A Prospective Cohort Study of Outpatient Interdisciplinary Rehabilitation of Chronic Headache Patients.

OBJECTIVE: To evaluate the efficacy of an intensive outpatient program designed to improve functioning and reduce psychological impairment in chronic headache patients. BACKGROUND: Chronic headaches, occurring 15 or more days per month, for three or more months, may arise from multiple International Classification of Headache Disorders diagnoses: Chronic Migraine, Chronic Tension Type Headache, New Daily Persistent Headache, Chronic Post Traumatic Headaches, and Medication Overuse Headache. Several interdisciplinary programs that treat patients with chronic headaches have reported decreases in headache frequency. This study sought to evaluate the effect of a 3 week interdisciplinary treatment program for patients with chronic headache disorders on headache severity, functional status, and psychological impairment. METHODS: Subjects were 379 patients admitted to an outpatient chronic headache treatment program. Assessments of headache severity, psychological status, and functional impairment were completed by 371 (97.8%) of these at the time of admission. At discharge, 340 subjects (89.7%) provided assessment data, and 152 (40.1%) provided data at 1-year follow-up. RESULTS: Subjects' mean ratings on a 0-10 scale for their headache pain in the prior week declined, and these improvements were maintained at follow-up. (Estimated marginal means on a 0-10 scale for Average pain: admission 6.1, discharge 3.5, follow-up 3.3; for Least pain: admission 3.2; discharge 1.5; follow-up 1.3; for Worst pain: admission 8.2; discharge 6.4; follow-up 5.7), and similar results were found for current pain (admission 4.7; discharge 2.8; follow-up 2.4): Measures of functional impairment also improved following treatment, and these gains were maintained at 12 month follow up (Estimated marginal mean Headache Impact Test-6 score: admission 66.1, discharge 55.4, follow-up 51.9; Estimated marginal mean Pain Disability Index score: admission 36.2, discharge 14.1, follow-up 11.6). As measured by the Depression, Anxiety and Stress Scale, anxiety and reactivity to stress decreased following treatment, and remained improved at follow-up (Estimated marginal mean score for Anxiety: admission 8.7, discharge 5.2, follow-up 4.4; Estimated marginal mean score for stress: admission 14.9, discharge 7.2, follow-up 7.6). Depression decreased with treatment, but while 1-year follow-up depression scores remained significantly lower than at admission, they were also significantly higher than at discharge (Estimated marginal means: admission 13.3, discharge 4.1, follow-up 6.6). CONCLUSIONS: The study supports the efficacy of the treatment model. Limitations of the study and suggestions for future research are also discussed.

Long-Term Outcomes and Clinical Characteristics of Hypnic Headache Syndrome: 40 Patients Series From a Tertiary Referral Center.

OBJECTIVE: Hypnic headaches (HHs) are unique because of late life onset and characteristic periodic nocturnal awakening. We retrospectively identified 40 cases at a tertiary headache referral center over the course of 6 years and assessed response to conventional treatments. METHODS: This was a retrospective study in which patients were identified using primary and secondary ICD-9 diagnostic codes of HHs (339.81) from October 2008 until December 2014 using the International Classification of Headache Disorders II and III-beta criteria for diagnosis. Baseline characteristics were collected. Primary outcome was response to medications divided into 4 categories: complete response (headaches completely gone), moderate response (≥50% decrease in frequency), partial response (<50% decrease in frequency), no response. RESULTS: Forty (40) patients (80% females) were identified with HHs, and mean follow-up was 929 days (range 42-2555). Average age of headache onset was 62 years (range 44-86). Twenty (50%) patients had previous history of migraine, 5% had bilateral cranial autonomic features, and 40% underlying sleep abnormalities. The average duration per day and frequency per month of headaches were 186 minutes (range 30-720 minutes) and 21 days (range 5-30), respectively. Among 15 different medications tried, the best response was seen with lithium (7/10 [70%] complete response and 2/10 [20%] moderate response). With caffeine, there was a complete response in 6/21 (28%) and moderate response in 9/21 (43%) subjects. A telephone follow-up survey revealed that 5 patients in the bedtime caffeine group also benefited from taking a caffeinated drink at the time of awakening. CONCLUSIONS: HH is an infrequent primary headache disorder that can present with cranial autonomic features. It can persist for years in the elderly. Lithium appeared to be the most effective treatment option, followed by caffeine at bedtime. Caffeine ingestion on awakening with an HH also demonstrated benefit. Cervicogenic headaches in the elderly and presence of active migraine are major confounders in the diagnosis of HHs.

Cluster headache: potential options for medically refractory patients (when all else fails).

The most evidence exists for mixed anesthetic/steroid occipital nerve blocks (which are also useful in non-refractory patients), deep brain stimulation, sphenopalatine ganglion (SPG) blocks, SPG radiofrequency ablation, and SPG stimulation with the Autonomic Technologies, Inc (ATI) SPG Neurostimulator, the latter approved in the European Union and reimbursed in several countries.

QT prolongation, Torsade de Pointes, myocardial ischemia from coronary vasospasm, and headache medications. Part 2: review of headache medications, drug-drug interactions, QTc prolongation, and other arrhythmias.

Serotonin (5-hydroxytryptamine)(1B/1D) agonists can vasoconstrict coronary and cerebral arteries. Chest, jaw, and arm discomfort, so-called "triptan sensations," are often felt to be noncardiac. In Part 1 of this review, the relationship of triptans, coronary artery narrowing, and spasm was discussed, along with a case of a 53-year-old woman without cardiac risk factors who developed polymorphic ventricular tachycardia and cardiac ischemia with acquired corrected QT (QTc) interval prolongation following oral sumatriptan. In Part 2 of this review, headache medications, drug-drug interactions, QTc prolongation, and cardiac arrhythmias are appraised and discussed. Triptans, cardiac arrhythmias, and ischemia by prescribing information are summarized. The reader is provided tables on QTc prolongation by medication. The problem of QTc prolongation with a variety of headache medications at conventional doses, including triptans, serotonin reuptake inhibitors (selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors), other antidepressants, antihistamines, and antinauseants should lead to proactively obtaining electrocardiograms and more vigilant surveillance of headache patients. This may be the place to start in protecting patients from these cardiac adverse events.

QT prolongation, Torsade de Pointes, myocardial ischemia from coronary vasospasm, and headache medications. Part 1: review of serotonergic cardiac adverse events with a triptan case.

Serotonin (5-hydroxytryptamine)(1B/1D) agonists are vasoconstrictors that can affect coronary and cerebral arteries. Retrosternal chest, arm, and jaw pain following triptan use is generally attributed to "triptan sensations" and dismissed as noncardiac. However, triptans narrow normal coronary arteries and occasionally trigger vasospasm. They are contraindicated in atherosclerotic vascular disease. Part 1 of this review examines the relationship of medications used in migraine with the likelihood of causing vasospasm or vasoconstriction, and the triggering of cardiac arrhythmias. We report an illustrative case of polymorphic ventricular tachyarrhythmia, electrocardiogram changes consistent with cardiac ischemia, and acquired corrected QT interval lengthening following oral sumatriptan in a 53-year-old migraineur without risk factors for coronary artery disease (CAD). Extensive evaluation revealed insignificant single coronary vessel atherosclerosis and coronary artery vasospasm on ergonovine challenge. The report highlights the hidden risk that may underlie a "triptan sensation" and the possible association of the vasospastic features of Raynaud's phenomenon, migraine headaches, and coronary vasospasm. Part 1 discusses the risks for Torsade de Pointes, vasospasm, and ischemia, with a review and discussion of case reports of triptan-associated cardiovascular events in migraineurs with and without CAD risk factors or documented CAD; of the epidemiology and studies of triptans, vasospasm, and cardiovascular morbidity; and of the relationship of variant angina, migraine, and vasospastic disease. In the second part of this review, headache medications and their propensity for corrected QT prolongation will be summarized.

Headache following intracranial neuroendovascular procedures.

AIMS: Predicting who will develop post-procedure headache (PPH) following intracranial endovascular procedures (IEPs) would be clinically useful and potentially could assist in reducing the excessive diagnostic testing so often obtained in these patients. Although limited safety data exist, the use of triptans or dihydroergotamine (DHE) often raise concern when used with pre/post-coiled aneurysms. We sought to determine risk factors for PPH following IEP, to evaluate the utility of diagnostic testing in patients with post-coil acute headache (HA), and to record whether triptans and DHE have been used safely in this clinical setting. METHODS: We conducted a retrospective chart review of adult patients undergoing IEPs. Bivariate analyses were conducted to compare patients who did and did not develop PPH. RESULTS: We reviewed records pertaining to 372 patients, of whom 263 underwent intracranial coil embolizations, 21 acrylic glue embolizations, and 88 stent placements. PPH occurred in 72% of coil patients, 33% of glue patients, and 14% of stent patients. Significant risk factors for post-coil HA were female gender, any pre-coil HA history, smoking, and anxiety/depression. A pre-stent history of HA exceeding 1 year's duration, and smoking were risk factors for post-stent HA. A pre-glue history of HA exceeding 1 year was the only risk factor for post-glue HA. In the small subgroup available for study, treatment with triptans or DHE was not associated with adverse events in pre/post-coiled aneurysms. Diagnostic testing was low yield. CONCLUSIONS: Occurrence of PPH was common after IEPs and especially so with coiling and in women, smokers, and those with anxiety/depression, and was often of longer duration than allowed by current International Classification of Headache Disorders-II criteria. The yield of diagnostic testing was low, and in a small subgroup treatment with triptans or DHE did not cause adverse events in pre/post-coiled aneurysms. Prospective studies are needed to confirm these findings.

Iron deposition in pain-regulatory nuclei in episodic migraine and chronic daily headache by MRI.

BACKGROUND: Progression of migraine toward a more disabling chronic form of at least 15 days/month is linked with frequency of attacks. Magnetic resonance imaging (MRI) findings of iron accumulation in the brain, especially in periaqueductal gray and red nucleus, have been correlated with both duration of illness and frequency of attacks. METHODS: This study therefore evaluated iron deposition as measured with MRI in basal ganglia and pain regulatory nuclei in neurologically healthy control volunteers and in patients with various migraine subtypes: episodic migraine (n = 10) with (n = 4) or without aura (n = 6), and chronic daily headache (n = 11), including medication overuse headache (MOH, n = 8), chronic tension-type headache (n = 1), and primary chronic migraine (n = 2). The goal was to assess differences in iron deposition among migraine subtypes and controls in the hopes of linking the by-products of frequent attacks or long duration of illness with these changes. RESULTS: The study sought to evaluate the tradeoff between sensitivity and specificity in T2 imaging of patients with migraine, and found that only T2 imaging in the globus pallidus was able to distinguish between episodic and chronic migraine, suggesting that this technique may be the most appropriate to assess migraine frequency. Patients with MOH did not demonstrate T2' shortening. CONCLUSIONS: Because iron accumulation should cause shortening of both T2 and T2', although the lack of significance in observed T2' difference could be due to increased variance in T2' the measurement, these results suggest that a mechanism other than increased iron deposition may play a role in the genesis or pathophysiology of MOH.

Dihydroergotamine and its use in migraine with posterior fossa symptoms.

BACKGROUND: Dihydroergotamine (DHE) has been used for decades to treat migraine, but is currently contraindicated in patients with hemiplegic migraine and basilar-type migraine (BTM). OBJECTIVE: To assess the safety of DHE in patients with symptoms of BTM that do not meet criteria for BTM. METHODS: Retrospective analysis of patients admitted to an outpatient infusion room at a tertiary care center caring for patients with headache disorders. Incidence and types of adverse events as well as pain levels were reviewed and analyzed. Pain was assessed via the visual analog scale (VAS). RESULTS: Fifty consecutive patient records were reviewed. Mean age was 38.42. All patients met International Classification of Headache Disorders-II (ICHD-II) criteria for migraine and reported 1 posterior fossa symptom as defined by the ICHD-II criteria for BTM. Patients did not necessarily have a posterior fossa symptom in the attack treated. Eighteen percent (9/50) patients had adverse events, and only 3 of these halted DHE infusion. No patients had neurologic or cardiologic events. The mean decrease in pain was 3 points on the VAS (P <.0001). Sixty-two percent of patients achieved complete relief of headache with co-administration of DHE and other medications. CONCLUSION: Dihydroergotamine showed no serious adverse events in patients with 1 posterior fossa symptom and migraine. Larger, adequately powered, controlled, prospective trials are indicated to assess safety of DHE in BTM.

A practice guide for continuous opioid therapy for refractory daily headache: patient selection, physician requirements, and treatment monitoring.

OBJECTIVES: To provide a guide to the use and limitations of continuous opioid therapy (COT, or daily scheduled opioids) for refractory daily headache, based on the best available evidence and expert clinical experience. BACKGROUND: There has been a dramatic increase in opioid administration over the past 25 years, with limited evidence of efficacy for either pain reduction or increased function, and increasing evidence of adverse effects, including headache chronification. To date, there has been no consensus on headache-specific guidelines for selecting patients for COT, physician requirements, and treatment monitoring. METHODS: A multidisciplinary committee of physicians and allied health professionals with extensive experience and expertise in the administration of opioids to headache patients, undertook a review of the available evidence from the research and clinical literature (using the PubMed database for articles through December 2009) to develop headache-specific treatment recommendations. This guide reflects the opinions of its authors and is not an official document of the American Headache Society. RESULTS: The guide identifies factors that would qualify or disqualify the use of COT, including, determination of intractability prior to initiating COT, requisite experience of the prescriber, and requirements for a formal monitoring system to assess appropriate use, safety, efficacy, and functional impact. An appendix reviews the available evidence for efficacy of COT in chronic headache and noncancer pain, paradoxical effects (opioid-induced hyperalgesia, medication overuse headache, opioid-related reduction in triptan and nonsteroidal anti-inflammatory drug efficacy), other adverse effects (nausea and constipation, insomnia and sleep apnea, respiratory depression and sudden cardiac death, reductions in sex hormones, issues during pregnancy, neurocognitive functioning), and issues related to comorbid psychiatric disorders. CONCLUSIONS: Only a select and very limited group (estimate of 10-20%) of refractory headache patients who meet criteria for COT respond with convincing headache reduction and functional improvement over the long-term. Conservative and empirically based guidelines will help identify those patients for whom a COT trial may be appropriate, while protecting their welfare and safety.

Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine.

Calcitonin gene-related peptide (CGRP) is linked to migraine and other primary headache disorders. It is found in every location described in migraine genesis and processing, including meninges, trigeminal ganglion, trigeminocervical complex, brainstem nuclei, and cortex. It is released in animal models following stimulation of the CNS similar to that seen in migraine, and triptans inhibit this release. Injection of CGRP into migraineurs results in delayed headache similar to migraine. Elevation of CGRP occurs during migraine, resolving following migraine-specific treatment. Finally, and most importantly, CGRP receptor antagonists terminate migraine with efficacy similar to triptans. Both intravenous olcegepant (BIBN 4096 BS) and oral telcagepant (MK-0974) have been effective, safe, and well tolerated in phase I and II studies. Telcagepant is currently in phase III trials, and preliminary results are favorable. The potential for a migraine-specific medication without vasoconstrictive or vascular side effects is enormous. CGRP receptor blockade may also have applications in other pathologic and pain syndromes.

New developments in the pharmacotherapy of tension-type headaches.

The first International Headache Society classification defined tension-type headaches (TTHs) by itemising those characteristics of migraines TTHs did not possess [1]. As a result, TTHs, both episodic and chronic, remain the most nonspecific of all the commonly observed primary headaches. Until recently, there has been little impetus on the part of the pharmaceutical industry to investigate TTHs; many of the potentially useful drugs are now generic and unprofitable. In addition, few investigators have pursued the study of TTHs in lieu of its more glamorous neighbour, migraine. As a result, there are few well-designed studies on the pharmacotherapy of TTHs. The few studies that exist support the use of age-old standard drug classes, the tricyclic antidepressants and the NSAIDs. New research is now emerging that points to the potential utility of botulinum toxin type A, NMDA-receptor antagonists including Mg(2+) and nitric oxide synthase inhibitors. More scientifically rigorous clinical studies are needed.

Testosterone replacement therapy for treatment refractory cluster headache.

OBJECTIVES: To describe the clinical characteristics and laboratory findings of cluster headache patients whose headaches responded to testosterone replacement therapy. BACKGROUND: Current evidence points to hypothalamic dysfunction, with increased metabolic hyperactivity in the region of the suprachiasmatic nucleus, as being important in the genesis of cluster headaches. This is clinically borne out in the circadian and diurnal behavior of these headaches. For years it has been recognized that male cluster headache patients appear overmasculinized. Recent neuroendocrine and sleep studies now point to an association between gonadotropin and corticotropin levels and hypothalamically entrained pineal secretion of melatonin. RESULTS: Seven male and 2 female patients, seen between July 2004 and February 2005, and between the ages of 32 and 56, are reported with histories of treatment resistant cluster headaches accompanied by borderline low or low serum testosterone levels. The patients failed to respond to individually tailored medical regimens, including melatonin doses of 12 mg a day or higher, high flow oxygen, maximally tolerated verapamil, antiepileptic agents, and parenteral serotonin agonists. Seven of the 9 patients met 2004 International Classification for the Diagnosis of Headache criteria for chronic cluster headaches; the other 2 patients had episodic cluster headaches of several months duration. After neurological and physical examination all patients had laboratory investigations including fasting lipid panel, PSA (where indicated), LH, FSH, and testosterone levels (both free and total). All 9 patients demonstrated either abnormally low or low, normal testosterone levels. After supplementation with either pure testosterone in 5 of 7 male patients or combination testosterone/estrogen therapy in both female patients, the patients achieved cluster headache freedom for the first 24 hours. Four male chronic cluster patients, all with abnormally low testosterone levels, achieved remission. CONCLUSIONS: Abnormal testosterone levels in patients with episodic or chronic cluster headaches refractory to maximal medical management may predict a therapeutic response to testosterone replacement therapy. In the described cases, diurnal variation of attacks, a seasonal cluster pattern, and previous, transient responsiveness to melatonin therapy pointed to the hypothalamus as the site of neurological dysfunction. Prospective studies pairing hormone levels and polysomnographic data are needed.

Traditional and evidence-based acupuncture in headache management: theory, mechanism, and practice.

Acupuncture, traditional Chinese needle therapy, has become widely used for the relief of headache. The history of the practice of acupuncture in the United States and the theoretical framework for acupuncture in Chinese medicine are reviewed. The basic scientific background and clinical application of acupuncture in the headache management are discussed.

Pharmacotherapy of tension-type headaches.

The first International Headache Society classification defined tension-type headaches by itemizing characteristics of migraines that tension-type headaches did not possess. As a result, tension-type headaches (episodic and chronic) remain the most nonspecific of all the commonly observed primary headaches. Until recently, there has been little impetus on the part of the pharmaceutical industry to investigate tension-type headaches; many of the potentially useful drugs are now generic and unprofitable. In addition, few investigators have pursued the study of tension-type headache because of its more glamorous neighbor, migraine. As a result, there are few well-designed studies on the pharmacotherapy of tension-type headaches. The few studies that exist support the use of age-old standard drug classes, the tricyclic antidepressants and the nonsteroidal anti-inflammatory drugs. New research is emerging that points to the potential use of botulinum toxin and nitric synthase inhibitors. More scientifically rigorous clinical studies are needed.

Treatment of primary headache disorders with intravenous valproate: initial outpatient experience.

OBJECTIVES: To evaluate the effectiveness of intravenous valproate in managing moderate to severe headaches. BACKGROUND: Despite major strides in the understanding of primary headache disorders, there have been few additions to acute headache management other than introduction of the triptans. An intravenous antiepileptic preparation, sodium valproate, has been reported to be effective in the management of status epilepticus and acute headache. METHODS: Between March 13, 2000 and October 11, 2000, we prospectively treated, in a nonrandomized and open-label study, every patient with a moderate to severe headache (4 or greater on a visual analog scale of head pain from 1 to 10) who wanted treatment with intravenous valproate. Using a verbal visual analog scale for pain (0 = no headache and 10 = most severe headache), we measured head pain before treatment and at time of discharge. The treating nurse monitored vital signs and side effects. A positive response was defined as a 50% or greater reduction at discharge in baseline pain. Information was collected regarding patient demographics, type of headache (according to criteria of the International Headache Society and that recently proposed for chronic headache), observation time in the treatment suite, cumulative dose of valproate, and use of concurrent medications. Univariable and multivariable correlates of response to treatment were identified using logistic regression analysis. RESULTS: One hundred thirty treatments were given to 89 women and 17 men, aged 17 to 76 years; 92 patients received only one treatment. Valproate doses ranged between 300 and 1200 mg. Thirty-three patients (31%) presented with episodic migraine, with or without aura; 45 patients (42%) presented with chronic daily headache with a history of episodic migraine, with or without aura (transformed migraine); 22 (21%) with unclassifiable chronic headache; 2 (2%) with episodic cluster headache; and 4 (4%) with chronic tension-type headache. For first treatments only, 61 patients (57.5%) responded to treatment, whereas for all treatments, 82 patients (63.1%) responded. Age and gender did not affect likelihood of response, whereas increasing duration of treatment (P=.003) and the additional use of analgesics (P=.021) were each negatively associated with response. Among headache types, unclassifiable chronic headache segregated from all other classified headaches in terms of poor response. Aside from rare dizziness (n = 2) and one spell interpreted as a pseudoseizure, no side effects were noted. CONCLUSIONS: Intravenous valproate is a safe, rapidly effective, abortive headache agent. It appears to be an effective analgesic for identifiable primary headaches, especially episodic headache, and less effective for unclassifiable chronic headache. Randomized, double-blind, controlled studies are warranted.