Neuroscience Education as Therapy for Migraine and Overlapping Pain Conditions: A Scoping Review

Abstract

Background

Neuroscience education therapy (NET) has been successfully used for numerous overlapping pain conditions, but few studies have investigated NET for migraine.

Objective

We sought to 1) review the literature on NET used for the treatment of various pain conditions to assess how NET has been studied thus far and 2) recommend considerations for future research of NET for the treatment of migraine.

Design/Methods

Following the PRISMA guideline for scoping reviews, co-author (TR), a medical librarian, searched the MEDLINE, PsychInfo, Embase, and Cochrane Central Clinical Trials Registry databases for peer-reviewed articles describing NET to treat migraine and other chronic pain conditions. Each citation was reviewed by two trained independent reviewers. Conflicts were resolved through consensus.

Results

Overall, a NET curriculum consists of the following topics: pain does not equate to injury, pain is generated in the brain, perception, genetics, reward systems, fear, brain plasticity, and placebo/nocebo effects. Delivered through individual, group, or a combination of individual and group sessions, NET treatments often incorporate exercise programs and/or components of other evidence-based behavioral treatments. NET has significantly reduced catastrophizing, kinesiophobia, pain intensity, and disability in overlapping pain conditions. In migraine-specific studies, when implemented together with traditional pharmacological treatments, NET has emerged as a promising therapy by reducing migraine days, pain intensity and duration, and acute medication intake.

Conclusion

NET is an established treatment for pain conditions, and future research should focus on refining NET for migraine, examining delivery modality, dosage, components of other behavioral therapies to integrate, and migraine-specific NET curricula.

Introduction

Migraine is the second most disabling condition affecting more than 40 million people in the United States each year [1, 2]. Typical care consists of abortive and preventive treatment in individuals with at least four headache days per month [3]. Preventive treatments consist mainly of medication, behavioral therapy, and device therapy [4, 5]. There is strong evidence that the best preventive treatment involves a combination of medication and behavioral therapy [6, 7]. Unfortunately, numerous studies have shown that few patients pursue behavioral therapy for treating migraine [8–10].

Neuroscience education therapy (NET) is a nonpharmacologic treatment that consists of educating patients about the neurophysiology of pain to enhance their understanding of migraine, which is essential in improving perception of pain, disability, fear, catastrophization, and avoidance [11]. Research has shown that patients are capable of understanding the neurophysiology of pain as long as the language is not esoteric [12]. NET can include topics such as pain does not equate to injury, pain is generated in the brain, perception, genetics, reward systems, fear, brain plasticity, and placebo and nocebo effects. Importantly, it can be incorporated with aspects of known evidence-based behavioral therapies (cognitive-behavioral therapy [CBT], biofeedback, and relaxation) [13]. Of note, NET has been referred to by various names in the literature, including pain neurophysiology education, pain biology education, pain physiology education, neurophysiology of pain education, and therapeutic neuroscience education [11, 14].

Given the current limitations in migraine treatment and the growing research on NET for pain, we 1) provide a rationale for NET for migraine (i.e., why NET might be the treatment of choice for migraine); 2) report the results of a scoping review of NET to understand overall NET content, delivery, and potential mechanisms of action for overlapping pain conditions, including migraine; and 3) provide considerations for further research on NET for migraine.

Rationale for NET as a Migraine Treatment: New Nonpharmacologic Treatments Are Needed for Migraine Prevention, and NET May Be a Treatment of Choice

Stigma

While behavioral therapies are frequently used in combination with pharmacological options for migraine treatment, they are often met with high rates of attrition [15]. Many patients with migraine report willingness to try nonpharmacological therapies [16] but fear the stigma associated with psychological treatment when referred to treatments such as CBT [8].

Additionally, the invisible nature of migraine hinders social understanding of it as a legitimate medical condition, which is internalized by people with migraine and leads patients to feel viewed as less credible [17]. Patients may also feel that their physicians do not understand the burden of their pain [16], which can result in distrust of providers and prescribed treatments [17].

The title and content of NET may avoid the stigma associated with psychological treatment and thereby increase patient openness and adherence. Furthermore, by concentrating on the neurological nature of migraine, NET may validate the legitimacy of the disease and increase patient recognition and trust in medical care.

Improving Patient Understanding and Advocacy

The complex etiology, diverse set of symptoms and triggers, and history of suspected causes of migraine have resulted in the lack of a uniform disease profile for migraine [17]. Patients and providers also use varying language when discussing migraine [17]. This likely explains why many patients report poorly understanding their migraine diagnosis [16]. By educating patients about the underlying mechanisms of migraine, NET can allow patients to understand their diagnosis and subsequently improve communication and self-advocacy in health care settings.

Barriers to Behavioral Therapies

Though existing behavioral therapies (CBT, biofeedback, and relaxation) have been successfully used with migraine patients, barriers to access and adherence persist. Notably, poor communication by physicians who may inadequately explain the rationale for behavioral therapies for migraine and encourage patient adherence presents a barrier, particularly when patients may be in opposition due to stigma, unfamiliarity, and time and cost considerations. A lack of referral options due to physician and patient unfamiliarity also presents a barrier [8].

There are few providers trained in behavioral treatment and issues related to scalability exist. Traditional CBT for pain management, for example, is often tailored based on each patient’s unique pain, beliefs, and experiences, which restricts treatment to single patients at a time [18]. Third-wave forms of CBT like mindfulness-based cognitive therapy have traditionally been developed in a group format, but recent mindfulness-based cognitive therapy for migraine research was conducted with individual sessions [19]. NET can provide uniform factual information that can improve pain experience while allowing participants time to also consider their individual circumstances. NET has been effective in individual sessions [13, 20–33], group sessions [34–44], and a combination of individual and group sessions [45–47,50] and therefore lends itself to widespread use. While NET group sessions may be more affordable, it is also possible to develop short, cost-effective one-on-one sessions as NET has been delivered in sessions as short as 30 minutes [53,51].

Other major barriers to behavioral therapies include the time and costs associated with treatment, as patients often perceive CBT as time consuming and likely to cause additional stress [8]. Patients may be unaware of how insurance coverage applies to the treatment, and practitioners may overlook applicable billing codes. Even still, these codes may not be recognized by all insurance companies, and reimbursement is often issued at low rates compared with mental health Current Procedural Terminology (CPT) codes [8].

Methods

As per Arksey et al. [54], the purpose of the scoping review is to 1) “examine the extent, range and nature of research activity”; 2) “summarize and disseminate research findings”; and 3) “identify research gaps in the existing literature.” As outlined in Arksey and colleagues’ suggested framework, we developed our research question, “Given the breadth of publications about Neuroscience Education Therapy (NET) for pain conditions, what is known from the existing literature about the effectiveness of Neuroscience Education Therapy (NET) for pain conditions and how might it be applied to migraine?” Following the PRISMA guideline for scoping reviews (PRISMA-ScR) [55], co-author (TR), an experienced medical librarian, searched the MEDLINE PsychInfo, Embase, and Cochrane Central Clinical Trials Registry databases using the Ovid platform for peer-reviewed articles describing NET to treat migraine and other chronic pain conditions including tension type headache, chronic fatigue syndrome, fibromyalgia, vulvodynia, irritable bowel syndrome, urologic chronic pelvic pain syndromes, temporal mandibular, dysfunction, chronic pain, and low back pain. Each search strategy included a combination of key words and control vocabulary specific to each database. The search protocol and the complete Ovid Medline Search are included in the Appendix to this article. The search was conducted in January 2021 and was not limited by language or publication date. In the Embase database, conference abstracts were excluded from search results. The team also checked the reference list of the reviews and the original manuscripts to determine if we were missing any key articles. The citations and abstracts were uploaded to the Covidence software [56] for review. After duplicates were removed, 1,518 titles and abstracts were screened by a team of reviewers (SC, SA, DK, JG, KK, MEP) based on the inclusion/exclusion criteria (see Figure 1). Prior to Covidence screening, all reviewers met with the medical librarian (TR) for a brief training to ensure consistency in screening technique and to affirm inclusion and exclusion criteria. During abstract/title and full-text screenings, the screening team checked in one-quarter of the way and then halfway through the process to discuss questions and disagreements. In both screening processes, the conflict rate was below 20%.

Figure 1.

PRISMA diagram

Studies were included in our study if 1) they were related to a pain condition being investigated (i.e., could not be related to postsurgical pain or pain due to a psychiatric condition); 2) NET was used in the original study, whether it was with or without other therapies; and 3) there was inclusion of a control group in which participants did not receive any variation of NET. Each citation was screened independently by two different reviewers and subsequently received two votes, and conflicts were resolved through consensus. The full text of 106 citations was screened by the same reviewers, again each article was reviewed independently by two different reviewers and received two votes, and conflicts were resolved through consensus. Ultimately, 35 articles were included. The exclusion reasons for the remaining articles are included in Figure 1. Of note, the Critical Appraisal of Individual Sources of Evidence is an optional step in the PRISMA Extension for Scoping Reviews (PRISMA-ScR) Checklist [55] and was not conducted. As a scoping review, we were seeking to provide an overview of the existing evidence regardless of methodological quality or risk of bias [55, 57].

We then charted all data for author(s), year of publication, study population, intervention, measurements, and results. We collated, summarized, and report our findings in this paper.

NET in Overlapping Pain Conditions

Many studies have investigated the efficacy of NET in overlapping pain conditions and can inform the proposed use of NET for migraine. There is considerable evidence for the efficacy of NET in reducing pain catastrophizing, kinesiophobia, pain intensity, and disability in overlapping conditions. The Supplemental Data Table (available online) consists of relevant NET original articles, some of which have been discussed in systematic reviews and meta-analyses [58, 59]. A randomized controlled trial (RCT) with partial crossover for nonspecific chronic pain found that a booklet delivering NET through metaphors and stories resulted in a greater increase in pain biology knowledge (d = 1.7) and decrease in pain catastrophizing (d = 0.7), suggesting that a successful NET program for migraine should include vivid metaphors and relatable examples [60]. The following sections detail the successful use of NET with various specific pain states. Of the 35 studies we reviewed, 8 had a patient population of 0 to 50, 11 articles had 50 to 100, and 16 articles had more than 100. A total of four articles had a dropout rate higher than 20%, and 31 had one equal to or less than 20%.

NET for Back Pain

Chronic Spinal Pain

As seen in Table 1, multiple studies have examined the effect of NET on chronic spinal pain (CSP). An RCT by Malfliet et al. [46] found that CSP patients who received pain neurophysiology education instead of back neck education had reduced kinesiophobia (d = 0.56), though neither treatment had significant effects on perceived disability, pain catastrophizing, and hypervigilance. Similarly, NET significantly improved kinesiophobia (P < 0.001) in another study by Malfliet and colleagues [47] in which pain catastrophizing was significantly reduced in participants with high central sensitization symptoms (P < 0.05). In a third RCT by Malfliet and colleagues [50], NET with sensorimotor control training reduced pain at 3 months (d = 0.46), lowered central sensitization at 6 months (d = 0.73), improved mental and physical health, and significantly decreased disability at 3 months (d = 0.49). In the pragmatic RCT by Galan-Martin et al. [37], compared with participants in physiotherapy sessions, CSP patients who participated in NET along with physical therapeutic exercise showed improvement in health-related quality of life; higher satisfaction with services provided; and reduction in catastrophism (d = -1.7), kinesiophobia (d = -1.8), and pain intensity (d = -3.3). Interestingly, the study also found that analgesic intake was less at 6 months in the experimental group, suggesting that future research into NET for migraine should study the interaction between NET and acute medication intake over time.

Table 1.

NET modality and content for spinal pain

Title	Modality of NET	NET Content
Patients with Chronic Spinal Pain Benefit from Pain Neuroscience Education Regardless the Self-Reported Signs of Central Sensitization: Secondary Analysis of a Randomized Controlled Multicenter Trial [47]	Frequency: three sessions, two PNE1 and one 1:1 conversation Duration: 2 weeks; first 30 min to 1 hr, second not detailed, third 30 min. Delivered by: physical therapist Format: first in a group, second at home, third 1:1	Topics: the physiology of the neuron, the synapse, peripheral sensitization, and central sensitization Material: pictures, PowerPoints, video from the Explain Pain [48](Butler DS and Moseley GL, 2013 ) and the Textbook of Pain [49](Wall P and Melzack R)
Effect of Pain Neuroscience Education Combined with Cognition-Targeted Motor Control Training on Chronic Spinal Pain: A Randomized Clinical Trial [50]	Frequency: three PNE and motor control training sessions Duration: 12 weeks Delivered by: therapist Format: first in a group (6 people max), second an online home module, and third individual session	Topics: the neuron, the synapse, descending nociceptive inhibition and facilitation, peripheral sensitization, and central sensitization Material: derived from Explain Pain [48] (Butler and Moseley 2013) and Applying Contemporary Neuroscience in Exercise Interventions for Chronic Spinal Pain: Treatment Protocol by [62](Malfliet et al.)
Pain Neuroscience Education and Physical Therapeutic Exercise for Patients with Chronic Spinal Pain in Spanish Physiotherapy Primary Care: A Pragmatic Randomized Controlled Trial [37]	Frequency: six PNE sessions (2/wk for 3 wk) and 18 sessions of physical exercise (3/wk for 6 wk) Duration: total 10 hr, each around 1.5 hr; physical exercise totaled 18 hr, each 1 hr long Delivered by: physiotherapists Format: in a group	Topics: inhibitory system dysfunction and pain role Material: Presentations, infographics, and explanatory/motivational videos from Pain Neuroscience Education and Physical Exercise for Patients with Chronic Spinal Pain in Primary Healthcare: A Randomized Trial Protocol (Galan-Martin et al. 2019); [51] additional material from Explain Pain [48] (Butler and Moseley 2013)
Blended-Learning Pain Neuroscience Education for People with Chronic Spinal Pain: Randomized Controlled Multicenter Trial [46]	Frequency: three PNE sessions Duration: first 30 min to 1 hr, second not determined, third 30 min. Delivered by: physical therapists Format: first in a group (with a max of 6 participants), second an online home module, third a 1:1 conversation	Topics: the nervous and pain system, the physiology of the neuron, the synapse, the descending nociceptive inhibition and facilitation, and the peripheral and central sensitization Materials: videos and an educational booklet with photographs, drawing, graphs based on Explain Pain [48] (Butler and Moseley 2013) and Pijneducatie: Een Practice Handleiding voor (Para) medici [52]

PNE = Pain Neuroscience Education.

Chronic Neck Pain

In a RCT delivering NET through an educational booklet, a significant difference on the neck pain and disability scale was seen between patients who finished reading the booklet vs those who did not, highlighting the need to consider duration and attrition when devising NET for migraine [63]. This is consistent with results from an RCT on nonspecific chronic neck pain comparing a control group receiving only manual therapy, an intervention group receiving manual therapy and NET, and an intervention group receiving manual therapy, NET, and therapeutic exercise. Both intervention groups showed greater improvements in Neck Disability Index scores (P < 0.01) than the control group, with the group receiving therapeutic exercise showing greatest improvement [13]. Both intervention groups also showed improved fear (Exp 1: d = 1.22; Exp 2: d = 1.02) [13]. This study suggests that, though effective alone, NET may have improved outcomes when used in combination with other proven, relevant therapies. This is why we propose that a NET curriculum for migraine should incorporate both exercise and proven behavioral therapies, such as deep breathing exercises and cognitive behavioral therapy worksheets. NET modality and content are further outlined in Table 2.

Table 2.

NET modality and content for neck pain

Title	Modality of NET	NET Content
Does Pain Neuroscience Education and Cognition-Targeted Motor Control Training Improve Cervical Motor Output? Secondary Analysis of a Randomized Clinical Trial [45]	Frequency: three sessions Duration: spread over 2 wk Delivered by: uncertain Format: one group (60 min, maximum 6 individuals), two individuals (30 min each, 1 at home online)	Topics: encompassed general physiology of the nervous system, specific physiology of the pain system; following topics were explained using nontechnical terms, content, and images: the neuron, the synapse, descending nociceptive inhibition and facilitation, peripheral sensitization, and central sensitization Material: derived from Explain Pain [61](Butler and Moseley 2003) and Applying Contemporary Neuroscience in Exercise Interventions for Chronic Spinal Pain: Treatment Protocol [62] (Malfliet et al.)
Manual Therapy, Therapeutic Patient Education, and Therapeutic Exercise, an Effective Multimodal Treatment of Nonspecific Chronic Neck Pain. A Randomized Controlled Trial [13]	Frequency: seven sessions with other treatments (manual therapy and manual therapy+ exercise) that occurred after sessions 1 and 5 of manual therapy Duration: 20 min/session Delivered by: physiotherapist Format: one-on-one	Topics: Based on biobehavioral model and consisted of three sections: cognitive, operant, respondent; cognitive component consisted of pain physiology education, neck anatomy, and biomechanics; operant component consisted of about lifestyle changes; respondent component focused on self-treatment techniques Material: PowerPoint and informational booklet
The Effects of Pain Neuroscience Education and Exercise on Pain, Muscle Endurance, and Anxiety in Adolescents with Chronic Idiopathic Neck Pain: A School-Based Pilot, Randomized and Controlled Study [64]	Frequency: PNE and exercises once a week, for 4 consecutive weeks Duration: each session took 45–60 min (time spent PNE diminished from session 1 [45 min] to session 4 [15 min]) Delivered by: two physiotherapists Format: group (4–7 participants)	Topics: neurophisiology of pain, the nervous system, and the transition from acute to chronic pain Material: A booklet with figures and activities for each session. Pictures and diagrams from Explain Pain [48] (2013)
Pain Management Using Multimodal Physiotherapy Program Including a Biobehavioral Approach for Chronic Nonspecific Neck Pain: A Randomized Controlled Trial [65]	Frequency: total of 2 sessions Duration: each session 20 min Delivered by: two physiotherapists Format: one-on-one	Topics: pain and disability, coping strategies, cervical motor behavior, neurophysiological basis of pain Material: PowerPoint presentation with images, information booklet summarizing important parts of the educational talk
Effects of Pain Neuroscience Education and Dry Needling for the Management of Patients with Chronic Myofascial Neck Pain: A Randomized Clinical Trial [41]	Frequency: 3 sessions over 1 week Duration: 30 mins each Delivered by: physiotherapists Format: one-on-one	Topics: neurophysiology of pain, importance of pain thoughts or beliefs, and relevance of adaptive coping strategies, such as stress management, graduated physical activity, or progressive return to work Material: an introductory video on chronic pain introduced by the Spanish Pain Society [66]

PNE = Pain Neuroscience Education.

In a single-blind RCT, a randomization schedule was developed to compare manual therapy (MT) in the control group with MT plus therapeutic patient education for one experimental group and MT plus therapeutic exercise in the second experimental group, in patients with chronic nonspecific neck pain. The results from this study vary depending on which experimental group was being compared with the control. Using a repeated-measures analysis of variance for pain intensity, there was a higher reduction of pain in the therapeutic exercise group when compared with the control (d = 1.21) [65]. This study also suggests that the combination of therapeutic education and exercise would yield the most beneficial results. When both experimental groups were compared with one another, there was no statistically significant difference in pain intensity(d = 0.31), pain catastrophizing (d = -0.1), and illness severity (d = 0.14).

Another RCT, combining pain neuroscience education with myofascial trigger point dry needling to treat chronic myofascial neck pain, showed similar benefits; a 30% reduction in pain intensity on the visual analog scale of participants who received myofascial trigger point dry needling and pain neuroscience education, representing the minimal clinically important difference when compared with the control group [41]. This is consistent with results from an RCT that looked at the effects of pain neuroscience education and exercise on neck pain. The group that received pain neuroscience education showed a significant increase in the neck extensors endurance (P = 0.004) when compared with the control group [64]. In this study, 47.6% (n = 10/21) reported a “definite improvement that has made a real and worthwhile difference” against 4.5% (n = 1/22) participants of the control group. For NET content and modality for neck pain, refer to Table 2.

Chronic Low Back Pain

As seen in Table 3, a total of 12 studies were reviewed for NET benefits for chronic low back pain (CLBP). Of the 12 studies, 7 were longitudinal with assessments done at 3, 6, or 12 months after intervention. Of these studies, four found significant differences mainly in relation to pain intensity and disability at 3 months [35, 36] and 12 months [22, 27]. On the other hand, three studies show that benefits are short lasting with no significant difference between the control and intervention groups at 12 months when NET is used alone [31, 64, 69]. The five remaining studies had shorter assessment periods and reported significant benefits on CLBP in the NET intervention groups [20, 21, 23, 26, 67]. The length of each NET session ranged from as little as two 30- to 50-minute sessions to 4 hours of NET, suggesting NET has the potential to be effective in various session lengths, and, as such, studies on NET for patients with migraine should look for optimal duration. One study showed greater improvements in groups where physiotherapists conducted the intervention compared with a general practitioner. This pattern was seen in both the control and intervention groups led by the physiotherapists. While the authors do not comment much on the possible reasons for the difference, there may have been potentially beneficial information the physiotherapists shared with the scripted NET curriculum (for intervention group) or health care guidelines (for control group), and future studies might determine if there is a difference in outcomes if people with different trainings/backgrounds conduct the NET sessions [69]. Most of these studies demonstrated significant effects of neuroscience education for CLBP when coupled with other therapeutic treatments such as physiotherapy, trigger point dry needling, and motor and sensory retaining [22, 23, 33, 35, 36]. According to one article, the benefits of neuroscience education when combined with physiotherapy were maintained long term (12 months) [22]. Additionally, NET in one RCT resulted in a greater reduction in pain, catastrophization (d = 6.0), physical ineptitude, and negative pain beliefs (d = 9.0), when compared with a session on the anatomy and physiology of the back [20]. However, NET alone did not yield a clinically significant reduction in perceived disability (d = 2.0) in this study, suggesting that NET is one component—but not the sole component—of a successful treatment plan [20]. Yet, another study that used NET alone showed significant reduction in disability and pain intensity in the intervention group compared with control. This study had a goal-oriented approach with a 2-month timeline in which the sessions were delivered [27].

Table 3.

NET modality and content for low back pain

Title	Modality of NET	NET Content
Effect of Intensive Patient Education vs Placebo Patient Education on Outcomes in Patients with Acute Low Back Pain: A Randomized Clinical Trial [31]	Frequency: two sessions within a 6 wk from the start of acute back pain Duration: 1 hr each Delivered by: clinicians Format: individual format based on the patient’s concerns	Topics: biological basis of low back pain and pain in general, shifting of unhelpful beliefs, and developing new techniques for recovery Material: diagrams, stories, and metaphors; information based on the book Explain Pain [58] (Butler and Moseley 2013)
Short-Term Effect on Pain and Function of Neurophysiological Education and Sensorimotor Retraining Compared to Usual Physiotherapy in Patients with Chronic or Recurrent Non-Specific Low Back Pain, a Pilot Randomized Controlled Trial [67]	Frequency: two to four education sessions Duration: 30 min each Delivered by: physiotherapist Format: individual, at home using internet-based platform	Topics: neurophysiology of pain, biopsychosocial model of low back pain (LBP), cortical dysfunction in pain and body perception; meant to shift perspective of disability Material: participants received a copy of German version Explain Pain [68](Butler and Moseley) and had to read ten pages daily for 2 weeks
Evaluation of Individualized Quality of Life and Illness Perceptions in Low Back Pain. A Patient Education Cluster Randomized Controlled Trial [33]	Frequency: one session/wk for 4 wk Duration: 30 min Delivered by: general practitioner or physiotherapists Format: individual one-on-ones	Topics: education on the physiology of pain based on topics in PNE manual—examples of topics include pain does not equate to injury and an understanding of how the body’s alarm system processes threat Materials: an adapted version of the published manual for PNE—Explain Pain [58](Butler and Moseley 2003)
Cognitive Patient Education for Low Back Pain in Primary Care: A Cluster Randomized Controlled Trial and Cost-Effectiveness Analysis [69]	Frequency: once/week Duration: 4 weeks, each for 30 mins Delivered by: general practitioners and physiotherapists Format: all sessions were 1:1	Topics: pain mechanisms and neurophysiology Material: content delivered from the Explain Pain model [20]
Combined Education and Patient-Led Goal Setting Intervention Reduced Chronic Low Back Pain Disability and Intensity at 12 Months: A Randomized Controlled Trial [27]	Frequency: five face-to-face sessions Duration: 2 months; first was 1 hr and other four were 15–30 min each Delivered by: an experienced physiotherapist Format: all sessions were face to face	Topics: neurobiology and neurophysiology of pain as it relates to the nervous system Material: Handbook content from The Effect of Neuroscience Education on Pain, Disability, Anxiety, and Stress in Chronic Musculoskeletal Pain [11] (Louw A, Diener I, Butler DS, et al.)
Neuroscience Education in Addition to Trigger Point Dry Needling for the Management of Patients with Mechanical Chronic Low Back Pain: A Preliminary Clinical Trial [23]	Frequency: two sessions Duration: each session was 30 min Delivered by: dry needling administered by clinician Format: in person, 1:1 presentation with written information for home review distributed after sessions	Topics: sessions contained information about the neurophysiology of pain, the difference between acute nociception and chronic pain, and the role that beliefs and attitudes have in relation to pain Material: PowerPoint compiled using information from Explain Pain (Butler and Moseley) [61]
Combined Physiotherapy and Education Are Efficacious for Chronic Low Back Pain [22]	Frequency: four sessions Duration: each session was 1 hour Delivered by: physiotherapists Format: one-on-one	Topics: focused on the neurophysiology of pain with no particular reference to the lumbar spine Material: workbook with review and comprehension material
Aquatic Exercise and Pain Neurophysiology Education Versus Aquatic Exercise Alone for Patients with Chronic Low Back Pain: A Randomized Controlled Trial [36]	Frequency: two sessions Duration: each session was 90 min Delivered by: not discernable Format: in group	Topics: nervous system; transition from acute to chronic pain; central sensitization; the perception of pain; psychosocial, cognitive, and behavioral responses; flare-up management and pacing Material: from Explain Pain [61] (Butler and Moseley) and How to Explain Central Sensitization to Patients with “Unexplained” Chronic Musculoskeletal Pain [70] (Nijis et al.)
Evidence for a Direct Relationship Between Cognitive and Physical Change During an Education Intervention in People with Chronic Low Back Pain [21]	Frequency: one session Duration: 3 hours Delivered by: physiotherapist Format: one-on-one seminar	Topics: the neuron: receptor, axon, terminal; the synapse; spinal and descending inhibition and facilitation; peripheral sensitization; central sensitization Material: Explain Pain [61] (Butler and Moseley)
A Randomized Controlled Trial of Intensive Neurophysiology Education in Chronic Low Back Pain [20]	Frequency: one session followed by workbook to do every day for 2 weeks Duration: 3 hour/session Delivered by: physical therapist Format: one-on-one	Topics: the nervous system, synapses, and plasticity Material: Content based on Textbook of Pain [49] (Wall and Melzack)
Pain Neurophysiology Education and Therapeutic Exercise for Patients with Chronic Low Back Pain: A Single-Blind Randomized Controlled Trial [35]	Frequency: two sessions occurring 1 month apart Duration: 30–50 mins/session Delivered by: physiotherapists Format: group of 4–6 participants	Topics: “all main concepts of the neurophysiology of pain” Material: study by Van Oosterwijck et al. (2011), Pain Neurophysiology Education Improves Cognitions, Pain Thresholds, and Movement Performance in People with Chronic Whiplash: A Pilot Study [71] and Explain Pain (Butler and Moseley 2003) [61] and website and Pain in Motion [83]
Results of a feasibility Randomized Clinical Trial on Pain Education for Low Back Pain in Nepal: The Pain Education in Nepal-Low Back Pain (PEN-LBP) Feasibility Trial [26]	Frequency: one session Duration: 1 hour Delivered by: principal investigator (nonspecific) Format: one-on-one, individual session	Topics: education content included biological explanation of pain with metaphors and stories from Nepal, the normalization of pain, pain doesn’t equal physical damage, external factors’ influence on pain (social and environmental), body’s relation to pain (learning to experience pain) Materials: a pain education handbook was created using contents from the following books: Moseley G, Butler D—Explain Pain Supercharged (2017)[72], Explain Pain Handbook: Protectometer (2015)[74]; as well as clinical practice guidelines on LBP

PNE = Pain Neuroscience Education.

Research by Moseley [21] has also shown that, compared with education focused on anatomy, NET has the potential to increase physical activity within 1 day, suggesting that when pain is reconceptualized, negative psychological factors contributing to the subjective experience of pain diminish and pain threshold changes. Additionally, the study by Pires et al. [36] demonstrated that while neuroscience education aids in a decrease of pain (F(2,120) = 4.699; P < 0.05) and disability scores (F(2,120) = 5.415; P < 0.05), it does not always show significant changes in kinesiophobia for CLBP. This suggests that the pain reduction can be a result of changes in cognitive factors such as functional self-efficacy and catastrophizing and not necessarily pain-related fear. Thus, these cognitive changes may lessen the impact of pain-related fear, which decreases the experience of pain. More research needs to examine this association.

NET for Other Pain Conditions

Chronic Musculoskeletal Pain

As seen in Table 4, four studies (one RCT, one non-RCT, two observational longitudinal cohort studies) focusing on the use of NET in patients with overall chronic musculoskeletal pain were reviewed. The RCT by Kohns et al. [30] found that after a single one-on-one session of internet-delivered NET (NET video and survey self-assessments), participants reported lower pain severity and pain interference than the control group (non-NET video), increased belief that pain is a subjective experience, and greater readiness for self-management of pain at a 1-month follow-up. At a 10-month follow-up, while increased readiness to attribute pain to psychological factors was sustained in the intervention group, there were no significant differences in other measures.

Table 4.

NET modality and content for chronic musculoskeletal pain

Title	Modality of NET	NET Content
Pain Neuroscience Education Plus Usual Care Is More Effective than Usual Care Alone to Improve Self-Efficacy Beliefs in People with Chronic Musculoskeletal Pain: A Non-Randomized Controlled Trial [44]	Frequency: one session Duration: 2-hr session Delivered by: physiotherapists Format: five study participants and five companions to help reinforce learning via audio-visual material, oral explanation, summaries, images, metaphors, diagrams, written educational material	Topics: meaning of feeling pain (pain neurophysiology, pain as an alarm signal, danger sensors, nociception, nervous system functioning), pain does not equate to injury (psych-social nature as opposed to injury related), understanding why and how it hurts (brain is bioplastic, central sensitization, pain experience may be influenced by different factors, pain depends on balancing of safety–danger), negative thoughts and beliefs (SIMS and DIMS ), individuals can promote their recovery (alternatives to medication, bioplastics, knowledge can change pain), internet reinforcement resources Materials: audio-visual (images, metaphors, and diagrams), oral explanation, written educational material, Explain Pain [48] (Butler and Moseley 2013)
Health-Related Quality of Life Improvements Among Women with Chronic Pain: Comparison of Two Multidisciplinary Interventions [42]	Frequency: 12 sessions Duration: each session 45 min, total of 4 weeks Delivered by: a specialized interdisciplinary pain management team of physical therapists, a psychologist, and a psychiatric nurse Format: 8–12 people	Topics: normal sleep vs disrupted sleep; mental well-being and chronic pain; having chronic pain and being associated with those without; definitions of pain; own experiences of pain; changes in health status and acceptance, pain memory and movement, neurobiology and neurophysiology of pain and pain processing; pain interpretation by tissues within the nervous system; pain modulation, central sensitization and pain memory, behavioral patterns, and catastrophic thoughts; movement as stress management; definitions of stress, fight and flight reaction, general benefits of exercising, goal setting and time management, problem solving Materials: study by Adriaan Louw et al., The Effect of Neuroscience Education on Pain, Disability, Anxiety, and Stress in Chronic Musculoskeletal Pain [11]
Long-Lasting Improvements in Health-Related Quality Of Life Among Women with Chronic Pain, Following Multidisciplinary Rehabilitation [43]	Frequency: 12 sessions Duration: each session 45 min, total of 4 weeks Delivered by: a specialized interdisciplinary pain management team of physical therapists, a psychologist, and a psychiatric nurse Format: 8–12 people	Topics: normal sleep vs disrupted sleep; mental wellbeing and chronic pain; having chronic pain and being associated with those without; definitions of pain; own experiences of pain; changes in health status and acceptance, pain memory and movement, neurobiology and neurophysiology of pain and pain processing; pain interpretation by tissues within the nervous system; pain modulation, central sensitization and pain memory, behavioral patterns, and catastrophic thoughts; movement as stress management; definitions of stress, fight and flight reaction, general benefits of exercising, goal setting and time management, problem solving Materials: study by Adriaan Louw et al., The Effect of Neuroscience Education on Pain, Disability, Anxiety, and Stress in Chronic Musculoskeletal Pain [11]
The Effects of a Pain Psychology and Neuroscience Self-Evaluation Internet Intervention: A Randomized Controlled Trial Kohns et al. 2020 [30]	Frequency: one session Duration: 20–25 min Delivery: remotely, online self-learning Format: video, survey self-assessments	Topics: pain perception, how pain can be driven by fears/expectations instead of injury, and brain’s pathways for generating pain can be unlearned Materials: intervention titled “Pain Psychology and Neuroscience Self-Evaluation Internet Intervention (PPN)”: 3 min video on “Neural Pathways”; self-assessments: 1) a body map showing the 19 possible pain locations of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia Survey, checklist of other central sensitization or stress-related syndromes or diagnoses; 2) modified survey items representative of popular pain catastrophizing, kinesiophobia, and pain anxiety scales; (3) checklist of personality traits related to stress and pain chronicity; (4) checklist of life stressors that may have invoked the pain/occurs when pain is intensified; (5) 10-item Adverse Childhood Experiences Scale

SIMS = “Save in Me”; DIMS = “Danger in Me”.

A second study also examined the effects of a single session of NET comprised of audio-visual material, though in a group setting and not through an RCT. The results showed a statistically significant increase in self-efficacy, reduction of pain intensity, and decrease in pain interference, even after controlling for pain duration. No differences in analgesic consumption were found between the intervention and control groups during the intervention at 4-weeks follow-up and at 4-months follow-up [44].

A third and fourth study utilized different subsets and research designs to analyze the effects of NET in the same original longitudinal cohort of women with chronic musculoskeletal pain. In the first analysis, the NET intervention group was compared with both a second non-NET multidisciplinary pain management intervention group and a control group who received no interventions. The study found that compared with control groups, both intervention groups (NET and non-NET) experienced notable improvement in pain intensity and quality of life (except for financial status). Between the two intervention groups, no significant differences were observed except for the sleep domain of the health-related quality of life (HRQL) scale. Participants in the NET intervention group had better sleep outcomes than both the non-NET intervention and control groups (8.0 vs 4.4; 8.0 vs 1.5, respectively). Of note, the non-NET multidisciplinary pain management intervention group showed more improvement in pain intensity than the NET intervention group (21.8 vs 17. 2 mm on visual analog scale) with both intervention groups reporting less pain intensity than the control group [42].

In the second analysis of a subset of this same population, the NET intervention group was compared directly with the non-NET multidisciplinary pain management group, which then served as a control group. The results showed that from study discharge to 6 months follow-up, both groups experienced significant and sustained improvements across almost all aspects of HRQL. Additionally, the intervention group showed a nonsignificant decline in social functioning, physical health, and pain measurement on the quality-of-life scale and the visual analog scale. A significant decline was observed for all other measures. Of note, women with low HRQL at baseline improved more at the 6-month follow-up, across both groups. No significant difference was found between the intervention and control groups in regular exercise or practice of relaxation and/or meditation [43].

Fibromyalgia

As seen in Table 5, six studies evaluated NET as a treatment for fibromyalgia (FM), and studies vary in their results regarding efficacy. Two studies, one comparing NET with pain self-management education [29] and one comparing NET plus therapeutic exercise with therapeutic exercise alone [28] showed improved pain outcomes with NET compared with the control. In their study, Van Oosterwijck et al. [29] showed improved long-term pain scores and endogenous pain inhibition vs the control and improved physical functioning, general health perceptions, vitality, and mental health over time. Similarly, the Ceballos-Laita et al. [28] showed decreased pain intensity after NET in the short term. However, neither study showed significant improvement in a number of factors including catastrophizing, vigilance and awareness, FM impact, kinesiophobia, psychological distress, or quality of life [28, 29]. Ceballos-Laita and colleagues also reported no effect on mechanical pain sensitivity [28]. These findings suggest that, while effective in improving pain outcomes, NET may be best used when combined with techniques that target psychological and other components of pain.

Table 5.

NET modality and content for fibromyalgia

Title, Author, Year	Modality of NET	NET Content
Effectiveness of a Multicomponent Treatment for Fibromyalgia Based on Pain Neuroscience Education, Exercise Therapy, Psychological Support, and Nature Exposure (NAT-FM): A Pragmatic Randomized Controlled Trial Serrat et al. 2020 [38]	Frequency: once/week for 12 weeks Duration: full sessions were 2 hr, Pain Neuroscience Education (PNE) portion lasted 12 min Delivered by: physiotherapist, aid from fibromyalgia patient who recently completed relevant FIBROWALK study Format: group, approximately 21 participants/group	Topics: beliefs, modulation, pain system, CNS and CS, acute vs chronic pain, origin of acute pain, “pain versus damage,” pain neuromatrix theory, pain mechanisms and pathways, cognitions emotions and behavior, hypersensitivity, perception and memory, stress, cause, progression to chronicity, treatment and therapies Materials: Explain Pain [48] (Butler and Moseley 2013)
Therapeutic Exercise and Pain Neurophysiology Education in Female Patients with Fibromyalgia Syndrome: A Feasibility Study Ceballos-Laita et al. 2020 [28]	Frequency: 8 weeks, once/week Duration: 30–45 min Delivered by: medical doctor Format: face-to-face, individual vs group not specified	Topics: acute vs chronic pain, purpose of acute pain, physiological origin of pain, CS, pain becoming chronic, emotions behaviors and cognitions; use of metaphors and examples Materials: Explain Pain [48](Butler and Moseley 2013)
Emotional Awareness and Expression Therapy, Cognitive Behavioral Therapy, and Education for Fibromyalgia: A Cluster-Randomized Controlled Trial Lumley et al. 2017 [39]	Frequency: 8 weeks, once/week Duration: 90 min Delivered by: nurse educators Format: group meeting with educators, addition of handouts	Topics: FM central sensitization, diagnosis, medications, co-morbid disorders, and assessment of pain Materials: Study by Lumley et al., The Effects of Written Emotional Disclosure and Coping Skills Training in rheumatoid Arthritis: A Randomized Clinical Trial (2014)[73]
How Much Is Needed? Comparison of the Effectiveness of Different Pain Education Dosages in Patients with Fibromyalgia Amer-Cuenca et al. 2020 [75]	Frequency/Duration (by group): high-dose Pain Neuroscience Education (PNE): 6 sessions, 45 min/session; low dose concentrated PNE: 2 sessions, 45 min/session; diluted low-dose PNE: 6 sessions, 15/min session Delivered by: physiotherapists Format: not specified, PowerPoint used	Topics: physiology of nervous system, acute vs chronic pain, the purpose of pain, physiological origin of acute pain, pain perception and memory, how pain becomes chronic, CS, cognitions, and emotions Materials: PNE delivered in accordance to How to Explain Central Sensitization to Patients with “Unexplained” Chronic Musculoskeletal Pain: Practice Guidelines [70] (Nijs J, et al.): participants asked to read book Explicando el Dolor[76] (Spanish version of Explain Pain [Butler and Moseley 2003])
Pain Physiology Education Improves Health Status and Endogenous Pain Inhibition in Fibromyalgia: A Double Blind Randomized Controlled Trial Van Oosterwijck et al. 2013 [29]	Frequency: two sessions Duration: 30 min (first session), (second session, phone call, time not detailed) Delivered by: physiotherapist Format: one session; visual presentation, written pamphlet, phone call	Topics: acute vs chronic pain, nociception vs pain, purpose of acute pain, physiological origin of pain, CS, pain becoming chronic, emotions behaviors and cognitions Materials: based on Explain Pain [61] (Butler and Moseley, 2003)
Written Pain Neuroscience Education in Fibromyalgia: A Multicenter Randomized Controlled Trial van Ittersum et al. 2014 [25]	Frequency: participants had total of 6 weeks to read booklets Duration: N/A Delivered by: therapist Format: informational booklet, limited phone calls, and/or emails with therapist for clarification	Topics: structure and function of nervous system, nociception vs pain, tissue damage vs pain, CS and contributing factors, hypersensitivity, how to incorporate information into daily life Materials: NET booklet based on Explain Pain [61] (Butler and Moseley, 2003)

CNS = central nervous system; CS = central senzitization;.

Further, a study by Serrat et al. [38] comparing a multimodal treatment consisting of NET, exercise, CBT, mindfulness, and exposure to nature vs treatment as usual found that the multimodal treatment including NET was significantly more effective in improving functional impairment, pain, depression, physical functioning, fatigue, anxiety, positive affect, kinesiophobia, pain catastrophizing, personal perceived competence, and measures of cognition-emotion regulation. Lumley et al. [39] found that emotion awareness and expression therapy resulted in significantly improved symptoms, physical functioning, and lower widespread pain as well as a number of psychological factors compared with NET and significantly improved symptoms, lower widespread pain, and pain reduction at follow-up compared with CBT. These studies further suggest that NET is most effective when it incorporates approaches that target psychological and emotional factors of pain conditions.

Van Ittersum et al. [25] examined NET vs relaxation training in written forms and found that written forms of NET alone were ineffective. Another study evaluated the effect of differing NET dosages (high dose of six 45-minute sessions, low-concentrated dose of two 45-minute sessions, diluted low dose of six 15-minutes sessions, and control biomedical education) on patients with FM and concluded that higher dosages of Pain Neuroscience Education (PNE) resulted in better pain severity improvements, though the higher dosed intervention did not differ from the control in central nociceptive processing, disability, or psychological factors [75].

Chronic Fatigue Syndrome with Chronic Pain

In an RCT assessing NET vs pacing and self-management education on patients with chronic fatigue syndrome with chronic pain, participants who engaged in NET had an increased understanding of pain (d = 2.53), with scores higher than 99% of participants in the pacing and self-management education, and reported intention to ruminate less on the pain catastrophizing scale (d = -0.79) [24]. This once again provides a basis for the cognitive changes NET has the potential to impart, as opposed to the sole use of coping-focused patient education. NET modality and content are detailed in Table 6.

Table 6.

NET modality and content for chronic fatigue syndrome

CHRONIC FATIGUE SYNDROME
Title, Author, Year	Modality of NET	NET Content
Pain Physiology Education Improves Pain Beliefs in Patients with Chronic Fatigue Syndrome Compared with Pacing and Self-Management Education: A Double-Blind Randomized Controlled Trial Meeus et al. 2010 [24]	Frequency: one individual pain physiology education session (one-on-one) Duration: each lasted for 30 min Delivered by: physical therapist Format: In-person	Topics: physiology of the nervous system and pain system Materials: pictures and examples were provided; content was taken from Explain Pain [61] (Butler and Moseley 2003)

Migraine

Two RCTs studied the effects of combining NET with traditional primary health care treatments (regularly prescribed medication and a headache diary) for people with migraine. The first study compared participants with migraine who received conventional health care (control group) with those who also received NET (intervention group). At a 6-month follow-up, researchers found a significantly greater reduction in migraine disability assessment scores in the intervention group (an average of 21.2 points; P < 0.05). Intervention group participants were also three times less likely to use prescription drugs, less likely to overuse analgesics, had fewer headache-related calls, and had fewer unscheduled visits to the clinic [40].

In a second RCT, an intervention group attended group NET sessions while continuing regular care and a control group received only regular care. From baseline to 12-months follow-up, there was a greater reduction in migraine disability assessment scores in the intervention group compared with the control group (68.9% vs 36.6%) as well as a greater reduction in medication intake (odds ratio [OR] = 13.267; P < 0.001), limitation of activities due to migraine attacks, and duration and intensity of headaches (OR = 9.116; P = 0.005) [34].

A pilot study tested the effectiveness of a 1-day acceptance and commitment training plus migraine education workshop on comorbid depression and migraine [77]. The workshop included education on migraine pathology, migraine treatments and triggers, and risk of migraine chronification. The authors found results consistent with the two previously mentioned RCTs. The experimental group had greater improvement in depressive symptoms when compared with the control group (P = 0.0008, effect size = 1.18). There was also a 10.8-point greater mean decrease in the workshop group when compared with the control. There was significantly greater improvement in functionality within the workshop group, as displayed in the World Health Organization Disability Assessment Schedule II (P = 0.01), Short Form Health Survey (P = 0.11), and Headache Disability Inventory (P = 0.02) when compared with the control, (P = 0.60; P < 0.05; P = 0.006, respectively). The results of these studies suggest that including NET along with conventional treatments could produce more long-lasting and effective results than providing patients with traditional health care alone. Table 7 gives details on the NET content and modality of the three articles discussed in this section.

Table 7.

NET modality and content for migraine

MIGRAINE
Title, Author, Year	Modality of NET	NET Content
One-Day Behavioral Treatment for Patients with Comorbid Depression and Migraine: A Pilot Study Dindo et al. 2012 [77]	Frequency: assessment of depressive symptoms, general functioning, and migraine-related disability were completed at baseline, 2, 6, and 12 weeks after the workshop for both groups migraine education with Acceptanc & Comitment Therapy (ACT) as well as Control Group (CG) Duration: 5-hr workshop = 1 hr edu. and 4 hr of ACT CG: treatment as usual or waitlisted for the workshop Delivered by: headache specialist: education component; two psychologists: ACT component	Topics: “the pathology of migraine, risks for migraine chronification, migraine triggers, treatment of migraines, medication overuse migraine, lifestyle factors contributing to migraine. Acceptance and behavioral change training: managing troubling thoughts, feelings, and pain sensations, how to recognize ineffective patterns of behavior and habits.” Materials: not directly stated but a relevant study cited is from McCracken et al. (2005), Acceptance-Based Treatment for Persons with Complex, Long Standing Chronic Pain: A Preliminary Analysis of Treatment Outcome in Comparison to a Waiting Phase. Behaviour Research and Therapy[78]
Effectiveness of a Primary Care-Based Group Educational Intervention in the Management of Patients with Migraine: A Randomized Controlled Trial Aguirrezabal et al. 2019 [34]	Frequency: five sessions total, first four occurred weekly and the fifth occurred 1 month after the fourth session Duration: 1 hr and 45 min/session Delivered by: two family doctors, one neurologist Format: group of 10–12 participants, audio-visual and written materials used	Topics: pain does not equate to injury, perception, pain is generated in the brain, nociception, necrosis, apoptosis, and inflammation; congenital and acquired components of defense systems, analogy with the immune system, memory and learning in pain, genetics and the environment; mirror neurons and learning by imitation; cultural learning and learning with experts; reward systems; fear, brain plasticity, placebo, and nocebo effects and the efference copy system Materials: Migraine, Una Pesadilla Cerebral (Migraine: A Brain Nightmare) [83] (Goicoechea 2009); Explain Pain [48] (Butler and Moseley 2013); blog: Know Pain, No Pain [84] (Goicoechea 2017)
The Impact of Intensive Patient Education on Clinical Outcome in a Clinic-Based Migraine Population Rothrock et al. 2006 [40]	Frequency: three sessions held on evenings and weekends Duration: 90 min Delivered by: two patients who had previously received NET curriculum by neurology investigator; these patients had undergone 12 hours of classroom time focused on information about headache and 12 hours of observation in headache clinics Format: 30/45 min didactic learning, then a review of hard copy of materials relating to topic, demonstration of any therapeutic devices, and ending with question-and-answer session about learned topics	Topics: migraine biogenesis, acute treatment, and prevention of migraine Materials: NET curriculum material used in this study was requested from researchers but was no longer available

NET Content and Delivery

In reviewing the content of NET sessions used for the overlapping pain conditions mentioned above, similar components were observed across studies and diagnoses. As mentioned, Tables 1–7 outline the NET modality and content for each of these studies. Ultimately, NET aimed to correct patients’ false beliefs about pain and reduce patient fear and catastrophizing. It also introduced methods of relief such as goal setting, diaphragmatic breathing, relaxation, exercise, and physical therapy. Most studies evaluating NET for various chronic pain conditions have compiled interventions using material from Explain Pain by David S. Butler and G. Lorimer Moseley [58], published in 2003 [21, 23–26, 29, 31, 32, 35, 36, 46,47,50, 67, 75]. A newer edition of the book, published in 2013 [48], reflects slight changes in the field and is being used in more recent studies regarding NET [28, 34, 37, 64].

NET has been shown to offer benefits when delivered through individual sessions [13, 20–33], group sessions [34–44], or a combination of individual and group sessions [45–47,50]. Specifically for migraine, research has demonstrated that patients benefit most from a combination of pharmacologic treatment and behavioral therapy [6, 7]. Furthermore, similar to other pain conditions, exercise has proven effective in reducing pain in migraine patients [81] . We propose that a NET curriculum for migraine consists of either individual, group, or a combination of both individual and group interactive sessions on the neurophysiology of pain and migraine, exercise regimens, behavioral strategies for pain management such as relaxation, and conventional medication for migraine pain relief. The NET content should consist of metaphors, examples, pictures, and opportunities for patients to ask questions, clarify doubts, and reinforce material learned [14, 41]. Ultimately, as in the study by Aguirrezabal et al. [34], a peer mentor support system of people who have previously completed the curriculum might be helpful to current participants.

Proposed Mechanisms of NET

Of the 35 research articles reviewed, the majority attributed actual or expected results of NET to the modification of pain cognitions and/or behaviors. Examples include kinesiophobia, avoidance behaviors, equating pain to tissue damage, equating pain to nociception, catastrophizing, assignment of inappropriate threat value to pain, and overall pain anxiety and fear. One study attributed efficacy of NET to an increased patient ability to utilize therapies and treatment plans effectively [40]. Some studies discussed central sensitization as a key contributor to pain but did not discuss specific mechanisms mediating an effect of NET on central sensitization or other nervous system characteristics.

In contrast, eight articles [24, 25, 28, 29, 34, 35, 39, 75] discussed neurocircuitry that may mediate the effects of NET. Aguirrezabal et al. [34] proposed a decrease in activation of the pain neuromatrix due to cognitions rather than actual threat as a mechanism of treatment. Specifically, several articles proposed the influence of cognitions on centers involved in both pain pathways and cognition and emotion [39], like the limbic layer. In the Van Oosterwijck et al. [29] study of NET for fibromyalgia, central sensitization was attributed to inadequate function of descending nociceptive inhibitory pathways leaving from areas like the limbic system, which involve cognition and emotion and could therefore be modified by cognition and emotion. Lessened descending inhibition due to activation of the limbic system by cognitions was also cited by van Ittersum et al. [25] for fibromyalgia and Meeus et al. [24] in the context of chronic fatigue syndrome, the second of which made specific reference to the spinal dorsal horn. Bodes Pardo et al. [35] proposed a decrease in descending facilitatory pain mechanisms and increase in the activity of descending inhibitory pathways after NET for CLBP. Others also proposed improved nociceptive inhibition due to changed cognitions [28, 75]. As proposed by Van Oosterwijck et al. [29], modification of thoughts via NET could result in less pain facilitation and more inhibition centrally.

The Possible Role of Neurocircuitry: An Example Based Off of the Neuroimaging Findings from Behavioral Therapies for Migraine

Recent work has examined changes in brain activity resulting from behavioral therapies for migraine. One study by Nahman-Averbuch et al. [79] investigated the effect of CBT on brain activity and connectivity in children and adolescents with migraine. The authors found a decrease in headache frequency after CBT, greater activity in frontal regions involved in cognition and pain modulation, and changes in amygdala connectivity to frontal regions, among other findings. These results support the roles of cognition and behavioral therapies in migraine treatment. It also may indicate which areas of the brain may be involved in the mechanisms of NET for chronic pain, as the reconceptualization of pain (including correction of pain cognitions) carried out by NET may activate regions overlapping with those found in this study. This possibility is likely greater for NET curricula that include characteristic CBT concepts.

Despite these common understandings, relatively little is known about the mechanisms of NET. Specifically, for migraine, no original articles [34, 40, 64] included in this review discuss specific neurologic mechanisms underlying NET. Future work may focus on understanding potential neurocircuitry behind NET for migraine and related pain conditions.

Next Steps with NET

NET might be studied alone or in combination with other modalities for migraine treatment. Best methods for NET delivery and referral must be assessed, and research using hybrid effectiveness-implementation designs might be best to do this. Specifically, a hybrid design might encourage testing of clinical interventions using methods that can be applied to real-world cases [80]. Landes et al. note that this is ideal for interventions already tested and effective in studies related but not necessarily similar to the population being targeted, which is the case for NET as several articles have supported its efficacy in related pain conditions while few focus on migraine [80]. With NET, interventions supported with desired results can be combined to design a cost-benefit analysis of group vs individual treatments for an adequate referral system. Likewise, it would be beneficial to measure the impact of group size in relation to NET as it is usually administered at 10–12 participants per group session with migraine treatments [34].

There are various possibilities for delivering NET. As with many of the NET studies in this review, physiotherapists may deliver the treatment. Physiotherapists have sufficient knowledge of both the therapeutic process and neurophysiology [11] and are more populous, which may help overcome the shortage of other types of nonpharmacologic treatment providers in headache medicine. Further, physiotherapists may help combat stigma of behavioral therapy. However, behavioral therapists may also be involved in the delivery process. NET may also be delivered in-person or virtually via online modules and smartphones.

Providers must be able to discuss NET with their patients in a way that optimizes patient openness and adherence. This includes gaining patient trust, accurately describing NET and expected outcomes, and encouraging follow-through, which, along with patient understanding of the gravity of a problem, have been shown to result in higher adherence to treatment [8]. For NET specifically, the pain of migraine and the efficacy of NET must be communicated in ways to which patients can relate (i.e., change in days absent from work or school due to migraine, change in activity level, change in fear of migraine onset and pain). Thus, steps must be taken to increase NET as a treatment option while also encouraging patient openness and adherence.

Finally, there might be guidelines or best practices established for NET. As above, in this scoping review, we focused on the types of NET interventions (e.g., modalities, length, and duration of sessions) and did not focus on data quality in the individual studies. However, future work might examine data quality and risk of bias in an effort to develop such guidelines or set of best practices.

Conclusion

An abundance of research shows that similar NET curricula can be successfully used across various pain conditions. This paper has synthesized these curricula and discusses approaches for NET content, possible mechanisms explaining the basis of NET, and various methods for NET delivery. NET for migraine should have a multidisciplinary approach that includes explanations of what is known about the neuroscience behind migraine, the effects of behavioral treatments (e.g., CBT, relaxation, biofeedback), exercise, and the synergy in using pharmacologic treatment in combination with the behavioral treatment. More clinical trials with people with migraine are needed to evaluate the efficacy of NET for migraine and to iteratively refine and test the components of proposed curriculum and the modes by which NET is implemented.

Appendix

 

Ovid Medline Search Conducted January 15, 2021. No Limits Applied for Language, Publication Date, or Publication Type

1. ((neuroscience or pain or pain biology or neurophysiolog* or migraine) adj2 (intervention or education)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
2. (exp *Health Knowledge, Attitudes, Practice/or exp *Patient Education as Topic/) and exp Pain/
3. 1 or 2
4. (education* intervention adj10 (migraine* or pain*)).ti, ab, kw.
5. (migraine* or low back pain* or low backache* or chronic pain* or fibromyalgia or vulvodynia or Myalgic Encephalomyelitis or chronic fatigue or Postviral Fatigue or irritable bowel or irritable colon or mucous colitis or Idiopathic Headache or Stress Headache).ti, ab, kw.
6. (Tension adj2 Headache).ti, ab, kw.
7. ((TMJ or temporalmandibular) adj2 (disorder* or dysfunction* or syndrome*)).ti, ab, kw.
8. (urologic* chronic adj2 (pelvic or pain)).ti, ab, kw.
9. exp Migraine Disorders/or exp Tension-Type Headache/or exp Fatigue Syndrome, Chronic/or exp Fibromyalgia/or exp Vulvodynia/or Irritable Bowel Syndrome/or exp Temporomandibular Joint Disorders/or Chronic Pain/or Low Back Pain/
10. 5 or 6 or 7 or 8 or 9
11. 3 or 4
12. 10 and 11

 

Funding sources: This work was supported by funding from the NIH NCCIH (K23 AT009706‐01), and the Doris Duke Charitable Foundation.

Conflicts of interest: The authors have no conflicts of interest to report.