Headache Currents
HEADACHE CURRENTS—CLINICAL REVIEW
Behavioral and Mind/Body Interventions in Headache: Unanswered Questions and Future Research Directions Rebecca E. Wells, MD, MPH; Todd A. Smitherman, PhD; Elizabeth K. Seng, PhD; Timothy T. Houle, PhD; Elizabeth W. Loder, MD, MPH Background.—Many unanswered questions remain regarding behavioral and mind/body interventions in the treatment of primary headache disorders in adults. Methods.—We reviewed the literature to ascertain the most pressing unanswered research questions regarding behavioral and mind/body interventions for headache. Results.—We identify the most pressing unanswered research questions in this field, describe ideal and practical ways to address these questions, and outline steps needed to facilitate these research efforts. We discuss proposed mechanisms of action of behavioral and mind/body interventions and outline goals for future research in this field. Conclusions.—Although challenges arise from the complex nature of the interventions under study, research that adheres to published study design and reporting standards and focuses closely on answering key questions is most likely to lead to progress in achieving these goals. Key words: alternative medicine, headache, mind/body Abbreviations: CAM complementary and alternative medicine, TTH tension-type headache
Non-pharmacological interventions have long been perceived by patients and providers as beneficial for headaches, and strong evidence supports the useful effects of certain nonpharmacological interventions for migraine and tension-type headache (TTH). The US Headache Consortium Guidelines for prevention of migraine identified Grade A evidence to support several specific non-pharmacological interventions including relaxation training, thermal biofeedback combined with relaxation training, electromyographic (EMG) biofeedback, and cognitive behavioral therapy (CBT)1 (labeled as “evidence-based behavioral interventions” for this paper). The combination of preventive drug therapy and evidence-based behavioral therapies was identified as having Grade B evidence for producing added clinical benefit, although data published since these guidelines From the Department of Neurology, Wake Forest School of Medicine, Winston-Salem, NC, USA (R.E. Wells); Department of Psychology, University of Mississippi, Oxford, MS, USA (T.A. Smitherman); Ferkauf Graduate School of Psychology, Yeshiva University, New York, NY, USA; Albert Einstein College of Medicine of Yeshiva University, Bronx, NY (E.K. Seng); Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA (T.T. Houle); Department of Neurology, Brigham and Women’s Faulkner Hospital, Boston, MA, USA (E. Loder). Address all correspondence to R.E. Wells, MD, MPH, Department of Neurology, Medical Center Blvd., Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Accepted for publication March 2, 2014. ............. Headache © 2014 American Headache Society
were issued is likely to change the evidence to Grade A when the guidelines are updated.2,3 In addition to evidence-based behavioral interventions, a recent study found that more than 50% of US adults with migraines/severe headaches reported having used complementary and alternative medicine (CAM) techniques, most commonly “mind/body therapies” such as meditation and yoga.4 Thus, although data most strongly support evidence-based behavioral interventions, it seems that mind/body interventions are used frequently by adults with primary headache disorders. Despite their use, many unanswered questions remain regarding these non-pharmacological interventions in the treatment of primary headache disorders in adults. In 2005, Headache published an entire series of peer-reviewed papers (many cited in this review) that provided in-depth analysis of numerous methodological issues and suggested solutions in behavioral headache research. Given the increased utilization of mind/body therapies and potentially similar underlying mechanisms between evidencebased behavioral interventions and mind/body therapies, the goal of this paper is to identify the most pressing unanswered research questions in the field overall, describe ideal and practical ways to address these questions, and outline steps needed to facilitate these research efforts. We limit this discussion to the use of evidence-based behavioral interventions and mind/body interventions to treat the primary headache disorders of migraine and TTH in adults, as these headaches disorders are most prevalent in the population and the ones to which non-pharmacological interventions are most commonly applied. Other interventions that are sometimes referred to as non-pharmacological interventions, such as acupuncture or the use of herbal or dietary supplements, are beyond the scope of this paper. We conceptualize the differences between evidence-based behavioral interventions and mind/body interventions for headache across two domains, evidence-based and patient utilization. Historically, most non-pharmacological interventions used and studied in the treatment of headache have been behavioral or cognitive behavioral interventions that focus on teaching specific behaviors or skills to manage modifiable factors or behavioral patterns in a person’s life (eg, stress, sympathetic arousal, maladaptive thought processes) that may aggravate or trigger headaches. Evidence-based behavioral interventions include relaxation training (ie, deep breathing, progressive muscle relaxation training, and imagery); biofeedback training (thermal for migraine or EMG for TTH); and CBT (sometimes termed “stress management training”). These interventions have such ............. Conflict of Interest: None.
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strong evidence of efficacy for headaches that they are not considered “alternative” approaches but instead standard nonpharmacological treatments for headaches.5 However, many adults with headaches report using a broader array of “mind/ body” therapies that share a common intention “to enhance the mind’s capacity to affect bodily functions and symptoms.”6 These mind/body therapies focus on the interplay between brain, body, mind, and behavior, with specific attention to interactions among emotional, mental, social, and spiritual factors and how these influence health. These mind/body interventions sometimes incorporate components of evidence-based behavioral interventions (eg, deep breathing, guided imagery) and interventions with more limited evidence of efficacy in headache, such as meditation, yoga, and tai chi.7-9 Access to headache-specific care is problematic for both types of these non-pharmacological interventions. Despite the research evidence supporting the benefits of evidence-based behavioral interventions for headaches, access to behavioral providers trained specifically to treat headache can be limited. Utilization rates reported by patients tend to be relatively low (eg, less than 1% of the general US population with severe headaches/ migraines report using biofeedback), although techniques that may not require a provider are being used more frequently (24% of the same population report using deep breathing exercises).10 Further, many headache patients report using mind/body interventions, as 17% of the general US population with severe headaches/migraines report doing meditation, and 9% report doing yoga. However, these interventions are commonly used for overall well-being rather than to target headaches specifically. Despite the varying levels of evidence to support their use and the varying levels of patient utilization, many key research questions underlying both evidence-based behavioral and mind/body interventions need to be answered in order to move this field forward. Key Unanswered Research Questions Table 1 summarizes key unanswered research questions about evidence-based behavioral and mind/body practices for adults with common primary headache disorders. The questions are divided into two main areas, content-based research questions, and questions about the development and dissemination of interventions. Perhaps the most pressing content-based-research question is: “Which interventions are most helpful for headache patients?” (Question #1, Q1) Although research studies have demonstrated efficacy of evidence-based behavioral interventions for migraine and TTH,1,2,11-15 there are comparatively fewer effectiveness studies that have evaluated treatment response in more externally valid clinical practice settings.16 Nash and colleagues recommend a three-phase process to further answer this important question, which sequentially involves pilot testing, then efficacy testing, and finally effectiveness testing.16 As roughly one third of non-pharmacological studies compare an intervention to no treatment or to a wait-list control,13,17 future studies
Headache Currents
Table 1.—Unanswered Questions About Behavioral and Mind/ Body Practices for Adults With Primary Headaches Content-Based Research Questions 1. Which interventions are most helpful for headache patients? 1A. Which types of patients and headaches are most responsive to these interventions? 2. What is the optimal “dose” of these interventions? (eg, frequency, duration, length of treatment) 2A. To what extent do patients need to be taught these interventions by a professional, or can they learn them on their own? 3. What are the putative mechanism(s) of action? 3A. What role do these interventions have on headache threshold(s)? 4. What are the side effects and adverse events associated with treatment? Development and Dissemination of Interventions 5. How can standardized protocols be made more accessible to researchers and practitioners? 6. How can these interventions be better integrated into medical practice settings for providers? 7. How can matching of appropriate treatment to patient responders be facilitated? 8. How can these practices be made more accessible and practical for patients?
with comparisons to alternative active treatments are needed,18 allowing different non-pharmacological interventions to be compared against each other and providing insights into potential mechanisms of action. More specifically, we need to understand which techniques are most effective for specific types of patients and headache disorders (ie, moderator variables) (Q1A),19 as well as the treatment components that account for the response (ie, mediator variables).20 Many evidence-based behavioral and mind/body interventions require a significant commitment to out-of-session time from patients, and identification of the optimal “dose” of treatment thus is essential (Q2). In order to recommend these interventions for clinical use, we need to better understand how frequently these interventions should be practiced, for how long, and over what period of time in order to maximize clinical benefit and minimize patient burden. For example, are classes lasting 2 hours once a week more or less beneficial than a daily 15-min practice session? Once a patient learns a technique, does it need to be continually practiced to maintain benefit and if so, for how often and how long? Numerous trials of evidence-based behavioral interventions have demonstrated benefits that last for months or even up to 5-7 years after the intervention ends.2,11,14,21-23 It is unclear, however, whether the persistent benefit results from the initial teaching or continued regular practice. Many of the mind/ body intervention trials have not included long follow-up periods,7,8 and this remains an important issue for future research on these interventions.
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Many trials have demonstrated that a minimal-therapistcontact intervention can provide similar clinical benefit compared to a more intensive clinic-based intensive treatment.24-31 Although additional studies are needed to better characterize the efficacy of limited contact mind/body interventions in headache, these approaches hold promise as ways to increase adherence, reduce costs, and improve treatment accessibility in resourcelimited or remote areas. Since most evidence-based behavioral and mind/body practices require a significant investment of time by the patient, it is crucial to understand what level of interaction with a trained professional is required for successful acquisition of these skills, ranging from provision of online or written materials, to brief skills training in a medical office, to a more in-depth course of treatment with a behavioral health-care provider or mind/body instructor. (Q2A). There is some evidence of modest benefit from treatment groups led by trained nonprofessionals.32,33 The shortage of behavioral headache treatment providers within medical settings has likely contributed to the underuse of evidence-based behavioral interventions, and training a larger number of behavioral providers remains a significant need. The physiological or psychological mechanisms that underlie the effects of evidence-based behavioral and mind/body practices are not fully understood (Q3). Many are multi-component interventions, and thus more than one mechanism may be responsible for therapeutic effects; possible synergistic effects among treatment components might explain particularly longlasting effects. Better understanding of the mechanisms of action of these interventions would allow refinement and targeting of treatments to improve clinical benefits, increase patient/provider interest and adherence, and enhance scientific credibility among those who view their benefits as resulting primarily from nonspecific processes.34 For example, it would be helpful to understand how these interventions affect headache threshold(s) (Q3A) in order to target interventions and understand mechanisms of action. Specifically, such techniques may increase the distance between an individual’s headache baseline and headache threshold by (A) lowering the individual’s baseline level of brain excitability; (B) raising an individual’s headache threshold, or; (C) both (Figure). The extensive research on evidence-based behavioral interventions and growing research on mind/body practices indicates that these treatments are generally acceptable, safe, and without significant side effects.2,7,8,11-13,35 However, anecdotal reports of musculoskeletal injuries with certain types of yoga practices exist in the media,36 and rare case reports of meditation-induced psychosis have been reported,37 although recent studies have demonstrated the benefit of mindfulness-based interventions even in adults with psychosis.38-40 Better reporting and understanding of the potential harms, patient acceptability, and adverse events associated with these practices are additional research priorities and will facilitate comparisons of these treatments with conventional medication treatments (Q4).
Headache Currents
}
Headache Threshold
}
Individual Baseline
Lowered Baseline
Raised Threshold
B
A Figure.—Possible mechanisms of action of behavioral and mind/body treatments for headache. Behavioral and mind/body treatments may exert their effects by increasing the distance between an individual’s baseline and their headache threshold by (A) lowering the individual’s baseline level of brain excitability; (B) raising an individual’s headache threshold; or (C) both (not pictured). (Reproduced with permission from the journal Headache.65)
Another priority is the development, testing, publication, and dissemination of standardized intervention protocols that are feasible for use in clinical practice (Q5).41 Treatment manuals are not routinely published, presenting a barrier for widespread dissemination. Investigators and practitioners must continue to work toward more consistency in treatment delivery methods across studies to allow for cross-study comparisons and synthesis for systematic reviews or meta-analyses. Despite extensive research in this field, a lack of published treatment manuals perhaps has hampered their dissemination and uptake in clinical practice. Thus, publishing and openly distributing standardized treatment manuals for behavioral and mind/body interventions that can be easily applied in usual clinical settings is a significant need (Q5). Research papers describing the effects of these interventions should provide, either in the paper’s methods section or as an online appendix, sufficient detail about the treatment protocols used so that they can be replicated in further research. Additionally, determining how these practices can be better integrated into clinical practice so they are easily accessible to providers for routine headache care is crucial (Q6). Training healthcare providers to competently provide these services would likely play an important role in this process. Being able to implement clinically effective behavioral interventions outside of the research context and finding the best ways to standardize dissemination to practitioners is a burgeoning area of research that needs to be further addressed in the field of headache.16,42-45 A number of barriers can prevent patients from accessing and using evidence-based behavioral and mind/body treatments for headache.46 As previously described, these interventions often require a significant commitment of time, energy, and in some cases financial resources, from patients. It is imperative to identify
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Table 2.—Proposed Mechanisms of Change for Behavioral and Mind/Body Headache Treatments* A. Stress reduction Decreased stress hormones (eg, cortisol) Altered autonomic arousal B. Changes in relevant psychological constructs Improved coping skills Increased self-efficacy Decreased external locus of control Decreased pain catastrophizing Decreased depression and anxiety C. Effects on other behaviors Improved sleep Improved diet, exercise, and other healthy behaviors D. Change in pain processing Change in neural pain processing Activation of natural endogenous analgesic processes E. Placebo Altered expectations “Common factors” (eg, ritual, empathy, alliance, etc.)
*See text for references.
subgroups of patients most likely to respond to these treatments in order to facilitate treatment matching and to avoid use in those unlikely to benefit (Q7). Research aimed at identifying and reducing treatment barriers is also critical to ensure that effective treatments will be accessible and widely used (Q8). Potential Mechanisms of Change of Behavioral and Mind/ Body Headache Treatments Although the mechanisms that mediate the benefits of evidencebased behavioral and mind/body interventions in adults with headaches are not fully understood, many hypotheses have been posited (Table 2). Psychological stress is among the most frequently endorsed triggers of headache,47 and interventions that reduce stress or improve patients’ abilities to cope with stress are integral in behavioral headache management. While stress reduction is one of the mechanisms most commonly evoked to explain the beneficial effects of evidence-based behavioral and mind/ body interventions, how these practices lead to stress reduction is unclear and may vary by intervention. Stress is thought to impact headache by (1) directly impacting pain perception; (2) fostering activation and sensitization of nociceptors over time; and (3) worsening headache-related disability and quality of life. The headache experience itself serves as a stressor that compromises well-being.48 Evidence-based behavioral and mind/body practices may alter central pain processing. A study assessing experimental pain during meditation showed that meditation decreased pain unpleasantness by 57% and pain intensity by 40%.49 Neuroimaging showed that these reductions were associated with increased activity in the anterior cingulate cortex and anterior
Headache Currents insula (ie, areas involved in the cognitive regulation of nociception) and with thalamic deactivation.49 Meditation and other non-pharmacological practices may activate natural endogenous analgesic processes, or observed results could be attributable to distraction or altered expectations.50 Yet the exact physiological mechanisms of stress-reducing interventions on headache are not clearly elucidated. If stress-reducing interventions are effective because they alter autonomic reactivity, it is important to determine whether they alter autonomic responses to individual stressful events or the patient’s baseline autonomic levels. Non-pharmacological interventions also may exert beneficial effects by affecting psychological constructs. An increased sense of headache “self-efficacy,” or confidence in one’s ability to persist with behavioral change efforts that one believes will manage headache symptoms, and a reduced external “locus of control,” or belief that nothing can exert control over the onset and course of headache, are potent predictors of behavioral treatment outcomes. Foundational research on evidence-based behavioral interventions decades ago identified increased self-efficacy as the key mediator of successful EMG biofeedback for TTH, regardless of whether the patient was taught to increase or decrease muscle tension.51 More recent research has confirmed that both self-efficacy and locus of control are important factors for the success of evidence-based behavioral headache treatments.52 Evidence-based behavioral and mind/body interventions may be useful also because they improve psychiatric conditions commonly comorbid with headache, such as anxiety and depression, and are often associated with a poorer prognosis.53-55 Improvements in these affective conditions, even if present at a level not warranting a clinical diagnosis, in turn may improve the ability to cope with pain and enhance adherence to treatment recommendations. Even adults without formal psychiatric diagnoses may experience disabling anxiety related to the fear of individual attacks, the fear of triggers, or at the onset of prodrome or aura. This process of fearing the worst possible outcome (ie, catastrophizing) may prompt unwarranted avoidance behaviors that further perpetuate pain and increase pain sensitivity over time.56,57 Evidence-based behavioral and mind/body practices that directly or indirectly target these psychological factors can teach patients more effective ways of coping with these fears. As with their effects on psychiatric symptoms, evidence-based behavioral and mind/body interventions may produce improvements in headache by fostering other healthy lifestyle habits. Poor sleep duration and quality are common headache triggers, and some non-pharmacological interventions (eg, relaxation, stress management, meditation) may improve sleep, which in turn may mediate improvements in headaches. It is also possible that evidence-based behavioral and mind/body interventions act through the complex mechanisms of placebo. Other components that are unique to these interventions, such as the rituals associated with such practices, the therapeutic alliance between patient–provider, and the empathy provided by the
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provider, may all have a powerful role in these interventions.58,59 At present, however, rigorous methodological attempts to tease apart proportions of treatment improvement attributable to specific techniques vs these “common factors” within the field of headache are largely lacking. A notable exception is a recent trial for pediatric migraine sufferers in which CBT plus amitriptyline was compared with education plus amitriptyline.3 Because therapist time and attention were equivalent between groups, the finding that CBT produced superior reductions in headache frequency and disability suggest that a therapeutic relationship alone is unlikely to account for differential treatment gains. To better clarify putative mechanisms of action, clinical trials employing factorial and dismantling designs are needed, as is a concerted effort by trials researchers to include pre- and post-treatment assessment of relevant psychological constructs. Research Challenges There are many inherent difficulties in researching behavioral and mind/body practices.18,46,60,61 Double-blinded placebo-controlled randomized clinical trials (RCTs) are the gold standard for assessing clinical efficacy of an intervention, but double-blinded trials are impossible in most non-pharmacological interventions, and attempts at “psychological placebo controls” have been fraught with logistical and interpretive challenges.18 It is virtually impossible to blind participants to allocation (with the possible exception of non-contingent biofeedback), and even in well-executed single-blinded trials of behavioral interventions, blinding the treatment provider is usually not feasible. Participant recruitment and retention in RCTs present challenges for trials of long duration and because of limited availability of funding. As a result, some studies of behavioral interventions have small sample sizes. For example, the average number of subjects was 16 in a recent meta-analysis of 55 biofeedback studies.14 Such sample sizes may be sufficient to address the principal outcome of interest, but may be somewhat underpowered to address sensitivity analyses or interaction effects. Despite these limitations, prior high-quality research studies of behavioral treatments have been conducted, which culminated in the aforementioned Grade A evidence rating for relaxation training, thermal biofeedback combined with relaxation training, EMG biofeedback, and CBT.1 Since then, a meta-analysis of 55 studies of biofeedback has confirmed that blood-volume-pulse biofeedback also has strong efficacy for migraine.14 Table 3 outlines suggested goals for future behavioral and mind/body research trials. Guidelines for pharmacological trials of migraine preventive treatments have been published by the International Headache Society,62 and some of those recommendations made are applicable to trials of non-pharmacological interventions. Given the methodological issues unique to non-pharmacological studies, researchers should familiarize themselves with the American Headache Society’s Guidelines for Trials of Behavioral Treatments,63 which provides numerous methodological recom-
Headache Currents
Table 3.—Goals for Future Behavioral and Mind/Body Research Trials Randomized controlled trials Adequate and appropriate controls Intervention upholds therapy integrity and treatment fidelity is assessed Clear specification of primary and secondary outcomes Appropriate handling of treatment dropouts Post-intervention follow-up is of sufficient length Assessments of potential mechanisms of action Clear specifications of the intervention protocol
mendations for conducting behavioral trials. Many, if not most, of these recommendations apply also to mind/body interventions in headache, although a similar guideline for mind/body interventions does not currently exist. These published resources should be consulted early in trial design, since they identify many aspects of trial design, outcome choices, and interpretation that are unique to the field of headache. When feasible, RCTs are desirable because of their methodological rigor (as compared to case reports, single-group longitudinal or cohort studies, or cross-sectional studies). Crossover designs are often not feasible because “erasing” the impact of a learned skill is impossible, and carry-over effects are inevitable. To ensure the highest level RCT designs, a number of criteria should be met.63 Control conditions should match for the time and attention of the intervention group and be of sufficient impact that participants have equal expectancy for positive outcomes and treatment credibility. The intervention under investigation needs to be of sufficient quality to uphold therapy integrity and treatment fidelity, and patient adherence should be monitored and reported. Assessment of treatment integrity and fidelity are important, and researchers in other broader fields have published methods and strategies for accomplishing this in clinical trials.43,44 Primary and secondary outcomes should be delineated from the start of the trial, the trial should be registered in an approved trial registry before the first participants are enrolled (eg, clinicaltrials.gov), statistical procedures for handling dropouts should be clearly articulated, and the intervention should be well described to enable replication.64 The post-intervention evaluation period must be long enough to detect and determine the time course of change, in most cases a minimum of 3 months, and, ideally, 12 months post-treatment. In addition to assessments of efficacy, clinical trials that evaluate treatment moderators and mechanisms of action are essential, given our limited knowledge in this area.
CONCLUSIONS Many patients with headache and headache medicine practitioners use or recommend evidence-based behavioral interventions
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and mind/body interventions to manage headache pain, but many unanswered questions remain. In consideration of unique methodological challenges that arise from the complex nature of the non-pharmacological interventions under study, we have outlined key research questions and goals for future studies in hopes of furthering the evaluation and dissemination of these interventions for patients with primary headache disorders. Research that adheres to published guideline recommendations and is designed to properly answer key questions is most likely to lead to progress in these goals. References 1. Silberstein SD. Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review): Report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2000 26;55:754-762. 2. Holroyd KA, Cottrell CK, O’Donnell FJ, et al. Effect of preventive (beta blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: Randomised controlled trial. BMJ. 2010;341: c4871. 3. Powers SW, Kashikar-Zuck SM, Allen JR, et al. Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: A randomized clinical trial. JAMA. 2013;310:26222630. 4. Wells RE, Bertisch SM, Buettner C, Phillips RS, McCarthy EP. Complementary and alternative medicine use among adults with migraines/severe headaches. Headache. 2011;51:1087-1097. 5. Rains JC, Penzien DB, McCrory DC, Gray RN. Behavioral headache treatment: History, review of the empirical literature, and methodological critique. Headache. 2005;45(Suppl. 2):S92-S109. 6. National Institutes of Health National. Center for Complementary Alternative Medicine Definition of Mind/Body Therapies 2012 cited 2012 January. Available at: http://nccam.nih.gov/health/ mindbody. 7. Abbott RB, Hui KK, Hays RD, Li MD, Pan T. A randomized controlled trial of tai chi for tension headaches. Evid Based Complement Alternat Med. 2007;4:107-113. 8. John PJ, Sharma N, Sharma CM, Kankane A. Effectiveness of yoga therapy in the treatment of migraine without aura: A randomized controlled trial. Headache. 2007;47:654-661. 9. Wahbeh H, Elsas SM, Oken BS. Mind-body interventions: Applications in neurology. Neurology. 2008;70:2321-2328. 10. Wells RE, Bertisch SM, Buettner C, Phillips R, McCarthy EP. Complementary and alternative medicine use among adults with migraines/severe headaches. Headache. 2011;51:1087-1097. 11. Holroyd KA, O’Donnell FJ, Stensland M, Lipchik GL, Cordingley GE, Carlson BW. Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: A randomized controlled trial. JAMA. 2001;285:2208-2215. May 2. 12. Holroyd KA, Penzien DB. Pharmacological versus nonpharmacological prophylaxis of recurrent migraine headache: A meta-analytic review of clinical trials. Pain. 1990;42:1-13.
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headache: A meta-analysis of controlled trials. Cephalalgia. 1997; 17:113-118. Rowan AB, Andrasik F. Efficacy and cost effectiveness of minimal therapist contact treatments for chronic headache: A review. Behav Ther. 1996;27:207-234. Merelle SY, Sorbi MJ, van Doornen LJ, Passchier J. Lay trainers with migraine for a home-based behavioral training: A 6-month follow-up study. Headache. 2008;48:1311-1325. Rothrock JF, Parada VA, Sims C, Key K, Walters NS, Zweifler RM. The impact of intensive patient education on clinical outcome in a clinic-based migraine population. Headache. 2006;46:726731. Andrasik F, Holroyd KA. A test of specific and nonspecific effects in the biofeedback treatment of tension headache. J Consult Clin Psychol. 1980;48:575-586. Goslin RE, Gray RN, McCrory DC, Penzien D, Rains J, Hasselblad V. Behavioral and Physical Treatments for Migraine Headache. Technical Review 2.2, February 1999. (Prepared for the Agency for Health Care Policy and Research under Contract No. 290-94-2025. Available from the National Technical Information Service; NTIS Accession No. 127946.) Broad WJ. The Science of Yoga: The Risks and the Rewards. New York: Simon & Schuster Paperbacks; 2012. Kuijpers HJ, van der Heijden FM, Tuinier S, Verhoeven WM. Meditation-induced psychosis. Psychopathology. 2007;40:461-464. Jacobsen P, Morris E, Johns L, Hodkinson K. Mindfulness groups for psychosis: Key issues for implementation on an inpatient unit. Behav Cogn Psychoth 2011;39:349-353. Langer AI, Cangas AJ, Salcedo E, Fuentes B. Applying mindfulness therapy in a group of psychotic individuals: A controlled study. Behav Cogn Psychoth 2012;40:105-109. van der Valk R, van de Waerdt S, Meijer CJ, van den Hout I, de Haan L. Feasibility of mindfulness-based therapy in patients recovering from a first psychotic episode: A pilot study. Early Interv Psychiatry 2013;7:64-70. Penzien DB, Rains JC, Lipchik GL, Nicholson RA, Lake AE 3rd, Hursey KG. Future directions in behavioral headache research: Applications for an evolving health care environment. Headache. 2005;45:526-534. MacDermid JC, Law M, Buckley N, Haynes RB. “Push” versus “pull” for mobilizing pain evidence into practice across different health professions: A protocol for a randomized trial. Implement Sci. 2012;7:115. Maclaren JE, Cohen LL. Teaching behavioral pain management to healthcare professionals: A systematic review of research in training programs. J Pain. 2005;6:481-492. Muse K, McManus F. A systematic review of methods for assessing competence in cognitive-behavioural therapy. Clin Psychol Rev. 2013;33:484-499. Riis A, Jensen CE, Bro F, Maindal HT, Petersen KD, Jensen MB. Enhanced implementation of low back pain guidelines in general practice: Study protocol of a cluster randomised controlled trial. Implement Sci. 2013, 20;8:124. Smitherman TA, Penzien DB, Rains JC. Challenges of nonpharmacologic interventions in chronic tension-type headache. Curr Pain Headache Rep. 2007;11:471-477.
Headache Currents 47. Kelman L. The triggers or precipitants of the acute migraine attack. Cephalalgia. 2007;27:394-402. 48. Nash JM, Thebarge RW. Understanding psychological stress, its biological processes, and impact on primary headache. Headache. 2006;46:1377-1386. 49. Zeidan F, Martucci KT, Kraft RA, Gordon NS, McHaffie JG, Coghill RC. Brain mechanisms supporting the modulation of pain by mindfulness meditation. J Neurosci. 2011;31:5540-5548. 50. Zeidan F, Grant JA, Brown CA, McHaffie JG, Coghill RC. Mindfulness meditation-related pain relief: Evidence for unique brain mechanisms in the regulation of pain. Neurosci Lett. 2012;520:165-173. 51. Holroyd KA, Penzien DB, Hursey KG, et al. Change mechanisms in EMG biofeedback training: Cognitive changes underlying improvements in tension headache. J Consult Clin Psychol. 1984; 52:1039-1053. 52. Seng EK, Holroyd KA. Dynamics of changes in self-efficacy and locus of control expectancies in the behavioral and drug treatment of severe migraine. Ann Behav Med. 2010;40:235-247. 53. Smitherman TA, Penzien DB, Maizels M. Anxiety disorders and migraine intractability and progression. Curr Pain Headache Rep. 2008;12:224-229. 54. Smitherman TA, Rains JC, Penzien DB. Psychiatric comorbidities and migraine chronification. Curr Pain Headache Rep. 2009;13: 326-331. 55. Lake AE 3rd, Rains JC, Penzien DB, Lipchik GL. Headache and psychiatric comorbidity: Historical context, clinical implications, and research relevance. Headache. 2005;45:493-506. 56. Drahovzal DN, Stewart SH, Sullivan MJ. Tendency to catastrophize somatic sensations: Pain catastrophizing and anxiety sensitivity in predicting headache. Cogn Behav Ther. 2006;35:226-235. 57. Volz MS, Medeiros LF, Tarrago MD, et al. The relationship between cortical excitability and pain catastrophizing in myofascial pain. J Pain. 2013;14:1140-1147. 58. Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. 2008;336:999-1003. 59. Messer SB, Wampold BE. Let’s face facts: Common factors are more potent than specific therapy ingredients. Clin Psychol. 2002;9:21-25. 60. Holroyd KA, Powers SW, Andrasik F. Methodological issues in clinical trials of drug and behavior therapies. Headache. 2005;45: 487-492. May. 61. Hursey KG, Rains JC, Penzien DB, Nash JM, Nicholson RA. Behavioral headache research: Methodologic considerations and research design alternatives. Headache. 2005;45:466-478. 62. Tfelt-Hansen P, Pascual J, Ramadan N, et al. Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators. Cephalalgia. 2012;32:6-38. 63. Penzien DB, Andrasik F, Freidenberg BM, et al. Guidelines for trials of behavioral treatments for recurrent headache, first edition: American Headache Society Behavioral Clinical Trials Workgroup. Headache. 2005;45(Suppl. 2):S110-S132. 64. Schroter S, Glasziou P, Heneghan C. Quality of descriptions of treatments: A review of published randomised controlled trials. BMJ Open. 2012. 65. Wells RE, Loder E. Mind/body and behavioral treatments: The evidence and approach. Headache. 2012;52(Suppl. 2):70-75.
HEADACHE CURRENTS—CLINICAL REVIEW
Behavioral and Mind/Body Interventions in Headache: Unanswered Questions and Future Research Directions Rebecca E. Wells, MD, MPH; Todd A. Smitherman, PhD; Elizabeth K. Seng, PhD; Timothy T. Houle, PhD; Elizabeth W. Loder, MD, MPH Background.—Many unanswered questions remain regarding behavioral and mind/body interventions in the treatment of primary headache disorders in adults. Methods.—We reviewed the literature to ascertain the most pressing unanswered research questions regarding behavioral and mind/body interventions for headache. Results.—We identify the most pressing unanswered research questions in this field, describe ideal and practical ways to address these questions, and outline steps needed to facilitate these research efforts. We discuss proposed mechanisms of action of behavioral and mind/body interventions and outline goals for future research in this field. Conclusions.—Although challenges arise from the complex nature of the interventions under study, research that adheres to published study design and reporting standards and focuses closely on answering key questions is most likely to lead to progress in achieving these goals. Key words: alternative medicine, headache, mind/body Abbreviations: CAM complementary and alternative medicine, TTH tension-type headache
Non-pharmacological interventions have long been perceived by patients and providers as beneficial for headaches, and strong evidence supports the useful effects of certain nonpharmacological interventions for migraine and tension-type headache (TTH). The US Headache Consortium Guidelines for prevention of migraine identified Grade A evidence to support several specific non-pharmacological interventions including relaxation training, thermal biofeedback combined with relaxation training, electromyographic (EMG) biofeedback, and cognitive behavioral therapy (CBT)1 (labeled as “evidence-based behavioral interventions” for this paper). The combination of preventive drug therapy and evidence-based behavioral therapies was identified as having Grade B evidence for producing added clinical benefit, although data published since these guidelines From the Department of Neurology, Wake Forest School of Medicine, Winston-Salem, NC, USA (R.E. Wells); Department of Psychology, University of Mississippi, Oxford, MS, USA (T.A. Smitherman); Ferkauf Graduate School of Psychology, Yeshiva University, New York, NY, USA; Albert Einstein College of Medicine of Yeshiva University, Bronx, NY (E.K. Seng); Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA (T.T. Houle); Department of Neurology, Brigham and Women’s Faulkner Hospital, Boston, MA, USA (E. Loder). Address all correspondence to R.E. Wells, MD, MPH, Department of Neurology, Medical Center Blvd., Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Accepted for publication March 2, 2014. ............. Headache © 2014 American Headache Society
were issued is likely to change the evidence to Grade A when the guidelines are updated.2,3 In addition to evidence-based behavioral interventions, a recent study found that more than 50% of US adults with migraines/severe headaches reported having used complementary and alternative medicine (CAM) techniques, most commonly “mind/body therapies” such as meditation and yoga.4 Thus, although data most strongly support evidence-based behavioral interventions, it seems that mind/body interventions are used frequently by adults with primary headache disorders. Despite their use, many unanswered questions remain regarding these non-pharmacological interventions in the treatment of primary headache disorders in adults. In 2005, Headache published an entire series of peer-reviewed papers (many cited in this review) that provided in-depth analysis of numerous methodological issues and suggested solutions in behavioral headache research. Given the increased utilization of mind/body therapies and potentially similar underlying mechanisms between evidencebased behavioral interventions and mind/body therapies, the goal of this paper is to identify the most pressing unanswered research questions in the field overall, describe ideal and practical ways to address these questions, and outline steps needed to facilitate these research efforts. We limit this discussion to the use of evidence-based behavioral interventions and mind/body interventions to treat the primary headache disorders of migraine and TTH in adults, as these headaches disorders are most prevalent in the population and the ones to which non-pharmacological interventions are most commonly applied. Other interventions that are sometimes referred to as non-pharmacological interventions, such as acupuncture or the use of herbal or dietary supplements, are beyond the scope of this paper. We conceptualize the differences between evidence-based behavioral interventions and mind/body interventions for headache across two domains, evidence-based and patient utilization. Historically, most non-pharmacological interventions used and studied in the treatment of headache have been behavioral or cognitive behavioral interventions that focus on teaching specific behaviors or skills to manage modifiable factors or behavioral patterns in a person’s life (eg, stress, sympathetic arousal, maladaptive thought processes) that may aggravate or trigger headaches. Evidence-based behavioral interventions include relaxation training (ie, deep breathing, progressive muscle relaxation training, and imagery); biofeedback training (thermal for migraine or EMG for TTH); and CBT (sometimes termed “stress management training”). These interventions have such ............. Conflict of Interest: None.
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strong evidence of efficacy for headaches that they are not considered “alternative” approaches but instead standard nonpharmacological treatments for headaches.5 However, many adults with headaches report using a broader array of “mind/ body” therapies that share a common intention “to enhance the mind’s capacity to affect bodily functions and symptoms.”6 These mind/body therapies focus on the interplay between brain, body, mind, and behavior, with specific attention to interactions among emotional, mental, social, and spiritual factors and how these influence health. These mind/body interventions sometimes incorporate components of evidence-based behavioral interventions (eg, deep breathing, guided imagery) and interventions with more limited evidence of efficacy in headache, such as meditation, yoga, and tai chi.7-9 Access to headache-specific care is problematic for both types of these non-pharmacological interventions. Despite the research evidence supporting the benefits of evidence-based behavioral interventions for headaches, access to behavioral providers trained specifically to treat headache can be limited. Utilization rates reported by patients tend to be relatively low (eg, less than 1% of the general US population with severe headaches/ migraines report using biofeedback), although techniques that may not require a provider are being used more frequently (24% of the same population report using deep breathing exercises).10 Further, many headache patients report using mind/body interventions, as 17% of the general US population with severe headaches/migraines report doing meditation, and 9% report doing yoga. However, these interventions are commonly used for overall well-being rather than to target headaches specifically. Despite the varying levels of evidence to support their use and the varying levels of patient utilization, many key research questions underlying both evidence-based behavioral and mind/body interventions need to be answered in order to move this field forward. Key Unanswered Research Questions Table 1 summarizes key unanswered research questions about evidence-based behavioral and mind/body practices for adults with common primary headache disorders. The questions are divided into two main areas, content-based research questions, and questions about the development and dissemination of interventions. Perhaps the most pressing content-based-research question is: “Which interventions are most helpful for headache patients?” (Question #1, Q1) Although research studies have demonstrated efficacy of evidence-based behavioral interventions for migraine and TTH,1,2,11-15 there are comparatively fewer effectiveness studies that have evaluated treatment response in more externally valid clinical practice settings.16 Nash and colleagues recommend a three-phase process to further answer this important question, which sequentially involves pilot testing, then efficacy testing, and finally effectiveness testing.16 As roughly one third of non-pharmacological studies compare an intervention to no treatment or to a wait-list control,13,17 future studies
Headache Currents
Table 1.—Unanswered Questions About Behavioral and Mind/ Body Practices for Adults With Primary Headaches Content-Based Research Questions 1. Which interventions are most helpful for headache patients? 1A. Which types of patients and headaches are most responsive to these interventions? 2. What is the optimal “dose” of these interventions? (eg, frequency, duration, length of treatment) 2A. To what extent do patients need to be taught these interventions by a professional, or can they learn them on their own? 3. What are the putative mechanism(s) of action? 3A. What role do these interventions have on headache threshold(s)? 4. What are the side effects and adverse events associated with treatment? Development and Dissemination of Interventions 5. How can standardized protocols be made more accessible to researchers and practitioners? 6. How can these interventions be better integrated into medical practice settings for providers? 7. How can matching of appropriate treatment to patient responders be facilitated? 8. How can these practices be made more accessible and practical for patients?
with comparisons to alternative active treatments are needed,18 allowing different non-pharmacological interventions to be compared against each other and providing insights into potential mechanisms of action. More specifically, we need to understand which techniques are most effective for specific types of patients and headache disorders (ie, moderator variables) (Q1A),19 as well as the treatment components that account for the response (ie, mediator variables).20 Many evidence-based behavioral and mind/body interventions require a significant commitment to out-of-session time from patients, and identification of the optimal “dose” of treatment thus is essential (Q2). In order to recommend these interventions for clinical use, we need to better understand how frequently these interventions should be practiced, for how long, and over what period of time in order to maximize clinical benefit and minimize patient burden. For example, are classes lasting 2 hours once a week more or less beneficial than a daily 15-min practice session? Once a patient learns a technique, does it need to be continually practiced to maintain benefit and if so, for how often and how long? Numerous trials of evidence-based behavioral interventions have demonstrated benefits that last for months or even up to 5-7 years after the intervention ends.2,11,14,21-23 It is unclear, however, whether the persistent benefit results from the initial teaching or continued regular practice. Many of the mind/ body intervention trials have not included long follow-up periods,7,8 and this remains an important issue for future research on these interventions.
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Many trials have demonstrated that a minimal-therapistcontact intervention can provide similar clinical benefit compared to a more intensive clinic-based intensive treatment.24-31 Although additional studies are needed to better characterize the efficacy of limited contact mind/body interventions in headache, these approaches hold promise as ways to increase adherence, reduce costs, and improve treatment accessibility in resourcelimited or remote areas. Since most evidence-based behavioral and mind/body practices require a significant investment of time by the patient, it is crucial to understand what level of interaction with a trained professional is required for successful acquisition of these skills, ranging from provision of online or written materials, to brief skills training in a medical office, to a more in-depth course of treatment with a behavioral health-care provider or mind/body instructor. (Q2A). There is some evidence of modest benefit from treatment groups led by trained nonprofessionals.32,33 The shortage of behavioral headache treatment providers within medical settings has likely contributed to the underuse of evidence-based behavioral interventions, and training a larger number of behavioral providers remains a significant need. The physiological or psychological mechanisms that underlie the effects of evidence-based behavioral and mind/body practices are not fully understood (Q3). Many are multi-component interventions, and thus more than one mechanism may be responsible for therapeutic effects; possible synergistic effects among treatment components might explain particularly longlasting effects. Better understanding of the mechanisms of action of these interventions would allow refinement and targeting of treatments to improve clinical benefits, increase patient/provider interest and adherence, and enhance scientific credibility among those who view their benefits as resulting primarily from nonspecific processes.34 For example, it would be helpful to understand how these interventions affect headache threshold(s) (Q3A) in order to target interventions and understand mechanisms of action. Specifically, such techniques may increase the distance between an individual’s headache baseline and headache threshold by (A) lowering the individual’s baseline level of brain excitability; (B) raising an individual’s headache threshold, or; (C) both (Figure). The extensive research on evidence-based behavioral interventions and growing research on mind/body practices indicates that these treatments are generally acceptable, safe, and without significant side effects.2,7,8,11-13,35 However, anecdotal reports of musculoskeletal injuries with certain types of yoga practices exist in the media,36 and rare case reports of meditation-induced psychosis have been reported,37 although recent studies have demonstrated the benefit of mindfulness-based interventions even in adults with psychosis.38-40 Better reporting and understanding of the potential harms, patient acceptability, and adverse events associated with these practices are additional research priorities and will facilitate comparisons of these treatments with conventional medication treatments (Q4).
Headache Currents
}
Headache Threshold
}
Individual Baseline
Lowered Baseline
Raised Threshold
B
A Figure.—Possible mechanisms of action of behavioral and mind/body treatments for headache. Behavioral and mind/body treatments may exert their effects by increasing the distance between an individual’s baseline and their headache threshold by (A) lowering the individual’s baseline level of brain excitability; (B) raising an individual’s headache threshold; or (C) both (not pictured). (Reproduced with permission from the journal Headache.65)
Another priority is the development, testing, publication, and dissemination of standardized intervention protocols that are feasible for use in clinical practice (Q5).41 Treatment manuals are not routinely published, presenting a barrier for widespread dissemination. Investigators and practitioners must continue to work toward more consistency in treatment delivery methods across studies to allow for cross-study comparisons and synthesis for systematic reviews or meta-analyses. Despite extensive research in this field, a lack of published treatment manuals perhaps has hampered their dissemination and uptake in clinical practice. Thus, publishing and openly distributing standardized treatment manuals for behavioral and mind/body interventions that can be easily applied in usual clinical settings is a significant need (Q5). Research papers describing the effects of these interventions should provide, either in the paper’s methods section or as an online appendix, sufficient detail about the treatment protocols used so that they can be replicated in further research. Additionally, determining how these practices can be better integrated into clinical practice so they are easily accessible to providers for routine headache care is crucial (Q6). Training healthcare providers to competently provide these services would likely play an important role in this process. Being able to implement clinically effective behavioral interventions outside of the research context and finding the best ways to standardize dissemination to practitioners is a burgeoning area of research that needs to be further addressed in the field of headache.16,42-45 A number of barriers can prevent patients from accessing and using evidence-based behavioral and mind/body treatments for headache.46 As previously described, these interventions often require a significant commitment of time, energy, and in some cases financial resources, from patients. It is imperative to identify
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Table 2.—Proposed Mechanisms of Change for Behavioral and Mind/Body Headache Treatments* A. Stress reduction Decreased stress hormones (eg, cortisol) Altered autonomic arousal B. Changes in relevant psychological constructs Improved coping skills Increased self-efficacy Decreased external locus of control Decreased pain catastrophizing Decreased depression and anxiety C. Effects on other behaviors Improved sleep Improved diet, exercise, and other healthy behaviors D. Change in pain processing Change in neural pain processing Activation of natural endogenous analgesic processes E. Placebo Altered expectations “Common factors” (eg, ritual, empathy, alliance, etc.)
*See text for references.
subgroups of patients most likely to respond to these treatments in order to facilitate treatment matching and to avoid use in those unlikely to benefit (Q7). Research aimed at identifying and reducing treatment barriers is also critical to ensure that effective treatments will be accessible and widely used (Q8). Potential Mechanisms of Change of Behavioral and Mind/ Body Headache Treatments Although the mechanisms that mediate the benefits of evidencebased behavioral and mind/body interventions in adults with headaches are not fully understood, many hypotheses have been posited (Table 2). Psychological stress is among the most frequently endorsed triggers of headache,47 and interventions that reduce stress or improve patients’ abilities to cope with stress are integral in behavioral headache management. While stress reduction is one of the mechanisms most commonly evoked to explain the beneficial effects of evidence-based behavioral and mind/ body interventions, how these practices lead to stress reduction is unclear and may vary by intervention. Stress is thought to impact headache by (1) directly impacting pain perception; (2) fostering activation and sensitization of nociceptors over time; and (3) worsening headache-related disability and quality of life. The headache experience itself serves as a stressor that compromises well-being.48 Evidence-based behavioral and mind/body practices may alter central pain processing. A study assessing experimental pain during meditation showed that meditation decreased pain unpleasantness by 57% and pain intensity by 40%.49 Neuroimaging showed that these reductions were associated with increased activity in the anterior cingulate cortex and anterior
Headache Currents insula (ie, areas involved in the cognitive regulation of nociception) and with thalamic deactivation.49 Meditation and other non-pharmacological practices may activate natural endogenous analgesic processes, or observed results could be attributable to distraction or altered expectations.50 Yet the exact physiological mechanisms of stress-reducing interventions on headache are not clearly elucidated. If stress-reducing interventions are effective because they alter autonomic reactivity, it is important to determine whether they alter autonomic responses to individual stressful events or the patient’s baseline autonomic levels. Non-pharmacological interventions also may exert beneficial effects by affecting psychological constructs. An increased sense of headache “self-efficacy,” or confidence in one’s ability to persist with behavioral change efforts that one believes will manage headache symptoms, and a reduced external “locus of control,” or belief that nothing can exert control over the onset and course of headache, are potent predictors of behavioral treatment outcomes. Foundational research on evidence-based behavioral interventions decades ago identified increased self-efficacy as the key mediator of successful EMG biofeedback for TTH, regardless of whether the patient was taught to increase or decrease muscle tension.51 More recent research has confirmed that both self-efficacy and locus of control are important factors for the success of evidence-based behavioral headache treatments.52 Evidence-based behavioral and mind/body interventions may be useful also because they improve psychiatric conditions commonly comorbid with headache, such as anxiety and depression, and are often associated with a poorer prognosis.53-55 Improvements in these affective conditions, even if present at a level not warranting a clinical diagnosis, in turn may improve the ability to cope with pain and enhance adherence to treatment recommendations. Even adults without formal psychiatric diagnoses may experience disabling anxiety related to the fear of individual attacks, the fear of triggers, or at the onset of prodrome or aura. This process of fearing the worst possible outcome (ie, catastrophizing) may prompt unwarranted avoidance behaviors that further perpetuate pain and increase pain sensitivity over time.56,57 Evidence-based behavioral and mind/body practices that directly or indirectly target these psychological factors can teach patients more effective ways of coping with these fears. As with their effects on psychiatric symptoms, evidence-based behavioral and mind/body interventions may produce improvements in headache by fostering other healthy lifestyle habits. Poor sleep duration and quality are common headache triggers, and some non-pharmacological interventions (eg, relaxation, stress management, meditation) may improve sleep, which in turn may mediate improvements in headaches. It is also possible that evidence-based behavioral and mind/body interventions act through the complex mechanisms of placebo. Other components that are unique to these interventions, such as the rituals associated with such practices, the therapeutic alliance between patient–provider, and the empathy provided by the
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provider, may all have a powerful role in these interventions.58,59 At present, however, rigorous methodological attempts to tease apart proportions of treatment improvement attributable to specific techniques vs these “common factors” within the field of headache are largely lacking. A notable exception is a recent trial for pediatric migraine sufferers in which CBT plus amitriptyline was compared with education plus amitriptyline.3 Because therapist time and attention were equivalent between groups, the finding that CBT produced superior reductions in headache frequency and disability suggest that a therapeutic relationship alone is unlikely to account for differential treatment gains. To better clarify putative mechanisms of action, clinical trials employing factorial and dismantling designs are needed, as is a concerted effort by trials researchers to include pre- and post-treatment assessment of relevant psychological constructs. Research Challenges There are many inherent difficulties in researching behavioral and mind/body practices.18,46,60,61 Double-blinded placebo-controlled randomized clinical trials (RCTs) are the gold standard for assessing clinical efficacy of an intervention, but double-blinded trials are impossible in most non-pharmacological interventions, and attempts at “psychological placebo controls” have been fraught with logistical and interpretive challenges.18 It is virtually impossible to blind participants to allocation (with the possible exception of non-contingent biofeedback), and even in well-executed single-blinded trials of behavioral interventions, blinding the treatment provider is usually not feasible. Participant recruitment and retention in RCTs present challenges for trials of long duration and because of limited availability of funding. As a result, some studies of behavioral interventions have small sample sizes. For example, the average number of subjects was 16 in a recent meta-analysis of 55 biofeedback studies.14 Such sample sizes may be sufficient to address the principal outcome of interest, but may be somewhat underpowered to address sensitivity analyses or interaction effects. Despite these limitations, prior high-quality research studies of behavioral treatments have been conducted, which culminated in the aforementioned Grade A evidence rating for relaxation training, thermal biofeedback combined with relaxation training, EMG biofeedback, and CBT.1 Since then, a meta-analysis of 55 studies of biofeedback has confirmed that blood-volume-pulse biofeedback also has strong efficacy for migraine.14 Table 3 outlines suggested goals for future behavioral and mind/body research trials. Guidelines for pharmacological trials of migraine preventive treatments have been published by the International Headache Society,62 and some of those recommendations made are applicable to trials of non-pharmacological interventions. Given the methodological issues unique to non-pharmacological studies, researchers should familiarize themselves with the American Headache Society’s Guidelines for Trials of Behavioral Treatments,63 which provides numerous methodological recom-
Headache Currents
Table 3.—Goals for Future Behavioral and Mind/Body Research Trials Randomized controlled trials Adequate and appropriate controls Intervention upholds therapy integrity and treatment fidelity is assessed Clear specification of primary and secondary outcomes Appropriate handling of treatment dropouts Post-intervention follow-up is of sufficient length Assessments of potential mechanisms of action Clear specifications of the intervention protocol
mendations for conducting behavioral trials. Many, if not most, of these recommendations apply also to mind/body interventions in headache, although a similar guideline for mind/body interventions does not currently exist. These published resources should be consulted early in trial design, since they identify many aspects of trial design, outcome choices, and interpretation that are unique to the field of headache. When feasible, RCTs are desirable because of their methodological rigor (as compared to case reports, single-group longitudinal or cohort studies, or cross-sectional studies). Crossover designs are often not feasible because “erasing” the impact of a learned skill is impossible, and carry-over effects are inevitable. To ensure the highest level RCT designs, a number of criteria should be met.63 Control conditions should match for the time and attention of the intervention group and be of sufficient impact that participants have equal expectancy for positive outcomes and treatment credibility. The intervention under investigation needs to be of sufficient quality to uphold therapy integrity and treatment fidelity, and patient adherence should be monitored and reported. Assessment of treatment integrity and fidelity are important, and researchers in other broader fields have published methods and strategies for accomplishing this in clinical trials.43,44 Primary and secondary outcomes should be delineated from the start of the trial, the trial should be registered in an approved trial registry before the first participants are enrolled (eg, clinicaltrials.gov), statistical procedures for handling dropouts should be clearly articulated, and the intervention should be well described to enable replication.64 The post-intervention evaluation period must be long enough to detect and determine the time course of change, in most cases a minimum of 3 months, and, ideally, 12 months post-treatment. In addition to assessments of efficacy, clinical trials that evaluate treatment moderators and mechanisms of action are essential, given our limited knowledge in this area.
CONCLUSIONS Many patients with headache and headache medicine practitioners use or recommend evidence-based behavioral interventions
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and mind/body interventions to manage headache pain, but many unanswered questions remain. In consideration of unique methodological challenges that arise from the complex nature of the non-pharmacological interventions under study, we have outlined key research questions and goals for future studies in hopes of furthering the evaluation and dissemination of these interventions for patients with primary headache disorders. Research that adheres to published guideline recommendations and is designed to properly answer key questions is most likely to lead to progress in these goals. References 1. Silberstein SD. Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review): Report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2000 26;55:754-762. 2. Holroyd KA, Cottrell CK, O’Donnell FJ, et al. Effect of preventive (beta blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: Randomised controlled trial. BMJ. 2010;341: c4871. 3. Powers SW, Kashikar-Zuck SM, Allen JR, et al. Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: A randomized clinical trial. JAMA. 2013;310:26222630. 4. Wells RE, Bertisch SM, Buettner C, Phillips RS, McCarthy EP. Complementary and alternative medicine use among adults with migraines/severe headaches. Headache. 2011;51:1087-1097. 5. Rains JC, Penzien DB, McCrory DC, Gray RN. Behavioral headache treatment: History, review of the empirical literature, and methodological critique. Headache. 2005;45(Suppl. 2):S92-S109. 6. National Institutes of Health National. Center for Complementary Alternative Medicine Definition of Mind/Body Therapies 2012 cited 2012 January. Available at: http://nccam.nih.gov/health/ mindbody. 7. Abbott RB, Hui KK, Hays RD, Li MD, Pan T. A randomized controlled trial of tai chi for tension headaches. Evid Based Complement Alternat Med. 2007;4:107-113. 8. John PJ, Sharma N, Sharma CM, Kankane A. Effectiveness of yoga therapy in the treatment of migraine without aura: A randomized controlled trial. Headache. 2007;47:654-661. 9. Wahbeh H, Elsas SM, Oken BS. Mind-body interventions: Applications in neurology. Neurology. 2008;70:2321-2328. 10. Wells RE, Bertisch SM, Buettner C, Phillips R, McCarthy EP. Complementary and alternative medicine use among adults with migraines/severe headaches. Headache. 2011;51:1087-1097. 11. Holroyd KA, O’Donnell FJ, Stensland M, Lipchik GL, Cordingley GE, Carlson BW. Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: A randomized controlled trial. JAMA. 2001;285:2208-2215. May 2. 12. Holroyd KA, Penzien DB. Pharmacological versus nonpharmacological prophylaxis of recurrent migraine headache: A meta-analytic review of clinical trials. Pain. 1990;42:1-13.
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