Does throbbing pain have a brain signature?

Pain sometimes has a throbbing, pulsating quality, particularly when it is severe and disabling. We recently challenged the presumption that this throbbing quality is a sensory experience of arterial pulsations, but were unable to offer an alternative explanation for its rhythmic character. Here we report a case study of a woman with a history of daily headache consistent with the diagnosis of chronic migraine, but whose throbbing quality persisted long after the resolution of the headache. This chronic, daily, and persistent throbbing sensation, in the absence of headache pain, prompted closer examination for its neurophysiological correlate. By simultaneously recording the subjective report of the throbbing rhythm, arterial pulse, and high-density electroencephalogram, we found that the subjective throbbing rate (48±1.7beats per minute) and heart rate (68±2beats per minute) were distinct, in accord with our previous observations that the 2 are unrelated. On spectral analysis of the electroencephalogram, we found that the overall amount of activity in the alpha range (8 to 12Hz), or alpha power, increased in association with greater throbbing intensity. In addition, we also found that the rhythmic oscillations of overall alpha power, the so-called modulations of alpha power, coincided with the timing of the throbbing rhythm, and that this synchrony, or coherence, was proportional to the subjective intensity of the throbbing quality. This index case will motivate further studies whose aim is to determine whether modulations of alpha power could more generally represent a neurophysiological correlate of the throbbing quality of pain.

Depression and risk of transformation of episodic to chronic migraine.

The aim of this study was to assess the role of depression as a predictor of new onset of chronic migraine (CM) among persons with episodic migraine (EM). The American Migraine Prevalence and Prevention (AMPP) study followed 24,000 persons with severe headache identified in 2004. Using random-effects logistic regression, we modeled the probability that persons with EM in 2005 or 2006 would develop CM in the subsequent year. Depression was assessed in two ways, using a validated questionnaire (PHQ-9 score ≥15) and based on self-reported medical diagnosis. Analyses were adjusted for multiple covariates including sociodemographics, body mass index, headache pain intensity, headache frequency, migraine symptom severity, cutaneous allodynia, acute medication overuse, anti-depressant use and anxiety. Of 6,657 participants with EM in 2005, 160 (2.4 %) developed CM in 2006. Of 6,852 participants with EM in 2006, 144 (2.2 %) developed CM in 2007. In fully adjusted models, PHQ-9 defined depression was a significant predictor of CM onset [odds ratio (OR) = 1.65, 95 % CI 1.12-2.45]. There was a depression-dose effect; relative to participants with no depression or mild depression, those with moderate (OR = 1.77, 95 % CI 1.25-2.52), moderately severe (OR = 2.35, 95 % CI 1.53-3.62), and severe depression (OR = 2.53, 95 % CI 1.52-4.21) were at increased risk for the onset of CM. Among persons with EM, depression was associated with an increased risk of CM after adjusting for sociodemographic variables and headache characteristics. Depression preceded the onset of CM and risk increased with depression severity suggesting a potentially causal role though reverse causality cannot be excluded.

Beyond neurovascular: migraine as a dysfunctional neurolimbic pain network.

No single model of migraine explains all of the known features of the disorder. Migraine has recently been characterized as an abnormality in pain-modulating circuits in the brainstem. The periaqueductal gray appears to have a critical role in migraine genesis and has been labeled the "migraine generator." The concept of a "pain matrix," rather than a specific locus of pain, is widely accepted in the pain literature and offers a new dimension to understanding migraine. Recent neuroimaging studies of migraineurs suggest altered functional connectivity between brainstem pain-modulating circuits and cortical (limbic) centers. Numerous clinical observations suggest that limbic influences play an important role in migraine expression. We propose a model of migraine as a dysfunction of a "neurolimbic" pain network. The influence between brainstem and cortical centers is bidirectional, reflecting the bidirectional interaction of pain and mood. Neurolimbic dysfunction may increase as migraine becomes more chronic or refractory. The neurolimbic model expands the model of migraine as a dysfunction of brainstem nuclei. A neurolimbic model may help bridge a gap in understanding the migraine attack, the interictal dysfunctions of episodic migraine, the progression to chronic migraine, and the common comorbidities with other disorders (such as fibromyalgia, irritable bowel syndrome, and mood and anxiety disorders), which may also be considered neurolimbic. A neurolimbic model of migraine may be a useful heuristic that would impact both clinical treatment and research agendas, as well as education of physicians and patients.

Psychiatric screening for headache patients.

There are numerous reasons to consider psychiatric screening for migraine patients, as well as valid objections to screening. Although psychiatric comorbidity has been consistently described for migraine patients, there is no evidence that treatment of psychiatric comorbidity influences headache outcomes. The author presents his perspectives on psychiatric screening, offers insight into currently available screening instruments, as well as some clinical pearls for screening.

The use of antidepressants for headache prophylaxis.

The focus of this review is on the efficacy of antidepressants as preventive treatments for migraine and chronic tension-type headache (TTH). Pharmacologic prophylaxis may be indicated for patients with frequent headaches, who respond insufficiently to acute therapies, or for whom medication overuse is a concern. The well-documented efficacy of the tricyclic antidepressant amitriptyline, both for migraine and chronic TTH, has been followed by widespread use of other antidepressants for headache prophylaxis. Although antidepressants in general share comparable efficacy for the treatment of depressive disorders, their efficacy as headache preventives varies widely. Evidence supporting use of the selective serotonin reuptake inhibitors as headache preventives is poor; their use should be reserved for treating comorbid depression in a patient who also has a headache disorder. Small randomized trials of venlafaxine indicate preliminary efficacy both for migraine and tension-type headache. Evidence for other antidepressants is lacking. Although antidepressants are often prescribed to headache patients under the assumption that the prescribed agent also will be effective in reducing symptoms of comorbid depression, the majority of studies have failed to find a strong relationship between depression symptoms and headache improvement. Suggestions for future research are discussed.

Clonazepam for refractory headache: three cases illustrative of benefit and risk.

Many patients with migraine are poorly responsive to conventional preventive therapies. Comorbid anxiety and depression may contribute to headache refractoriness, but studies of headache preventives have not typically addressed the patient with psychiatric comorbidity. The author has used clonazepam empirically to treat a subgroup of headache patients with associated anxiety, who were poorly responsive to conventional preventives. The use of a benzodiazepine as a headache preventive raises concerns regarding tolerance and addiction. The author presents 3 cases that illustrate different outcomes associated with this therapy, and suggests guidelines for its use.

Predictors of adherence to triptans: factors of sustained vs lapsed users.

OBJECTIVE: The present study was conducted to identify factors that predict adherence to triptans by migraine patients. BACKGROUND: Triptans have demonstrated efficacy for acute migraine yet many migraine sufferers discontinue their use. DESIGN AND METHODS: A survey study was conducted using 785 subjects (390 health maintenance organizations [HMO] and 395 non-HMO). Of those, 586 were sustained users of triptans (defined by at least 1 refill within the past year), and 199 were classified as lapsed users (ie, individuals who had 0 refills in the past year). Groups were compared on a variety of measures including a comprehensive Migraine Survey that included items related to efficacy and adverse events associated with the patient's current medication, as well as the Headache Impact Test (HIT)-6 and Migraine Disability Assessment Score (MIDAS) questionnaires. Data were analyzed with multivariate analysis of variance and stepwise multiple regression. RESULTS: Sustained users of triptans were significantly more satisfied with their medication, confident in the medication's ability to control headache, and reported control of migraine with fewer doses of medication. Sustained users also switched triptans products significantly less often than lapsed users, and reported greater benefit from triptan intervention in restoring normal daily functions, including improved cognitive ability, compared with lapsed users' ratings of their nontriptan medication. More lapsed users than sustained users reported adverse events associated with past triptan use. Results from multiple and logistic regression analyses correctly classified 95% of sustained users and identified the most significant predictors for sustained use as: satisfaction and belief in medication, reliability of response, effectiveness in rapidly restoring normal levels of productivity, and fewer doses of medication for resolving an attack. The HIT-6 and MIDAS distinguished between sustained and lapsed triptan users on days unable to do household work and missed family and social events. CONCLUSIONS: Predictors of adherence to triptans included satisfaction and confidence in triptans' ability to stop the migraine and associated symptoms and to return the individual to normal functioning. The findings suggest that lapsed users may not be receiving optimal treatment, and that if their past response to triptans was a consequence of inadequate education, they may benefit from additional education on proper use of triptans.

Anxiety disorders and migraine intractability and progression.

Comorbid psychopathology has been implicated as a risk factor for the chronification and progression of migraine. Although past research has focused principally on depression and migraine, recent research consistently has confirmed that a disproportionate number of migraineurs suffer from one or more comorbid anxiety disorders. Moreover, this research has implicated anxiety disorders as factors potentially associated with migraine intractability and progression; growing evidence suggests that anxiety disorders may be even more prognostically significant than depression. This article summarizes these recent developments, considers mechanisms underlying this comorbidity, discusses strategies for assessing and managing comorbid anxiety, and notes directions for future clinical and empiric work.

Headache chronification: screening and behavioral management of comorbid depressive and anxiety disorders.

A growing body of literature implicates comorbid psychopathology as a risk factor for chronification of headache. Despite their prevalence, comorbid psychiatric conditions are not routinely assessed among headache patients. Consequently, efforts to manage such conditions are not commonplace either. The present article briefly reviews a variety of strategies and measures for psychiatric screening among headache patients, focusing primarily on those that have been validated in medical settings, that can be administered quickly, and that involve minimal associated costs. We also describe basic strategies for behavioral management of comorbid depression and anxiety in headache patients.

An expert system for headache diagnosis: the Computerized Headache Assessment tool (CHAT).

BACKGROUND: Migraine is a highly prevalent chronic disorder associated with significant morbidity. Chronic daily headache syndromes, while less common, are less likely to be recognized, and impair quality of life to an even greater extent than episodic migraine. A variety of screening and diagnostic tools for migraine have been proposed and studied. Few investigators have developed and evaluated computerized programs to diagnose headache. OBJECTIVES: To develop and determine the accuracy and utility of a computerized headache assessment tool (CHAT). CHAT was designed to identify all of the major primary headache disorders, distinguish daily from episodic types, and recognize medication overuse. METHODS: CHAT was developed using an expert systems approach to headache diagnosis, with initial branch points determined by headache frequency and duration. Appropriate clinical criteria are presented relevant to brief and longer-lasting headaches. CHAT was posted on a web site using Microsoft active server pages and a SQL-server database server. A convenience sample of patients who presented to the adult urgent care department with headache, and patients in a family practice waiting room, were solicited to participate. Those who completed the on-line questionnaire were contacted for a diagnostic interview. RESULTS: One hundred thirty-five patients completed CHAT and 117 completed a diagnostic interview. CHAT correctly identified 35/35 (100%) patients with episodic migraine and 42/49 (85.7%) of patients with transformed migraine. CHAT also correctly identified 11/11 patients with chronic tension-type headache, 2/2 with episodic tension-type headache, and 1/1 with episodic cluster headache. Medication overuse was correctly recognized in 43/52 (82.7%). The most common misdiagnoses by CHAT were seen in patients with transformed migraine or new daily persistent headache. Fifty patients were referred to their primary care physician and 62 to the headache clinic. Of 29 patients referred to the PCP with a confirmed diagnosis of migraine, 25 made a follow-up appointment, the PCP diagnosed migraine in 19, and initiated migraine-specific therapy or prophylaxis in 17. CONCLUSION: The described expert system displays high diagnostic accuracy for migraine and other primary headache disorders, including daily headache syndromes and medication overuse. As part of a disease management program, CHAT led to patients receiving appropriate diagnoses and therapy. Limitations of the system include patient willingness to utilize the program, introducing such a process into the culture of medical care, and the difficult distinction of transformed migraine.

Results of screening with the brief headache screen compared with a modified IDMigraine.

BACKGROUND: Patients with chronic migraine and chronic daily headache syndromes have greater morbidity than patients with episodic migraine, and are less frequently diagnosed. A screening tool which identifies daily headache syndromes as well as migraine would promote more patients receiving appropriate treatment, including prophylaxis. METHODS: A post-hoc analysis of data obtained to evaluate the prevalence of somatic symptoms in primary care patients was conducted on a convenience sample of primary care patients who completed the Patient Health Questionnaire portion of the PRIME-MD (Primary Care Evaluation of Mental Disorders). Patients who endorsed the symptom of headache were asked to complete the Brief Headache Screen (BHS), a 4-item screening tool, supplemented by 3 clinical questions (nausea, light sensitivity, and noise sensitivity). The data obtained allowed a post-hoc comparison of the BHS with a modified version of the screening tool, IDMigraine(TM) (IDM(TM)). Diagnostic interviews were performed on patients whose diagnoses differed by the 2 screening methods, and on patients who screened positive for daily headache on BHS. RESULTS: Of the 1000 patients who completed the PRIME-MD, 302 (30.2%) indicated headache as a concern, and there were sufficient data for both the BHS and IDM(TM) for 259. There was substantial concordance between the 2 instruments with 82.6% agreement in identified migraine (95% confidence interval: 77.8%-87.4%). The BHS screened positive for migraine in an additional 15.1% of patients who were not identified by IDM(TM), whereas the IDM(TM) identified an additional 2.3% of patients. Of the 173 which both tools recognized as migraine, the BHS identified 42.8% as having a daily headache syndrome (chronic migraine: 23.1%; episodic migraine + chronic tension-type headache [CTTH]: 19.7%). BHS also identified 7 non-migraine patients as having CTTH alone. Diagnostic interviews confirmed that 6/18 (33%) of BHS+ but IDM-, and one of 2 (50%) patients BHS-/IDM+ met full criteria for migraine. Additionally, interviews confirmed the diagnoses of 85.4% of those patients who the BHS identified with daily headache and 67% of those who were identified as medication overuse headache. CONCLUSION: The BHS and a modified IDM(TM) are concordant in screening for migraine in 82.6% of a primary care population who endorsed the symptom of headache. However, the BHS screens effectively not only for migraine but also for chronic daily headache and medication overuse. A screening paradigm based on headache frequency and the frequency of medication use can rapidly and sensitively identify migraine, daily headache syndromes, and medication overuse. This paradigm may improve clinical care by identifying patients who merit preventive as well as acute therapy for migraine.

A review of screening tools for psychiatric comorbidity in headache patients.

Psychiatric comorbidity, especially depression and anxiety, has been well documented in patients with primary headache disorders. The presence of psychiatric comorbidity in headache patients is associated with decreased quality-of-life, poorer prognosis, chronification of disease, poorer response to treatment, and increased medical costs. Despite the prevalence and impact, screening for psychiatric disorders in headache patients is not systematically performed, either clinically or in research studies, and there are no guidelines to suggest which patients should be screened or in what manner. We review a variety of screening methods and instruments, focusing primarily on self-report measures and those available in the public domain. Informal verbal screening may be sufficient in a primary care setting, but should include screening for both anxiety and depression. Explicit screening for anxiety is important, as anxiety may have a more significant impact on headache than does depression and may occur in the absence of clinical depression. Formal screening with instruments that can identify a variety of psychiatric disorders is appropriate for patients with daily headache syndromes, patients who are refractory to usual care, and patients referred for specialty evaluation. Limitations of screening instruments include the influence of transdiagnostic symptoms and the need for confirmatory diagnostic interview. The following instruments appear most suitable for use in headache patients: for depression, the Patient Health Questionnaire Depression Module, the Beck Depression Inventory-II, or the Beck Depression Inventory-Primary Care; for anxiety, the Beck Anxiety Inventory and the Generalized Anxiety Disorder 7-item Scale; and for multidimensional psychiatric screening, the Patient Health Questionnaire or Primary Care Evaluation of Mental Disorders.

Antidepressants and antiepileptic drugs for chronic non-cancer pain.

The development of newer classes of antidepressants and second-generation antiepileptic drugs has created unprecedented opportunities for the treatment of chronic pain. These drugs modulate pain transmission by interacting with specific neurotransmitters and ion channels. The actions of antidepressants and antiepileptic drugs differ in neuropathic and non-neuropathic pain, and agents within each medication class have varying degrees of efficacy. Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, desipramine) and certain novel antidepressants (i.e., bupropion, venlafaxine, duloxetine) are effective in the treatment of neuropathic pain. The analgesic effect of these drugs is independent of their antidepressant effect and appears strongest in agents with mixed-receptor or predominantly noradrenergic activity, rather than serotoninergic activity. First-generation antiepileptic drugs (i.e., carbamazepine, phenytoin) and second-generation antiepileptic drugs (e.g., gabapentin, pregabalin) are effective in the treatment of neuropathic pain. The efficacy of antidepressants and antiepileptic drugs in the treatment of neuropathic pain is comparable; tolerability also is comparable, but safety and side effect profiles differ. Tricyclic antidepressants are the most cost-effective agents, but second-generation antiepileptic drugs are associated with fewer safety concerns in elderly patients. Tricyclic antidepressants have documented (although limited) efficacy in the treatment of fibromyalgia and chronic low back pain. Recent evidence suggests that duloxetine and pregabalin have modest efficacy in patients with fibromyalgia.

The patient with daily headaches.

The term "chronic daily headache" (CDH) describes a variety of headache types, of which chronic migraine is the most common. Daily headaches often are disabling and may be challenging to diagnose and treat. Medication overuse, or drug rebound headache, is the most treatable cause of refractory daily headache. A pathologic underlying cause should be considered in patients with recent-onset daily headache, a change from a previous headache pattern, or associated neurologic or systemic symptoms. Treatment of CDH focuses on reduction of headache triggers and use of preventive medication, most commonly anti-depressants, antiepileptic drugs, and beta blockers. Medication overuse must be treated with discontinuation of symptomatic medicines, a transitional therapy, and long-term prophylaxis. Anxiety and depression are common in patients with CDH and should be identified and treated. Although the condition is challenging, appropriate treatment of patients with CDH can bring about significant improvement in the patient's quality-of-life.