Refractory chronic migraine (RCM) is often a debilitating illness with an enormous impact on quality of life. Chronic migraine occurs in approximately 2% of the population (1), although the prevalence of RCM is unknown. Long-term outcomes for those with RCM have not been investigated. In addition, there is a range of severity among RCM patients that impacts treatment decisions. To advance clinical and basic research in this area, it is important to categorize RCM patients according to severity.
Although there have been challenges to classifying RCM, including the lack of a biological marker and disagreement among practitioners as to what constitutes refractoriness (2), criteria have been proposed by the Refractory Headache Special Interest Section of the American Headache Society (3). These include significant interference with function or quality of life despite modification of triggers, lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy.
To assess pain and quality of life in RCM patients over a 10-year period, I developed a novel RCM severity rating scale (4)(See table, below). The components of the scale reflect various elements of refractoriness, including comorbidities. For example, refractoriness to preventive or abortive medications are central hallmarks of RCM, and these factors are more heavily weighted than other components. Because plasticity of the brain may be an important factor in refractoriness, it is important to include the length of time of headache. Associated medical comorbidities, such as those included in the scale, often occur in those with chronic migraine and may complicate treatment and add to refractoriness. Psychiatric comorbidities, commonly seen in RCM patients, certainly complicate treatment.
Significant abuse in childhood, whether sexual, physical, or emotional, may predispose one to develop RCM, separately or in conjunction with other central sensitization syndromes such as fibromyalgia, irritable bowel syndrome, chronic pelvic pain, or temporomandibular disorder. Important comorbidities include anxiety, depression, the bipolar spectrum, personality disorders, somatization, and post-traumatic stress disorder (5,6).
The bipolar spectrum is seen relatively often in headache patients and particularly among migraineurs (5). The depression and hypomania of the bipolar spectrum complicate treatment; in RCM patients, these issues must be recognized. Studies have indicated that from 7.2% to 8.6% of migraine patients fit the bipolar spectrum (7). When not diagnosed, these patients often are given antidepressants alone, with predictably poor results. While of some benefit, these medications generally are not effective for the bipolar spectrum and may trigger mania or hypomania. Mood stabilizers that help both conditions, such as lamotrigine or sodium valproate, are important. Psychotherapy plays a vital role with these patients.
In patients with certain personality disorders, failure on the part of the physician to recognize Axis II pathology puts both doctor and patient at risk. Patients with antisocial, borderline, or paranoid personality disorders may wreak havoc on an unsuspecting medical practice. Although personality disorder characteristics seem extreme, they are often overlooked, and health care providers may react by treating these patients in a dysfunctional manner. The diagnosis of a moderate or severe personality disorder alters both our goal and approach and greatly complicates the treatment for chronic migraine. Antidepressants, mood stabilizers, and antipsychotics may ameliorate symptoms, and some of these medications may lessen headache pain as well. It is important to limit and closely monitor addicting medications: Opioids and benzodiazepines are best avoided, particularly in patients with borderline personality disorder.
Individuals who chronically function at a low level (disability) often are more resistant to migraine treatment and their RCM is less likely to improve. Medication overuse headache (MOH) adds to refractoriness and resistance to treatment, although determining who has MOH is difficult. Abortive medication overuse is a major risk factor for the progression of migraine into RCM, although some patients have medication overuse without an increase in headache.
A patient with a pattern of migraine that increases in intensity rather than decreases and who requests medication refills with increasing frequency is most likely suffering from MOH.
Approach to RCM Treatment
Several risk factors may drive the development of RCM, including lifestyle issues such as medication overuse, sleep habits, caffeine overuse, and obesity (8). While pharmacotherapy may be the cornerstone of treatment, other modalities are no less important. The patient must manage his or her triggers with regard to sleep, food, and caffeine. Exercise and weight reduction are encouraged. Stress, another major trigger, may be relieved by practicing biofeedback and/or yoga. Depending on the origin of the pain, physical therapy and massage may help. Problems with the teeth, jaw, eyes, or neck should be addressed.
Currently, there is no algorithm for migraine treatment. There are five pharmacologic approaches that this author has employed (opioids, botulinum toxin, daily or frequent triptans, stimulants, and monoamine oxidase inhibitors), some of which may be combined. The choices of medication will vary for each patient depending on headache severity, age, tendency toward addiction, and comorbidities. It is crucial to resolve medication overuse and eliminate rebound in all RCM patients. Comorbidities often steer where we go with medications: conditions such as IBS, fatigue, or psychiatric conditions have to be considered. Of course, the familiarity and confidence with a particular therapy on the part of the treating physician also plays a major role in selection.
In my practice, long-acting opioids (LAOs) are the most commonly utilized approach for RCM. The best candidate for LAOs is the person who has done well on short-acting opioids (SAO) and who does not have characteristics of a personality disorder. For patients with non-cancer breakthrough pain, such as chronic daily headache, I tend to minimize the total opioid and avoid layering pain medicines on top of each other. Prescribing short-acting medications for chronic headaches greatly increases the abuse rate. The occasional patient can remain on a low dose of the long-acting opioid, with one or two SAOs per day, but, in general, I try to avoid the SAOs.
Botulinum toxin type A (BoNT-A) has been utilized as a migraine and chronic daily headache preventive since the 1990s. The preponderance of evidence points to BoNT-A as being safe and efficacious. It acts as an antiinflammatory at the neuronal level, and, more importantly, it may also inhibit the level of secretion of calcitonin gene-related peptide (CGRP) (9). CGRP has now been recognized as a key inflammatory mediator in the cascade leading to headache. BoNT-A may also block the release of certain other neuropeptides that contribute to the “inflammatory soup.” This neuropeptide blockage, along with BoNT-A inhibitory effects on the excitatory neurotransmitter glutamate, results in a lessening of peripheral sensitization. With the use of BoNT-A, there is also a decrease in central sensitization (10). Relatively few other compounds have an effect on central sensitization, which is vital to the pathophysiology of chronic migraine.
Some patients respond only to triptan medications. Several studies have described the use of daily triptans for the preventive treatment of chronic daily headache (11,12). The primary issue with frequent triptan use, assuming rebound headache is not present, is long-term adverse events, particularly those affecting the cardiovascular system. Chronic ischemic changes, valvular abnormalities, or fibrosis are theoretical considerations. To date, there is no evidence of long-term triptan use producing any of these adverse events, although these have not been systematically studied.
When prescribed for headache patients, stimulants may be beneficial for various comorbidities, such as attention deficit hyperactivity disorder (ADHD), depression, and fatigue. In addition, stimulants do not cause the weight gain that is seen with a number of other current headache preventives. Amphetamines have been shown to possess intrinsic analgesic properties, primarily through brain catecholamine activity. They also intensify the analgesic effects of certain opioids (13).
For those with RCM and unipolar depression, MAOIs may be of help. MAOIs are sometimes effective for treatment-resistant depression (14) and for alleviating anxiety. For a select group of RCM patients, MAOIs greatly enhance quality of life, and I believe that they are underutilized.
New Treatment Approaches
New approaches, such as transcranial magnetic stimulation (TMS), are in various stages of development and already show promise in decreasing migraine recurrences and severity, particularly among patients with moderate to severe migraines. Occipital nerve stimulation has been beneficial for a small number of RCM patients, although technical challenges need to be overcome.
In pharmacotherapy, there are a number of emerging compounds that may eventually come to market. Although the triptans are highly effective in acute migraine attacks, they are contraindicated in patients with ischemic heart disease and unstable angina. Newer abortives, such as an oral 5-HT(1F) drug, works on the 5-HT F receptor, while the current triptans, which are associated with vasoconstriction, target B and D receptors. CGRP antagonists block and/or reverse CGRP-mediated dilation of intracranial vessels induced by activation of the main sensory nerves in the brain. Gap junction blockers at the neural-glial level are being assessed, and glutamate receptor antagonists are currently in Phase III trials.
RCM constitutes a small but important subset of migraine patients. For clinical and study purposes, it is helpful to categorize RCM patients as to the degree of refractoriness, so that treatment can be assigned appropriately, while taking such factors as comorbidities into consideration. Continuing research is needed to answer questions about the role of genetics, structural changes in the brain, central sensitization, peripheral vs. brainstem vs. cortical involvement, medication overuse headache (MOH), and the impact of psychiatric comorbidities in the development of RCM.
1. Robbins L. Refractory chronic migraine. Pract Pain Manage. 2010;10(3):10-24.
2. Levin M. Refractory headache: classification and nomenclature. Headache. 2008;48(6):783-790.
3. Schulman EA, Lake AE III, Goadsby P, et al. Defining refractory migraine and refractory chronic migraine: proposed criteria. Headache. 2008;48(6):778-782.
4. Robbins L. Refractory chronic migraine: long-term follow-up using a refractory rating scale. J Headache Pain. 2012;13:225-229.
5. Robbins L. The bipolar spectrum in migraine, cluster and chronic tension headache. Eur Neurol Rev. 2008;3(1):123-124.
6. Robbins L. Personality disorders in migraineurs. Pract Pain Manage. 2009;9(1):52-54.
7. Merikangas KR, Stevens DE. Comorbidity of migraine and psychiatric disorders. Neurol Clin. 1997. 15(1): 115-123.
8. Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden and the need for preventive therapy. Neurol. 2007. 68(5):343-349.
9. Ashkenazi A, Silberstein S. Botulinum toxin type A for the treatment of headache: why we say yes. Arch Neurol. 2008;65(1):146-149.
10. Oshinsky ML. Botulinum toxins and migraine: How does it work? Pract Neurol. 2004;(suppl):10-13.
11. Robbins L. Frequent triptan use: Observations on safety issues. Headache. 2004;44(2):178-182.
12. Robbins L, Maides J. Long-term daily triptan use: 59 patients. Headache Q. 2000;11(4):275-277.
13. Drago F, Caccomo G, Continella G, Scapagnini U. Amphetamine-induced analgesia does not involve brain opioids. Eur J Pharmacol. 1984;101(3-4):267-269.
14. Krishnan KR. Revisiting Monoamine Oxidase Inhibitors. J Clin Psychiatry. 2007;68(suppl 8):35-41.
15. Silberstein S, Dodick D, Pearlman S. Defining the pharmacologically intractable headache for clinical trials and clinical practice. Headache. 2010;50(9):1499-1506.
16. Headache Classification Committee of the International Headache Society. The international classification of headache disorders, 2nd edition. Cephalagia. 2004;24(Suppl 1):9-160.
17. Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J. Harrison’s Principles of Internal Medicine: Volumes 1 and 2. 18th ed. New York, NY: McGraw Hill; 2011.
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington DC: American Psychiatric Association; 1994.
Lawrence D. Robbins, MD, practices at the Robbins Headache Clinic in Northbrook, Illinois. He is the author of three popular books and 200 articles on headache. Dr. Robbins edits http://chicagoheadacheclinic.com, a primary source for headache information. He was selected as one of America’s Top Doctors from 2001 to 2012 and received the Janet Travell Clinical Pain Management Award from the American Academy of Pain Management in 2008. His research interests include the immune system and headache, refractory headache, and white matter imaging in migraine.
This article was originally published in The Pain Practitioner.