National Institutes of Health (NIH)

We are pleased to introduce the collection Frontiers in Pain Research – Highlights in Non-Pharmacological Treatment of Pain 2021/22. This collection will welcome and showcase a selection of high impact articles authored by leaders in the field. The work presented here highlights the broad diversity of research performed across the Non-Pharmacological Treatment of Pain section, and aims to put a spotlight on the main areas of interest. This collection aims to further support Frontiers’ strong community by shining a spotlight on our authors' highly impactful research.

National Center for Complementary and Integrative Health (NIH)

Massachusetts General Hospital, Harvard Medical School

Frontiers in Pain Research

Non-Pharmacological Treatment of Pain

Highlights in Non-Pharmacological Treatment of Pain ?2021/22

BackgroundChronic low back pain is a debilitating condition that impacts millions of individuals around the world, and also has an enormous economic impact. The impact of chronic pain does not only involve physical health, but can also play a detrimental role in a patient's mental health. Consequently, it is critical to approach these patients with multimodal management. Initially, a treatment plan which includes medications, psychotherapy, physical therapy, and invasive interventions can be utilized for chronic back pain. However, many patients experience refractory low back pain to these initial treatments, which can result in non-resolving chronic pain. As a result, many new interventions have been developed in recent years to treat refractory low back pain, including non-invasive transcranial magnetic stimulation. In recent years, there has been some limited and preliminary evidence for the treatment of chronic low back pain with transcranial magnetic stimulation, as further investigation on this intervention is warranted. After reviewing analytically high impact studies, our objective is to provide a narrative review of the treatment of chronic low back pain with repetitive transcranial magnetic stimulation (rTMS).</sec>MethodsWe performed a comprehensive database search on PubMed, Embase, PsychInfo, Web of Science, and CINAHL for literature that pertains to the treatment of chronic low back pain with transcranial magnetic stimulation using these terms: “Chronic Low Back Pain and Transcranial Magnetic Stimulation”, “Low Back Pain and Transcranial Magnetic Stimulation”, “Chronic Back Pain and Transcranial Magnetic Stimulation”, “Chronic Low Back Pain and TMS”, “Low Back Pain and TMS”, and “Chronic Back Pain and TMS”. We aim to provide a narrative review of the role of rTMS in CLBP.</sec>ResultsInitial search results from September to November 2021 using the above-mentioned search criteria included 458 articles, of which 164 duplicates were removed and 280 were further excluded by a three-person (CO, NM and RA) screening process. Articles were further filtered based on various exclusion and inclusion criteria. The resulting 6 studies are discussed.</sec>DiscussionThe studies reviewed suggest the potential benefit in chronic lower back pain symptoms after various rTMS protocols and sites of stimulation. However, the included studies are not without issues in design for example: not randomized, not blinded, or have small sample size. This review highlights the need for scaled, better controlled research studies and standardization of treatment protocols to determine if rTMS for chronic lower back pain will be accepted as a standard treatment option for patients with chronic lower back pain symptoms.</sec>

Background: Chronic low back pain is a debilitating condition that impacts millions of individuals around the world, and also has an enormous economic impact. The impact of chronic pain does not only involve physical health, but can also play a detrimental role in a patient's mental health. Consequently, it is critical to approach these patients with multimodal management. Initially, a treatment plan which includes medications, psychotherapy, physical therapy, and invasive interventions can be utilized for chronic back pain. However, many patients experience refractory low back pain to these initial treatments, which can result in non-resolving chronic pain. As a result, many new interventions have been developed in recent years to treat refractory low back pain, including non-invasive transcranial magnetic stimulation. In recent years, there has been some limited and preliminary evidence for the treatment of chronic low back pain with transcranial magnetic stimulation, as further investigation on this intervention is warranted. After reviewing analytically high impact studies, our objective is to provide a narrative review of the treatment of chronic low back pain with repetitive transcranial magnetic stimulation (rTMS).Methods: We performed a comprehensive database search on PubMed, Embase, PsychInfo, Web of Science, and CINAHL for literature that pertains to the treatment of chronic low back pain with transcranial magnetic stimulation using these terms: “Chronic Low Back Pain and Transcranial Magnetic Stimulation”, “Low Back Pain and Transcranial Magnetic Stimulation”, “Chronic Back Pain and Transcranial Magnetic Stimulation”, “Chronic Low Back Pain and TMS”, “Low Back Pain and TMS”, and “Chronic Back Pain and TMS”. We aim to provide a narrative review of the role of rTMS in CLBP.Results: Initial search results from September to November 2021 using the above-mentioned search criteria included 458 articles, of which 164 duplicates were removed and 280 were further excluded by a three-person (CO, NM and RA) screening process. Articles were further filtered based on various exclusion and inclusion criteria. The resulting 6 studies are discussed.Discussion: The studies reviewed suggest the potential benefit in chronic lower back pain symptoms after various rTMS protocols and sites of stimulation. However, the included studies are not without issues in design for example: not randomized, not blinded, or have small sample size. This review highlights the need for scaled, better controlled research studies and standardization of treatment protocols to determine if rTMS for chronic lower back pain will be accepted as a standard treatment option for patients with chronic lower back pain symptoms.

Transcranial magnetic stimulation for the treatment of chronic low back pain: a narrative review

The ability of non-invasive brain stimulation to induce neuroplasticity and cause long-lasting functional changes is of considerable interest for the reversal of chronic pain and disability. Stimulation of the primary motor cortex (M1) has provided some of the most encouraging after-effects for therapeutic purposes, but little is known about its underlying mechanisms. In this study we combined transcranial Direct Current Stimulation (tDCS) and fMRI to measure changes in task-specific activity and interregional functional connectivity between M1 and the whole brain. Using a randomized counterbalanced sham-controlled design, we applied anodal and cathodal tDCS stimulation over the left M1. In agreement with previous studies, we demonstrate that tDCS applied to the target region induces task-specific facilitation of local brain activity after anodal tDCS, with the stimulation effects having a negative relationship to the resting motor threshold. Beyond the local effects, tDCS also induced changes in multiple downstream regions distinct from the motor system that may be important for therapeutic efficacy, including the operculo-insular and cingulate cortex. These results offer opportunities to improve outcomes of tDCS for the individual patient based on the degree of presumed neuroplasticity. Further research is still warranted to address the optimal stimulation targets and parameters for those with disease-specific symptoms of chronic pain.

The ability of non-invasive brain stimulation to induce neuroplasticity and cause long-lasting functional changes is of considerable interest for the reversal of chronic pain and disability. Stimulation of the primary motor cortex (M1) has provided some of the most encouraging after-effects for therapeutic purposes, but little is known about its underlying mechanisms. In this study we combined transcranial Direct Current Stimulation (tDCS) and fMRI to measure changes in task-specific activity and interregional functional connectivity between M1 and the whole brain. Using a randomized counterbalanced sham-controlled design, we applied anodal and cathodal tDCS stimulation over the left M1. In agreement with previous studies, we demonstrate that tDCS applied to the target region induces task-specific facilitation of local brain activity after anodal tDCS, with the stimulation effects having a negative relationship to the resting motor threshold. Beyond the local effects, tDCS also induced changes in multiple downstream regions distinct from the motor system that may be important for therapeutic efficacy, including the operculo-insular and cingulate cortex. These results offer opportunities to improve outcomes of tDCS for the individual patient based on the degree of presumed neuroplasticity. Further research is still warranted to address the optimal stimulation targets and parameters for those with disease-specific symptoms of chronic pain.

Task-dependent plasticity in distributed neural circuits after transcranial direct current stimulation of the human motor cortex: A proof-of-concept study

From Where We've Come to Where We Need to Go: Physiotherapy Management of Chronic Whiplash-Associated Disorder

Background: Slow stroking touch is generally perceived as pleasant and reduces thermal pain. However, the tactile stimuli applied tend to be short-lasting and typically applied to the forearm. This study aimed to compare the effects of a long-lasting brushing stimulus applied to the facial region and the forearm on pressure pain thresholds (PPTs) taken on the hand. Outcome measurements were touch satiety and concurrent mechanical pain thresholds of the hand.Methods: A total of 24 participants were recruited and randomized to receive continuous stroking, utilizing a robotic stimulator, at C-tactile (CT) favorable (3 cm/s) and non-favorable (30 cm/s) velocities applied to the right face or forearm. Ratings of touch pleasantness and unpleasantness and PPTs from the hypothenar muscle of the right hand were collected at the start of stroking and once per minute for 5 min.Results: A reduction in PPTs (increased pain sensitivity) was observed over time (P < 0.001). However, the increase in pain sensitivity was less prominent when the face was stroked compared to the forearm (P = 0.001). Continuous stroking resulted in a significant interaction between region and time (P = 0.008) on pleasantness ratings, with a decline in ratings observed over time for the forearm, but not on the face. Unpleasantness ratings were generally low.Conclusion: We observed touch satiety for 5 min of continuous robotic brushing on the forearm confirming previous studies. However, we did not observe any touch satiety for brushing the face. Mechanical pain sensitivity, measured in the hand, increased over the 5-min period but less so when paired with brushing on the face than with brushing on the forearm. The differential effects of brushing on the face and forearm on touch satiety and pain modulation may be by the differences in the emotional relevance and neuronal pathways involved.

Background: Slow stroking touch is generally perceived as pleasant and reduces thermal pain. However, the tactile stimuli applied tend to be short-lasting and typically applied to the forearm. This study aimed to compare the effects of a long-lasting brushing stimulus applied to the facial region and the forearm on pressure pain thresholds (PPTs) taken on the hand. Outcome measurements were touch satiety and concurrent mechanical pain thresholds of the hand.Methods: A total of 24 participants were recruited and randomized to receive continuous stroking, utilizing a robotic stimulator, at C-tactile (CT) favorable (3 cm/s) and non-favorable (30 cm/s) velocities applied to the right face or forearm. Ratings of touch pleasantness and unpleasantness and PPTs from the hypothenar muscle of the right hand were collected at the start of stroking and once per minute for 5 min.Results: A reduction in PPTs (increased pain sensitivity) was observed over time (P &lt; 0.001). However, the increase in pain sensitivity was less prominent when the face was stroked compared to the forearm (P = 0.001). Continuous stroking resulted in a significant interaction between region and time (P = 0.008) on pleasantness ratings, with a decline in ratings observed over time for the forearm, but not on the face. Unpleasantness ratings were generally low.Conclusion: We observed touch satiety for 5 min of continuous robotic brushing on the forearm confirming previous studies. However, we did not observe any touch satiety for brushing the face. Mechanical pain sensitivity, measured in the hand, increased over the 5-min period but less so when paired with brushing on the face than with brushing on the forearm. The differential effects of brushing on the face and forearm on touch satiety and pain modulation may be by the differences in the emotional relevance and neuronal pathways involved.

Robotic Stroking on the Face and Forearm: Touch Satiety and Effects on Mechanical Pain

Background: Nonrestorative sleep is commonly reported by individuals with fibromyalgia, but there is limited information on the reliability and responsiveness of self-reported sleep measures in this population.Objectives: (1) Examine the reliability and validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) sleep measures in women with fibromyalgia, and (2) Determine the responsiveness of the PROMIS sleep measures to a daily transcutaneous electrical nerve stimulation (TENS) intervention in women with fibromyalgia over 4 weeks compared with other measures of restorative sleep.Methods: In a double-blinded, dual-site clinical trial, 301 women with fibromyalgia were randomly assigned to utilize either Active-TENS, Placebo-TENS, or No-TENS at home. Measures were collected at baseline and after 4 weeks of treatment. To assess self-reported sleep, the participants completed three PROMIS short forms: Sleep Disturbance, Sleep-Related Impairment, Fatigue, and the Pittsburgh Sleep Quality Index (PSQI). To assess device-measured sleep, actigraphy was used to quantify total sleep time, wake after sleep onset, and sleep efficiency. Linear mixed models were used to examine the effects of treatment, time, and treatment*time interactions.Results: The PROMIS short forms had moderate test–retest reliability (ICC 0.62 to 0.71) and high internal consistency (Cronbach's alpha 0.89 to 0.92). The PROMIS sleep measures [mean change over 4 weeks, 95% confidence interval (CI)], Sleep Disturbance: −1.9 (−3.6 to −0.3), Sleep-Related Impairment: −3 (−4.6 to −1.4), and Fatigue: −2.4 (−3.9 to −0.9) were responsive to improvement in restorative sleep and specific to the Active-TENS group but not in the Placebo-TENS [Sleep Disturbance: −1.3 (−3 to 0.3), Sleep-Related Impairment: −1.2 (−2.8 to 0.4), Fatigue: −1.1 (−2.7 to 0.9)] or No-TENS [Sleep Disturbance: −0.1 (−1.6 to 1.5), Sleep-Related Impairment: −0.2 (−1.7 to 1.4), Fatigue: –.3 (−1.8 to 1.2)] groups. The PSQI was responsive but not specific with improvement detected in both the Active-TENS: −0.9 (−1.7 to −0.1) and Placebo-TENS: −0.9 (−1.7 to 0) groups but not in the No-TENS group: −0.3 (−1.1 to 0.5). Actigraphy was not sensitive to any changes in restorative sleep with Active-TENS [Sleep Efficiency: −1 (−2.8 to 0.9), Total Sleep Time: 3.3 (−19.8 to 26.4)].Conclusion: The PROMIS sleep measures are reliable, valid, and responsive to improvement in restorative sleep in women with fibromyalgia.Clinical Trial Registration:<ext-link ext-link-type="uri" xlink:href="https://www.ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">www.ClinicalTrials.gov</ext-link>, identifier: NCT01888640.

Background: Nonrestorative sleep is commonly reported by individuals with fibromyalgia, but there is limited information on the reliability and responsiveness of self-reported sleep measures in this population.Objectives: (1) Examine the reliability and validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) sleep measures in women with fibromyalgia, and (2) Determine the responsiveness of the PROMIS sleep measures to a daily transcutaneous electrical nerve stimulation (TENS) intervention in women with fibromyalgia over 4 weeks compared with other measures of restorative sleep.Methods: In a double-blinded, dual-site clinical trial, 301 women with fibromyalgia were randomly assigned to utilize either Active-TENS, Placebo-TENS, or No-TENS at home. Measures were collected at baseline and after 4 weeks of treatment. To assess self-reported sleep, the participants completed three PROMIS short forms: Sleep Disturbance, Sleep-Related Impairment, Fatigue, and the Pittsburgh Sleep Quality Index (PSQI). To assess device-measured sleep, actigraphy was used to quantify total sleep time, wake after sleep onset, and sleep efficiency. Linear mixed models were used to examine the effects of treatment, time, and treatment*time interactions.Results: The PROMIS short forms had moderate test–retest reliability (ICC 0.62 to 0.71) and high internal consistency (Cronbach's alpha 0.89 to 0.92). The PROMIS sleep measures [mean change over 4 weeks, 95% confidence interval (CI)], Sleep Disturbance: −1.9 (−3.6 to −0.3), Sleep-Related Impairment: −3 (−4.6 to −1.4), and Fatigue: −2.4 (−3.9 to −0.9) were responsive to improvement in restorative sleep and specific to the Active-TENS group but not in the Placebo-TENS [Sleep Disturbance: −1.3 (−3 to 0.3), Sleep-Related Impairment: −1.2 (−2.8 to 0.4), Fatigue: −1.1 (−2.7 to 0.9)] or No-TENS [Sleep Disturbance: −0.1 (−1.6 to 1.5), Sleep-Related Impairment: −0.2 (−1.7 to 1.4), Fatigue: –.3 (−1.8 to 1.2)] groups. The PSQI was responsive but not specific with improvement detected in both the Active-TENS: −0.9 (−1.7 to −0.1) and Placebo-TENS: −0.9 (−1.7 to 0) groups but not in the No-TENS group: −0.3 (−1.1 to 0.5). Actigraphy was not sensitive to any changes in restorative sleep with Active-TENS [Sleep Efficiency: −1 (−2.8 to 0.9), Total Sleep Time: 3.3 (−19.8 to 26.4)].Conclusion: The PROMIS sleep measures are reliable, valid, and responsive to improvement in restorative sleep in women with fibromyalgia.Clinical Trial Registration: <a href="https://www.ClinicalTrials.gov">www.ClinicalTrials.gov</a>, identifier: NCT01888640.

Test–Retest Reliability and Responsiveness of PROMIS Sleep Short Forms Within an RCT in Women With Fibromyalgia

Background: Pain captures attention and interferes with competing tasks demanding cognitive effort. Brief mindfulness interventions involving both conceptual learning and meditation exercises have been shown to improve attention and reduce pain sensitivity, and could potentially reduce pain interference. This study assesses the effect of a 5-day mindfulness intervention (20 min/day) on the interference produced by thermal pain on working memory performance using a 2-back task.Methods: Healthy participants were randomized into three groups exposed to mindfulness meditation training (n = 15), an active educational control intervention comprising only conceptual information on mindfulness (n = 15), or no intervention (n = 15). The two active interventions were administered in a dual-blind fashion and outcomes were assessed by research personnel blind to this allocation. Evaluation sessions were conducted before and after the interventions to assess the effect of pain on 2-back performance (pain interference). Importantly, both pain stimuli and the 2-back task were calibrated individually and in each session before assessing pain interference, thereby controlling for possible changes in baseline pain sensitivity and cognitive performance. Secondary outcomes included heat pain sensitivity, cold pain tolerance, cognitive inhibition, cognitive flexibility, and divided attention.Results: Manipulation checks confirmed that heat pain interferes with the performance of the working-memory task. Compared to the no-intervention control group, pain interference was significantly reduced following the conceptual intervention but not the meditation intervention, although a corollary analysis suggests the effect might be due to regression toward the mean caused by baseline imbalance in pain interference. Secondary outcomes also suggested an increase in pain tolerance in the conceptual learning group only.Discussion: A short mindfulness meditation intervention was insufficient to reduce pain interference but conceptual learning about mindfulness produced some unexpected benefits. Although the generalization of experimental findings to clinical pain conditions may be premature, these results highlight the importance of distinguishing the contribution of mindfulness education and meditation training in future studies. Understanding the effects of mindfulness training on pain regulation and management must take into consideration the multiple factors underlying this complex intervention.

Background: Pain captures attention and interferes with competing tasks demanding cognitive effort. Brief mindfulness interventions involving both conceptual learning and meditation exercises have been shown to improve attention and reduce pain sensitivity, and could potentially reduce pain interference. This study assesses the effect of a 5-day mindfulness intervention (20 min/day) on the interference produced by thermal pain on working memory performance using a 2-back task.Methods: Healthy participants were randomized into three groups exposed to mindfulness meditation training (n = 15), an active educational control intervention comprising only conceptual information on mindfulness (n = 15), or no intervention (n = 15). The two active interventions were administered in a dual-blind fashion and outcomes were assessed by research personnel blind to this allocation. Evaluation sessions were conducted before and after the interventions to assess the effect of pain on 2-back performance (pain interference). Importantly, both pain stimuli and the 2-back task were calibrated individually and in each session before assessing pain interference, thereby controlling for possible changes in baseline pain sensitivity and cognitive performance. Secondary outcomes included heat pain sensitivity, cold pain tolerance, cognitive inhibition, cognitive flexibility, and divided attention.Results: Manipulation checks confirmed that heat pain interferes with the performance of the working-memory task. Compared to the no-intervention control group, pain interference was significantly reduced following the conceptual intervention but not the meditation intervention, although a corollary analysis suggests the effect might be due to regression toward the mean caused by baseline imbalance in pain interference. Secondary outcomes also suggested an increase in pain tolerance in the conceptual learning group only.Discussion: A short mindfulness meditation intervention was insufficient to reduce pain interference but conceptual learning about mindfulness produced some unexpected benefits. Although the generalization of experimental findings to clinical pain conditions may be premature, these results highlight the importance of distinguishing the contribution of mindfulness education and meditation training in future studies. Understanding the effects of mindfulness training on pain regulation and management must take into consideration the multiple factors underlying this complex intervention.