Chronic daily headache (CDH) is a relatively

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1 CHRONIC HEADACHE: TODAY AND INTO THE FUTURE * Nabih M. Ramadan, MD ABSTRACT Chronic daily headache (CDH) is the phenotypic manifestation of diverse conditions with varied etiologies and sometimes divergent underlying pathophysiology. Current therapeutic strategies for CDH are largely imported from migraine and chronic tension-type headache treatments, on the assumption of overlapping mechanisms between these conditions. Fear of chronic medication overuse and its comorbidity with psychiatric and chronic pain syndromes dictate that the treatment of CDH focuses on preventive pharmacologic measures, such as daily antidepressants, and nonpharmacologic interventions, such as biofeedback and improved coping skills. A better understanding of CDH mechanisms, more accurate definitions of its subtypes, and a thorough knowledge of its epidemiology and natural history undoubtedly will refine future therapeutic strategies. Chronic daily headache (CDH) is a relatively common painful disorder with diverse etiologies. To successfully manage CDH, and similar to any other medical condition, one must do the following: (1) clearly define the illness, its subtypes (drawing on current knowledge of genomics and proteomic influences), temporal profile, natural history, and underlying mechanisms; and (2) apply the principles of evidence-based treatment, when available. Although this approach is optimal, the reality sometimes falls short of our goals in the case of CDH. To date, the definitions and classification of the primary forms of CDH remain in debate. Furthermore, knowledge of the pathophysiologic mechanisms for CDH is in its infancy, lacking clear biomarkers (eg, biochemical, electrophysiological, radiologic, or genomic). Finally, evidence-based treatment of CDH is mainly at Level II or III (Table 1). 1 The purpose of this article is to review the current treatments of CDH, highlight their shortcomings, and provide insight into future therapy in light of putative mechanisms. COMPARING CDH TO OTHER CHRONIC PAIN CONDITIONS *This article is based on a roundtable symposium held in Chicago, Illinois, on June 3, Vice President, Strategic Development, Professor and Chair, Department of Neurology, Professor, Department of Psychiatry and Behavioral Sciences, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois. Address correspondence to: Nabih M. Ramadan, MD, Vice President, Strategic Development, Professor and Chair, Department of Neurology, Professor, Department of Psychiatry and Behavioral Sciences, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL nabih.ramadan@rosalindfranklin.edu. Similarities between CDH and other chronic pain or headache disorders (eg, migraine) may allow us to better characterize the disorder and subsequently offer optimal therapeutics. For example, Sternfeld et al noted an association between chest pain, stomach pain, heartburn, joint pain, neck pain, back pain, and migraine. 2 The authors noted that patients with migraine had an increased risk of pain from other organs, ranging from 2.5 to 4.3 times the relative risk. 2 Many of these conditions share the triad of pain, depression, and sleep disturbances, 3,4 which coexist in a self-perpetuating cycle. In addition, chronic pain, migraine, and CDH have similar biomodulatory mechanisms. In all, pain may not be directly pro-

2 Table 1. Levels of Evidence Level I Level II-1 Level II-2 Level II-3 Level III Evidence obtained from 1 properly designed randomized controlled trial. Evidence obtained from well-designed controlled trials without randomization. Evidence obtained from well-designed cohort or case-control analytic studies, preferably from >1 center or research group. Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials may also be regarded as this type of evidence. Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. Data from Centre for Evidence-Based Medicine. 1 portional to tissue damage and is modulated by several influences, including an individual s genetic composition, prior learning experience, current physiologic status, personal appraisals, expectations, mood state, and sociocultural influences. Therefore, the treatment of CDH could be optimized when we understand the mechanisms of these modulatory processes and decipher the biologic substrates of their interaction with nociception. Chronic daily headache shares biomechanisms with some inflammatory visceral painful disorders, conditions of neuropathic pain, and many functional pain disorders. For example, neurogenic vasodilation, sterile inflammation, and peripheral sensitization are shared mechanisms with inflammatory pain disorders. Also, CDH and neuropathic pain may overlap in mechanisms of central sensitization, facilitation, and activation of certain key brain regions (such as the anterior cingulate, the somato-cortex, the supplementary cortex area, and the secondary somatosensory cortex). Lastly, central sensitization, reduced inhibition, and/or enhanced facilitation of sensory nociception may be shared between CDH and functional pain disorders, such as irritable bowel syndrome (IBS) and fibromyalgia. Discovering common markers (eg, biochemical, imaging, or electrophysiologic) of these chronic pain disorders and CDH may open new therapeutic horizons. The natural course of migraine in a small yet significant proportion of individuals is characterized by an evolution into daily or near daily headaches. 5 Under common migraine scenarios, a low threshold for neuronal excitation is reduced to firing potentials by inciting triggers, such as fall in estrogen levels at onset of menses or minor head injury. Restorative mechanisms elevate the neuronal threshold to non-firing, albeit low, levels. On the other hand, an evolution into chronic migraine (CM) may stem from cycles of hyperexcitability in genetically predisposed individuals, which lead to persistent neuronal firing from either exaggerated perpetuating mechanisms or from aberrant inhibitory and restorative systems. Thus, the brain enters a state of persistent nociceptive activation. Accordingly, treatment would be directed at modulatory pathways in the brain stem and the brain hemispheres that influence nociceptive signal trafficking. EVIDENCE-BASED TREATMENT PRINCIPLES General principles of treatment for headache begin with making the proper diagnosis, followed by the identification and management of precipitants, aggravating factors, and comorbidities. Use of acute therapies should be limited to avoid medication overuse, and regimens should include pharmacologic (ie, acute and preventive treatments) and nonpharmacologic interventions (including nutraceuticals). 6 Behavioral management of CDH hinges on established treatments in migraine, such as biofeedback, relaxation training, and cognitive-behavioral therapy. 7 Nonpharmacologic, nonbehavioral therapies that are being used include electrostimulation interventions, such as deep brain stimulation for chronic cluster headache and occipital or vagal nerve stimulation for CM; local injections procedures, such as botulinum toxin injections for CM, tension-type headache (TTH), and cervicogenic headache, and C-2 facet blocks for chronic cervicogenic headaches; and more invasive surgical approaches, such as closure of patent foramen ovale or atrial septal defect for CM. The benefit and risk-benefit ratios of such therapies can be established only by wellcontrolled clinical trials, which to date have not been completed; therefore, one cannot recommend any of these interventions based on current level of evidence. Most commonly, CDH is managed on an outpatient basis, although occasional in-hospital management may be necessary, especially in cases of medication overuse, in

3 which there may be concerns regarding compliance and/or withdrawal issues. 6 Medication overuse headache (MOH) is best managed with removal of the offending drug. Additionally, some authors advocate the use of a pulse steroid regimen based on clinical observation and a small randomized trial. 8 Treatments from several pharmacologic classes have been used in the management of CDH (Table 2), including antidepressants, ion channel blockers, N- methyl-d-aspartate (NMDA) antagonists, γ-aminobutyric acid (GABA) agonists, opioids, nonsteroidal anti-inflammatory drugs, and miscellaneous other medications, such as atypical antipsychotic drugs and antiepileptic drugs (AED). However, the efficacy evidence for CDH treatment is Level I only for amitriptyline, and Level II or III for all other treatments, including gabapentin, tizanidine, botulinum toxin, opioids, valproate, nefazodone, fluoxetine, and paroxetine. Studies for the latter drugs involved small numbers of patients and/or were based on treatment analyses rather than intent-to-treat analyses. Other difficulties encountered with the evidence from these trials included crossover periods of short durations, negative nonconvergent study results, or patient populations that also may have included individuals with migraine, TTH, or medication overuse. Furthermore, some studies were additive and included acute and preventive medications. Thus, it is difficult to make clear therapeutic recommendations based on these studies. Results of a recent Class I randomized controlled trial of topiramate for CDH have been positive and were published in abstract form. 9 Full publication is awaited with major interest. Finally, empiric approach to CDH treatment includes polypharmacy with 2 or more previously listed drugs. Although empiric and not evidence-based, such a strategy may be rationale and mechanisms driven. Only well-designed clinical trials will test this hypothesis. FURTHER THERAPEUTIC TARGETS BASED ON THE PATHOPHYSIOLOGY OF CDH Bolay and Moskowitz studied the mechanisms of pain modulation in chronic syndromes. 10 The authors noted that transmission of pain from the periphery to the cortex depends on integration and signal processing within the spinal cord, brain stem, and forebrain. Central sensitization, which is an element of chronic pain, may develop through peripheral mechanisms or as a consequence of altered physiology in the spinal cord or forebrain. Several molecular and biophysical mechanisms contribute to the phenomenon of sensitization and persistent pain, including upregulation of sensory neuron-specific sodium channels and vanilloid receptors, phenotypic switching of large myelinated axons, sprouting within the dorsal horn, and loss of inhibitory neurons because of apoptotic cell death. In addition, forebrain structures have been implicated in the pathophysiology of persistent pain. Drugs that act specifically on sensory neuron-specific sodium channels and NMDA antagonists may thus show promise as therapeutic regimens for CDH. Other potential targets include modulators of the glycine transport system and drugs that interact with various intracellular mechanisms downstream from the activation of receptors that are linked to sensitization (eg, protein kinase). In those conditions of CDH that are linked to migraine (eg, CM), it should be explored if persistent, cortical spreading depression is responsible for the evolution of an episodic disorder into daily head pain. If this is the case, cortical spreading depression inhibitors may have a role in treatment. These would include σ- receptor (σr1) agonists, non-amino-methyl proprionic acid/kainate glutamate receptor modulators, potassium current modulators, chlorine channel enhancers, and connexin hemichannel modulators (eg, fenamates). Table 2. Pharmacologic Classes of Medications Used in Treatment of CDH Antidepressants Tricyclic Newer NRIs and SNRIs SSRIs Ion channel blockers Gabapentin Lamotrigine Lidocaine NMDA antagonists Memantine GABA agonists Valproate Opioids Mixed Topiramate Tramadol NSAIDs/COX-2 Levetiracetam Melatonin agonists Atypical antipsychotics Tizanidine Zonisamide CDH = chronic daily headache; COX-2 = cyclooxygenase-2; GABA = γ- aminobutyric acid; NMDA = N-methyl-D-aspartic acid; NRI = norepinephrine reuptake inhibitor; NSAID = nonsteroidal anti-inflammatory inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.

4 Perhaps the most important target for treatment of CDH is nociceptive dysmodulation. Many pharmacologic agents fall into this category, including, but not limited to, serotonin-norepinephrine reuptake inhibitors, sodium channel blockers, glutamate blockers, novel and selective opioid receptor agonists, novel AEDs, 5-hydroxytryptamine (5-HT; serotonin) modulators, and drugs that target glycine, GABA, galanin, kinases, adenosine, vanilloid, orexin, cannabinoids, and the related anandamide transport systems. FUTURE STRATEGIES AND ROUGH SEAS AHEAD There will be some rough seas ahead as researchers attempt to develop therapeutic strategies for CDH. Clinical trials are time consuming, do not yield immediate answers, and their methodologies in CDH require further refinement. Also, animal models may not be predictive of clinical results, particularly in chronic pain disorders. Furthermore, federal funding priorities are not high for migraine and CDH, and private companies avoid investing into disease categories that are surrounded with ambiguity, for fear of protracted regulatory approval processes. Thus, success in the battle against this chronic and painful condition lies with further delineation of the mechanisms of CDH that can lead to a clear definition and a clear path toward therapeutic victory. CONCLUSIONS To date, the treatment of CDH remains largely empiric with a strong emphasis on prevention and avoidance of MOH. Identifying comorbid conditions is key to effective management strategies. Specifically, antidepressants and perhaps topiramate combined with nonpharmacologic intervention are the mainstay of treatment. Large-scale, well-controlled clinical trials of existing putative therapies and novel agents are needed soon to apply the principle of evidence-based practice to the management of CDH. DISCUSSION Dr Mondell: Thank you, Dr Ramadan, for sharing an excellent scientific review of where we are now and where we need to go in the future. In your discussion of treatment options, you mentioned inpatient versus outpatient treatment. I think we recognize, for a variety of reasons, the benefits of treating a patient in his or her own natural setting. Dr Ramadan: Absolutely. Dr Mondell: Obviously, when one brings a patient into the hospital with the associated special attention paid to the patient, and all hosts of factors even if one gives the patient nothing but intravenous fluids you often get benefit, because you removed someone from a situation to which he or she has to go back. Then, when the patient has to go back to the situation, the failure is there. Dr Robbins: In 1991, I published a series of 100 patients that were treated with dihydroergotamine, as outpatients or inpatients. We compared how they did inpatient versus outpatient as far as adverse events, and we found that the same patients had significantly less annoying side effects as outpatients than inpatients. They are more comfortable, and it is easier. Dr Ramadan: Plus they anticipate the symptoms. Dr Mondell: There are a variety of reasons, but I think the key is not to place the patient in that artificial environment. Any patient can go anywhere and do very well, and then the patient comes back to the referring practitioner in their regular environment, and they are back in trouble. Dr Medina: Since I moved gradually from headache to pain, my practice is approximately 50% chronic pain versus 50% headaches. Dr Welch: Isn t headache a form of chronic pain? Dr Medina: Yes. I have a better impression of this condition. And I would say the similarities of fibromyalgia and chronic headache are quite significant, but when you look at the whole spectrum of chronic pain, I think the hallmark is mechanics. Fibromyalgia is a mechanical pain. On the contrary, when we look at headache, it is a biochemical disorder. Of course, both have a common end. The common end is the mind. The brain itself, which can prepare to aid itself by different mechanisms, also can end up in pain. Dr Ramadan: I agree that you can see it in terms of a mechanical or biochemical disorder, but the argument for headache is that all of the mechanical or physical changes are actually occurring in places that you do not see. For example, if the dura and the dural vessels are the trigger, here is a mechanical process that is ongoing that we do not see as compared to IBS, for example, or point tenderness with fibromyalgia or painful walking with osteoarthritis. I am not saying that CM is a form of chronic pain. Migraine itself has

5 many elements that are very particular to it, thus when we start talking about chronic head pain, it is a different story. The treatment approaches to CM are dissimilar to the treatment of chronic pain and functional pain disorders. Dr Robbins: I think that the experts in 5-HT 3; receptor antagonists feel that these drugs cancel each other out in general. This is true regarding the peripheral and the central effects of mirtazapine, for instance. Mirtazapine does work at the σr1, but some scientists refer to this phenomenon as the σ enigma because we are not quite sure what σ really does. Dr Ramadan: But you well know that mirtazapine does not just work on the 5-HT 3 and the σr1 only. It has a pretty rich pharmacology. Dr Medina: I would like to say a couple of things from the clinical point of view. I think that in clinical practice it is very difficult to find a pure muscle tension headache. We carefully talk to the patient and ask the appropriate questions. Most of the time, we will find episodic headaches in between the continuous background headache. Secondly, I think that we are looking at all of these transmitters and different receptors. We are looking at the endpoint of certain changes that the patient develops in the brain. But when we are seeing the patients in our offices, and we are looking at other issues looking at the happiness of the patient, frustration at his or her childhood, what went on in the patient s life that makes him or her prone to this type of headache, and so on very often, medication does not do the whole trick. We need to somehow reach the patient, make contact with the patient, and take the patient by the hand to resolve their problems. That is really the day-after-day work of the clinician. Dr Mondell: My goal is to initially raise the patient s awareness of any and all complicating factors. Even with the most intelligent patient, insight may be limited. Accordingly, practitioners must promote patient awareness, and, then, go 1 step beyond to resolve these problematic issues. Dr Ramadan: Yes, I mean actually this is what I was referring to when I alluded to the environment and genetics contributing to the state of the maladaptive system or the persistent state of nociceptive activation; those are the kinds of interactions that we are talking about. Dr Robbins: Yes, regarding the interaction between environment and genetics. I always say it takes a village to raise a patient with severe pain, and we get other villagers involved whether it is psychotherapy or biofeedback. Why are some people susceptible to severe daily headaches? Perhaps we will discover this is genetically determined, possibly like research being done into depression or personality disorders, and the role of a particular environment causing the genetic characteristic to be expressed. REFERENCES 1. Centre for Evidence-Based Medicine. Levels of Evidence and Grades of Recommendation. Available at: Accessed December 12, Sternfeld B, Stang P, Sidney S. Relationship of migraine headaches to experience of chest pain and subsequent risk for myocardial infarction. Neurology. 1995;45: Ashburn MA, Staats PS. Management of chronic pain. Lancet. 1999;353: Lepine JP, Briley M. The epidemiology of pain in depression. Hum Psychopharmacol. 2004;19:S3-S7. 5. Eriksen MK, Thomsen LL, Russell MB. Prognosis of migraine with aura. Cephalalgia. 2004;24: Dodick DW. Clinical practice. Chronic daily headache. N Engl J Med. 2006;354: Campbell JK, Penzien DB, Wall EM. Evidence-based guidelines for migraine: behavioral and physical treatments (2000). Available at: practice/pdfs/gl0089.pdf. Accessed September 25, Pageler L, Savidou I, Limmroth V. Medication-overuse headache. Curr Pain Headache Rep. 2005;9: Silberstein S, Lipton R, Dodick D, et al. Topiramate in chronic migraine: a multicenter, randomized, placebo-controlled trial. Presented at: American Headache Society 48th Annual Scientific Meeting; June 23, 2006; Los Angeles, Calif. Abstract OR Bolay H, Moskowitz MA. Mechanisms of pain modulation in chronic syndromes. Neurology. 2002;59:S2-S7.