respond to very specific agents require broader therapy; unintended side effects to broader agents must be controlled; if patients do not respond to broad and specific agents, reconsider mechanism of headache

Olanzapine: dopamine-based agent; Silberstein et al (2022) showed that olanzapine was effective for refractory headache; can trigger metabolic syndrome (long-term laboratory evaluation is crucial)

Important considerations: various options are available for patients who are refractory; layer medications and treatments, use alternative treatments, and encourage lifestyle changes (eg, diet, exercise) to help the patient achieve migraine freedom

Readings

D'Antona L, Matharu M. Identifying and managing refractory migraine: barriers and opportunities?. J Headache Pain. 2019 Aug 23; 20(1):89. doi: 10.1186/s10194-019-1040-x; Irimia P, Palma JA, Fernandez-Torron R, et al. Refractory migraine in a headache clinic population. BMC Neurol. 2011 Aug 1; 11:94. doi: 10.1186/1471-2377-11-94; Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies. Headache. 2015; 55:3; Robbins L. Refractory chronic migraine: long-term follow-up using a refractory rating scale. J Headache Pain. 2012 Apr; 13(3):225-9. doi: 10.1007/s10194-012-0423-z. Epub 2012 Feb 25; Sacco S, Braschinsky M, Ducros A, et al. European Headache Federation consensus on the definition of resistant and refractory migraine: Developed with the endorsement of the European Migraine & Headache Alliance (EMHA). J Headache Pain. 2020; 21(1):76. Published 2020 Jun 16. doi:10.1186/s10194-020-01130-5; Silberstein SD, Peres MF, Hopkins MM, et al. Olanzapine in the treatment of refractory migraine and chronic daily headache. Headache. 2002; 42(6):515-518. doi:10.1046/j.1526-4610.2002.02126.x.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Ailani is part of the advisory panel for AbbVie, Amgen, Biohaven, Impel Pharmaceuticals Inc, Satsuma Pharmaceuticals, Linpharma Inc, and Axsome Therapeutics; she is a consultant at AbbVie, H Lundbeck A/S, Teva Pharmaceuticals, Eli Lilly and Company, Miravo Healthcare, GSK plc, Nesos and CtrlM; and is associated with clinical trials in AbbVie, Biohaven and Zosano Pharma; and is part of the data monitoring board at AEON Biopharma. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Ailani was recorded at the 35th Annual Practicing Physician's Approach to the Difficult Headache Patient, held on May 26-29, 2022, and presented by Diamond Headache Clinic in San Diego, CA. For information about upcoming CME activities from this presenter, please visit Diamondheadache.com. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

NE132102

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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