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Biological Correlates of the Effects of Auricular Point Acupressure on Pain

Open AccessPublished:December 19, 2022DOI:https://doi.org/10.1016/j.pmn.2022.11.004

      Abstract

      Background

      Aims: To identify candidate inflammatory biomarkers for the underlying mechanism of auricular point acupressure (APA) on pain relief and examine the correlations among pain intensity, interference, and inflammatory biomarkers.

      Design

      This is a secondary data analysis.
      Settings:
      Participants/Subjects:

      Methods

      Data on inflammatory biomarkers collected via blood samples and patient self-reported pain intensity and interference from three pilot studies (chronic low back pain, n = 61; arthralgia related to aromatase inhibitors, n = 20; and chemotherapy-induced neuropathy, n = 15) were integrated and analyzed. This paper reports the results based on within-subject treatment effects (change in scores from pre- to post-APA intervention) for each study group (chronic low back pain, cancer pain), between-group differences (changes in scores from pre- to post-intervention between targeted-point APA [T-APA] and non-targeted-point APA [NT-APA]), and correlations among pain intensity, interference, and biomarkers.

      Results

      Within-group analysis (the change score from pre- to post-APA) revealed statistically significant changes in three biomarkers: TNF-α (cancer pain in the APA group, p = .03), β-endorphin (back pain in the APA group, p = .04), and IL-2 (back pain in the NT-APA group, p = .002). Based on between-group analysis in patients with chronic low back pain (T-APA vs NT-APA), IL-4 had the largest effect size (0.35), followed by TNF-α (0.29). A strong positive monotonic relationship between IL-1β and IL-2 was detected.

      Conclusions

      The current findings further support the potential role of inflammatory biomarkers in the analgesic effects of APA. More work is needed to gain a comprehensive understanding of the underlying mechanisms of APA on chronic pain. Because it is simple, inexpensive, and has no negative side effects, APA can be widely disseminated as an alternative to opioids.

      Keywords

      Chronic pain is a major health problem (
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      Skelly AC, C. R., Dettori JR, Turner JA, Friedly JL, Rundell SD, Fu R, Brodt ED, Wasson N, Kantner S, Ferguson AJR. (2020). Noninvasive nonpharmacological treatment for chronic pain: A systematic review update. Comparative effectiveness review no. 227. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2015-00009-I.) AHRQ Publication No. 20-EHC009. Retrieved October 22, 2022, from https://effectivehealthcare.ahrq.gov/products/noninvasive-nonpharm-pain-update/research.

      ), but these options are challenging for providers and patients alike.
      Acupuncture, a nonpharmacologic therapy, is included in current guidelines to manage chronic pain (
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      • Wilt T.J.
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      Centers for Medicare and Medicaid Services. (2020). Decision Memo for Acupuncture for Chronic Low Back Pain (CAG-00452N). Retrieved September 26, 2022 from https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=295

      ). When the cost of acupuncture is covered, the insurers often limit the number of visits to control the cost (
      • Heyward J.
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      ). Even with these advances, barriers to implementing acupuncture for pain management exist, including frequent office visits, cost, and lack of access to licensed acupuncturists (
      • Cui J.
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      Use of acupuncture in the USA: Changes over a decade (2002-2012).
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      ).
      Auricular acupuncture, with origins stemming from traditional (body) acupuncture, is a unique “microsystem” that uses only ear points for treatment. Compared to body acupuncture, it is easier to learn and administer. Paul Nogier, a French neurologist and physician (
      • Nogier P.
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      How did Paul Nogier establish the map of the ear?.
      ) described a somatotopic representation of the human body on the ears. As part of the system of diagnosis, the presence of active areas on the ear meriting treatment is confirmed by examination of the electrodermal response, via the use of a point finder (
      • Yeh C.H.
      • Huang L.C.
      Comprehensive and systematic auricular diagnosis protocol.
      ). Once identified, active points can be treated classically with acupuncture needles and/or electrical stimulation (
      • Huang L.C.
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      ;
      • Oleson T.
      Auriculotherapy Manual: Chinese and Western Systems of Ear Acupuncture.
      ). Another system of treatment is auricular point acupressure (APA) with the use of plant-based vaccaria seeds or metal beads (
      • Yeh C.H.
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      Comprehensive and systematic auricular diagnosis protocol.
      ). Receiving greatest attention worldwide is the use of five classical auricular points for the treatment of addiction by the U.S.

      National Acupuncture Detoxification Association. (2010). Training resource manual: A handbook for individuals training in the National Acupuncture Detoxification Association's Five-needle Acudetox Protocol (4th ed.).

      . The Defense and Veterans Center for Integrative Pain Management and Veterans Health Administration National Pain Management Program have offered battlefield auricular acupuncture training courses for non-acupuncturists to enhance their pain management skills (
      • Niemtzow R.
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      ).
      Clinical studies have increasingly demonstrated that auricular acupuncture/APA is emerging as an evidenced-based pain treatment (
      • Abaraogu U.O.
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      As acupressure decreases pain, acupuncture may improve some aspects of quality of life for women with primary dysmenorrhea: A systematic review with meta-analysis.
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      Efficacy of auricular acupressure for chronic low back pain: A systematic review and meta-analysis of randomized controlled trials.
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      • Yeh C.H.
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      Efficacy of auricular therapy for pain management: A systematic review and meta-analysis.
      ;
      • Yeh CH.
      • Campbell C.
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      • Garry C.
      • Zeng J.
      • Chen C.
      • Pinedoa M.
      • Khoshnoodi M.
      • Smith T.J.
      • Saligan L.N
      Preliminary effectiveness of auricular point acupressure on chemotherapy-induced neuropathy: Part 2 laboratory-assessed and objective outcomes.
      ;
      • You E.
      • Kim D.
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      ;
      • Zhong Q.
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      • Du S.Z.
      • Song Y.L.
      • Zhu J.
      Effectiveness of auricular acupressure for acute postoperative pain after surgery: A systematic review and meta-analysis.
      ). Compared to the literature on body acupuncture (
      • Kim T.H.
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      Plausible mechanism of sham acupuncture based on biomarkers: A systematic review of randomized controlled trials.
      ;
      • Shi G.X.
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      Effect of electro-acupuncture (EA) and manual acupuncture (MA) on markers of inflammation in knee osteoarthritis.
      ), the literature on the biological mechanisms of the analgesic effects of auricular acupuncture/APA is limited. The gaps between APA effectiveness and mechanistic research have significantly hindered the acceptance of APA by the mainstream health care system and have limited its application in clinical settings.
      Stimulation of ear points may cause a broad spectrum of systemic effects, such as modulation of inflammatory cytokine levels, which may explain pain relief (
      • Lin W.C.
      • Yeh C.H.
      • Chien L.C.
      • Morone N.E.
      • Glick R.M.
      • Albers K.M.
      The anti-inflammatory actions of auricular point acupressure for chronic low back pain.
      ;
      • Yeh C.H.
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      • Park N.J.
      • Wood L.J.
      • van Londen G.J.
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      Auricular point acupressure to manage arthralgia related to aromatase inhibitors in breast cancer survivors.
      ;
      • Yeh CH.
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      • Garry C.
      • Zeng J.
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      Preliminary effectiveness of auricular point acupressure on chemotherapy-induced neuropathy: Part 2 laboratory-assessed and objective outcomes.
      ). Multiple APA studies have shown a decrease in pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) among patients with axial neck pain after anterior cervical discectomy and fusion (
      • Xia B.
      • Xie Y.
      • Hu S.
      • Xu T.
      • Tong P.
      Effect of auricular point acupressure on axial neck pain after anterior cervical discectomy and fusion: A randomized controlled trial.
      ), patients with chronic low back pain (
      • Lin W.C.
      • Yeh C.H.
      • Chien L.C.
      • Morone N.E.
      • Glick R.M.
      • Albers K.M.
      The anti-inflammatory actions of auricular point acupressure for chronic low back pain.
      ), cancer patients with chemotherapy-induced neuropathy (
      • Yeh CH.
      • Campbell C.
      • Sair H.
      • Zhang F.
      • Mensaha S.
      • Garry C.
      • Zeng J.
      • Chen C.
      • Pinedoa M.
      • Khoshnoodi M.
      • Smith T.J.
      • Saligan L.N
      Preliminary effectiveness of auricular point acupressure on chemotherapy-induced neuropathy: Part 2 laboratory-assessed and objective outcomes.
      ), and breast cancer patients with aromatase inhibitor-induced arthralgia (
      • Yeh C.H.
      • Lin W.C.
      • Suen L.K.P.
      • Park N.J.
      • Wood L.J.
      • van Londen G.J.
      • Bovbjerg D.H.
      Auricular point acupressure to manage arthralgia related to aromatase inhibitors in breast cancer survivors.
      ). These finding suggest that the effect of APA on chronic pain might be achieved through neuroimmune signaling. While studies have shown promising findings of the effect of APA on inflammatory biomarkers, the interpretation of these findings is limited owing to the exploratory nature of the studies (small sample size) (
      • Lin W.C.
      • Yeh C.H.
      • Chien L.C.
      • Morone N.E.
      • Glick R.M.
      • Albers K.M.
      The anti-inflammatory actions of auricular point acupressure for chronic low back pain.
      ;
      • Xia B.
      • Xie Y.
      • Hu S.
      • Xu T.
      • Tong P.
      Effect of auricular point acupressure on axial neck pain after anterior cervical discectomy and fusion: A randomized controlled trial.
      ;
      • Yeh C.H.
      • Chien L.C.
      • Albers K.M.
      • Margolis L.
      • Liu R.Y.
      • Suen L.
      • Ren D.
      Function of auricular point acupressure in inducing changes in inflammatory cytokines during chronic low back pain: A pilot study.
      ;
      • Yeh C.H.
      • Lin W.C.
      • Suen L.K.P.
      • Park N.J.
      • Wood L.J.
      • van Londen G.J.
      • Bovbjerg D.H.
      Auricular point acupressure to manage arthralgia related to aromatase inhibitors in breast cancer survivors.
      ;
      • Yeh CH.
      • Campbell C.
      • Sair H.
      • Zhang F.
      • Mensaha S.
      • Garry C.
      • Zeng J.
      • Chen C.
      • Pinedoa M.
      • Khoshnoodi M.
      • Smith T.J.
      • Saligan L.N
      Preliminary effectiveness of auricular point acupressure on chemotherapy-induced neuropathy: Part 2 laboratory-assessed and objective outcomes.
      ).
      Because of the persistent nature of pain in many chronic conditions (e.g., cancer, fibromyalgia, back pain), the underlying mechanism is believed to be modulated by increasing responsiveness of peripheral nociceptive neurons (peripheral sensitization) and nociceptive neurons in the central nervous system (central sensitization) (

      International Association for the Study of Pain. (2017). IASP Task Force on Taxonomy. Retrieved October 22, 2022, from https://www.iasp-pain.org/terminology?navItemNumber=576.

      ). To enhance our understanding of the effect of APA on the mechanism of pain relief among patients with chronic pain conditions, we conducted a secondary data analysis of three pilot studies that tested the ability of APA to manage pain among patients with chronic low back pain (n = 61) (
      • Lin W.C.
      • Yeh C.H.
      • Chien L.C.
      • Morone N.E.
      • Glick R.M.
      • Albers K.M.
      The anti-inflammatory actions of auricular point acupressure for chronic low back pain.
      ), aromatase inhibitor-induced arthralgia (n = 20) (
      • Yeh C.H.
      • Lin W.C.
      • Suen L.K.P.
      • Park N.J.
      • Wood L.J.
      • van Londen G.J.
      • Bovbjerg D.H.
      Auricular point acupressure to manage arthralgia related to aromatase inhibitors in breast cancer survivors.
      ), and chemotherapy-induced neuropathy (n = 15) (
      • Yeh CH.
      • Campbell C.
      • Sair H.
      • Zhang F.
      • Mensaha S.
      • Garry C.
      • Zeng J.
      • Chen C.
      • Pinedoa M.
      • Khoshnoodi M.
      • Smith T.J.
      • Saligan L.N
      Preliminary effectiveness of auricular point acupressure on chemotherapy-induced neuropathy: Part 2 laboratory-assessed and objective outcomes.
      ). The purpose of this secondary data analysis was to further identify candidate inflammatory biomarkers of the mechanisms of APA on pain relief and examine the correlations among pain intensity, interference, and inflammatory biomarkers. In this article, we report the results on within-subject treatment effects (changes in scores from pre- to post-APA intervention) and between-group differences (changes in scores from pre- to post-intervention between targeted-point APA [T-APA] and non-targeted-point APA [NT-APA]), and correlations among pain intensity, interference, and biomarkers.

      Methods

      Table 1 summarizes the designs, samples, and data collection information of the three pilot studies included (
      • Lin W.C.
      • Yeh C.H.
      • Chien L.C.
      • Morone N.E.
      • Glick R.M.
      • Albers K.M.
      The anti-inflammatory actions of auricular point acupressure for chronic low back pain.
      ;
      • Yeh C.H.
      • Lin W.C.
      • Suen L.K.P.
      • Park N.J.
      • Wood L.J.
      • van Londen G.J.
      • Bovbjerg D.H.
      Auricular point acupressure to manage arthralgia related to aromatase inhibitors in breast cancer survivors.
      ;
      • Yeh CH.
      • Campbell C.
      • Sair H.
      • Zhang F.
      • Mensaha S.
      • Garry C.
      • Zeng J.
      • Chen C.
      • Pinedoa M.
      • Khoshnoodi M.
      • Smith T.J.
      • Saligan L.N
      Preliminary effectiveness of auricular point acupressure on chemotherapy-induced neuropathy: Part 2 laboratory-assessed and objective outcomes.
      ). All three studies were approved by the university's Institutional Review Board. All study participants received interventionist-administered APA weekly for four weeks. Data were collected at pre- and post-intervention. All participants received four weekly APA treatments depending on the assigned study intervention (T-APA or NT-APA). For the low back pain study, the intervention included two study groups (T-APA or NT-APA) (
      • Lin W.C.
      • Yeh C.H.
      • Chien L.C.
      • Morone N.E.
      • Glick R.M.
      • Albers K.M.
      The anti-inflammatory actions of auricular point acupressure for chronic low back pain.
      ), while the cancer pain study included only the APA intervention (
      • Yeh C.H.
      • Lin W.C.
      • Suen L.K.P.
      • Park N.J.
      • Wood L.J.
      • van Londen G.J.
      • Bovbjerg D.H.
      Auricular point acupressure to manage arthralgia related to aromatase inhibitors in breast cancer survivors.
      ;
      • Yeh CH.
      • Campbell C.
      • Sair H.
      • Zhang F.
      • Mensaha S.
      • Garry C.
      • Zeng J.
      • Chen C.
      • Pinedoa M.
      • Khoshnoodi M.
      • Smith T.J.
      • Saligan L.N
      Preliminary effectiveness of auricular point acupressure on chemotherapy-induced neuropathy: Part 2 laboratory-assessed and objective outcomes.
      ).
      Table 1Summary of the Study Information and Demographic Characteristics.
      Study designChronic low back pain (n=61)Arthralgia related to aromatase inhibitors (n=20)Chemotherapy induced neuropathy (n=15)
      Two groups, randomized controlled trialOne group, open trialOne group, open trial
      InterventionT-APANT-APAT-APA (n=20)T-APA (n=15)
      Age, y61±17.4466±16.0460.20±7.95
      Sex
       Male10 (33%)10 (32%)04 (27%)
       Female20 (67%)21 (68%)20(100%)11 (73%)
      Race/ethnicity, n (%)
       White26 (87%)25 (81%)16 (80%)12 (80%)
       Black/African American4 (13%)6 (19%)4(20%)3 (20%)
      Employment situation
       Working8 (27%)6 (20%)9 (45%)4 (26%)
       Not employed (unemployed, retired, homemaker)22 (73%)25(80%)11 (55%)11 (74%)
      T-APA = targeted-point auricular point acupressure; NT-APA = non-targeted-point auricular point acupressure.

      APA Treatment Protocol

      Intervention group
      The APA intervention included one treatment per week for four consecutive weeks. Auricular points on participants’ ears were detected with an electrical acupoint finder, which measures auricular cutaneous resistance to identify the potential acupoints for treatment. Ear points for T-APA included three for alleviating stress and pain (i.e., Shenmen, sympathetic, and nervous subcortex) and corresponding points to the anatomical sites (i.e., lower back, foot, or hand), depending on the body symptom (
      • Yeh C.H.
      • Huang L.C.
      Comprehensive and systematic auricular diagnosis protocol.
      ). Bilateral auricular points were identified for treatment. Vaccaria seeds (natural, non-toxic botanical seeds of no medicinal value, ≈ 2 mm in diameter) were placed on the ear points for stimulation, and small pieces of waterproof tape (≈ 6 mm2) were used to secure the seeds onto the ears. In our previously published APA protocol (
      • Lin W.C.
      • Yeh C.H.
      • Chien L.C.
      • Morone N.E.
      • Glick R.M.
      • Albers K.M.
      The anti-inflammatory actions of auricular point acupressure for chronic low back pain.
      ;
      • Yeh C.H.
      • Lin W.C.
      • Suen L.K.P.
      • Park N.J.
      • Wood L.J.
      • van Londen G.J.
      • Bovbjerg D.H.
      Auricular point acupressure to manage arthralgia related to aromatase inhibitors in breast cancer survivors.
      ;
      • Yeh CH.
      • Campbell C.
      • Sair H.
      • Zhang F.
      • Mensaha S.
      • Garry C.
      • Zeng J.
      • Chen C.
      • Pinedoa M.
      • Khoshnoodi M.
      • Smith T.J.
      • Saligan L.N
      Preliminary effectiveness of auricular point acupressure on chemotherapy-induced neuropathy: Part 2 laboratory-assessed and objective outcomes.
      ), participants were told to press/stimulate the seeds taped to the acupoints on their ears at least three times per day for three minutes each time. The seeds and tape were removed at the end of the fifth day each week to regain point sensitivity prior to the next treatment. The endpoint was the measure of pain intensity and pain interference after the completion of the four-week APA. All study participants received the same APA intervention process.

      NT-APA Group

      The acupoints selected for the NT-APA group were located away from the site where the participant was experiencing low back pain and included the stomach, mouth, duodenum, and kidney (
      • Yeh C.H.
      • Huang L.C.
      Comprehensive and systematic auricular diagnosis protocol.
      ). Participants in the NT-APA group were blinded to the group assignments.

      Measures

      Pain intensity and interference
      Pain intensity (worst) and pain interference were measured as clinical study outcomes using the Brief Pain Inventory Short Form (BPI-sf) (
      • Cleeland C.S.
      • Ryan K.M.
      Pain assessment: Global use of the Brief Pain Inventory [Review].
      ). Worst pain intensity is a 0-10-point numerical rating scale in the past seven days (0 = “no pain at all”-10 “the worst pain ever possible”). The pain interference subscale of the BPI-sf is composed of seven items on a 0-10-point scale assessing the effect of pain on daily function in the past seven days (0 = “Does not interfere”-10 = “Completely interferes). The reliability and validity of the BPI-sf have been cited in more than 400 publications (
      • Cleeland C.S.
      • Ryan K.M.
      Pain assessment: Global use of the Brief Pain Inventory [Review].
      ).

      Inflammatory Biomarkers

      The circulating levels of inflammatory cytokines (IL-1β, IL-2, IL-4, IL-6, IL-10, and TNF-α), β-endorphin, and calcitonin gene-related peptide (CGRP) were measured. The detailed blood sample collection, extraction, and testing processes were published in a previous manuscript (
      • Lin W.C.
      • Yeh C.H.
      • Chien L.C.
      • Morone N.E.
      • Glick R.M.
      • Albers K.M.
      The anti-inflammatory actions of auricular point acupressure for chronic low back pain.
      ).

      Data Analysis

      The assumption of the normal distribution of the data was checked. The square-root transformation for the pain interference scores and log-transformation for all biomarkers were used to reduce the skewness of the data before data analyses. Descriptive analysis was used to display the outcomes measurements (including inflammatory biomarkers, pain intensity, and pain interference). Within-subject changes were examined using the changes in scores from pre- to post-intervention for individual subjects in each study group. Between-group differences were examined using the within-subject changes in scores from pre- to post-intervention between the T-APA and NT-APA groups (in only the low back pain study). The Mann-Whitney U Test was used to examine the difference in between-group score changes (T-APA versus NT-APA in the back pain study). Effect size as the standardized differences in the mean between two means (Cohen's d: between-group = the mean score change in the T-APA group compared to the NT-APA group in the low back pain study; within-group = the mean score change from pre-intervention to post-intervention) was calculated to estimate the sample sizes for future randomized controlled trials. The Wilcoxon signed-rank test was performed to test the null hypothesis of no difference in outcome measures between pre- and post-intervention for each study group (within-group difference). Spearman's rank correlation coefficient was used to examine the relationship between clinical outcomes (pain intensity and interference) and biomarkers. Significance was set at a p value < .05 for the data analysis and the multiple testing was not adjusted. All data analyses were performed using SAS 9.4 and R-4.2.0.

      Results

      Characteristics of the Study Participants

      In total, 96 study participants were included (n = 61 patients with chronic low back pain, n = 20 breast cancer patients with arthralgia, and n = 15 cancer patients with chemotherapy-induced neuropathy) (Table 1). Most of the study participants were White (82%) and female (68% in the chronic low back pain study and 73% of the cancer patients with chemotherapy-induced neuropathy). Their ages ranged from 35-71 years.

      Clinical Outcomes and Biomarkers

      Table 2 presents data on clinical outcomes (pain intensity and pain interference) and biomarkers at pre- and post-APA treatment, within-subject changes (the change score between pre- and post-intervention) in biomarkers, pain intensity, and pain interference for each group (T-APA versus NT-APA), and between-group differences (the change in scores between pre- and post-intervention between the T-APA and NT-APA groups in the back pain study). Scores on all the study outcomes (pain intensity, pain interference, and biomarkers) decreased from pre-intervention to post-intervention. The only exceptions were TNF-α and IL-4 in the APA back pain group, whereby TNF-α increased and IL-4 did not change after the intervention.
      Table 2Summary Statistics of Auricular Point Acupressure Effect on Pain Intensity, Pain Interference, and Inflammatory Biomarkers.
      Outcomes/ChangesPre-T-APAPost-T-APAWithin-Subject Mean ChangeBetween-Group Difference
      Between-group effect size= (Mt-Ms)/σpooled. Mt mean change score for T-APA-Back group, Ms mean change score for NT-APA group (or th. σpooled = √[((nt-1)σt2+(ns-1)σs2)/(nt+ns)-2], nt = the sample size for T-APA-Back group, ns = the sample size for NT-APA group, σt = standard deviation of change score for T-APA-Back group, σs = standard deviation of change sccore for NT-APA group.
      Mean ± SDMean ± SDMean ± SD (p value)Effect Size
      Within-group effect size= (Mpost-Mpre)/σpooled. Mpost mean score of post-, Mpre mean score of pre- (or σpooled = √[((npost-1)σpost2+(npre-1)σpre2)/(npost+npre)-2], npost = the sample size for post-, npre = the sample size for the pre-, σpost = standard deviation of post-, σpre = standard deviation of of the post-. APA = auricular point acupressure; T-APA = targeted-point APA; NT-APA = non-targeted-point APA; SD = standard deviation; CGRP = calcitonin gene-related peptide; p = Mann-Whitney U Test (between T-APA-Back and NT-APA) and Wilcoxon signed rank test (within-group differences).
      Mean ± SD (p value)Effect Sizea
      Pro-inflammatory Cytokines
      IL-1βT-APA-Back (n=30)2.61 ± 0.562.54 ± 0.53-0.07 ± 0.25 (0.14)-0.12-0.03 ± 0.19 (0.57)-0.15
      T-APA-Cancer (n=35)2.43 ± 1.472.39 ± 1.43-0.04 ± 0.40 (0.48)-0.03
      NT-APA (n=31)2.60 ± 0.622.56 ± 0.62-0.04 ± 0.10 (0.08)-0.06
      IL-2T-APA-Back (n=30)2.71 ± 0.562.66 ± 0.52-0.05 ± 0.28 (0.66)-0.090.02 ± 0.22 (0.78)0.07
      T-APA-Cancer (n=35)3.38 ± 0.572.98 ± 1.10-0.40 ± 0.98 (0.06)-0.45
      NT-APA (n=31)2.70 ± 0.692.64 ± 0.71-0.07 ± 0.10 (0.002)-0.09
      IL-6T-APA-Back (n=30)3.38 ± 0.513.30 ± 0.54-0.08 ± 0.37 (0.89)-0.16-0.01 ± 0.33 (0.89)-0.04
      T-APA-Cancer (n=35)3.68 ± 0.793.42 ± 1.22-0.26 ± 0.87 (0.27)-0.25
      NT-APA (n=31)3.45 ± 0.503.38 ± 0.53-0.07 ± 0.29 (0.39)-0.14
      TNF-αT-APA-Back (n=30)4.65 ± 0.364.67 ± 0.370.02 ± 0.16 (0.99)0.050.05 ± 0.16 (0.27)0.29
      T-APA-Cancer (n=35)4.19 ± 0.914.09 ± 0.94-0.10 ± 0.24 (0.03)-0.11
      NT-APA (n=31)4.75 ± 0.504.72 ± 0.45-0.03 ± 0.17 (0.19)-0.06
      Anti-inflammatory Cytokines
      IL-4T-APA-Back (n=30)2.79 ± 0.532.79 ± 0.550.00 ± 0.10 (0.97)0.010.04 ± 0.13 (0.20)0.35
      T-APA-Cancer (n=35)2.89 ± 0.322.86 ± 0.30-0.03 ± 0.20 (0.56)-0.08
      NT-APA (n=31)2.71 ± 0.422.67 ± 0.37-0.04 ± 0.15 (0.22)-0.10
      IL-10T-APA-Back (n=30)3.33 ± 0.363.26 ± 0.32-0.06 ± 0.19 (0.08)-0.18-0.03 ± 0.20 (0.62)-0.13
      T-APA-Cancer (n=35)3.90 ± 0.833.69 ± 1.01-0.21 ± 1.09 (0.18)-0.23
      NT-APA (n=31)3.41 ± 0.363.38 ± 0.34-0.04 ± 0.21 (0.42)-0.10
      Neuropeptides
      CGRPT-APA-Back (n=30)2.62 ± 1.762.55 ± 1.63-0.07 ± 0.38 (0.40)-0.04-0.04 ± 0.35 (0.71)-0.11
      NT-APA-Back (n=31)2.99 ± 1.312.95 ± 1.46-0.03 ± 0.31 (0.52)-0.02
      EndorphinT-APA-Back (n=30)4.88 ± 0.304.82 ± 0.29-0.06 ± 0.14 (0.04)-0.20-0.01 ± 0.17 (0.83)-0.06
      NT-APA-Back (n=31)4.76 ± 0.294.71 ± 0.21-0.05 ± 0.20 (0.08)-0.20
      Clinical Outcomes
      Pain IntensityT-APA-Back (n=30)6.31 ± 1.932.44 ± 2.23-3.88 ± 2.93 (<0.0001)-1.86-3.05 ± 2.75 (<0.0001)-1.11
      T-APA-Cancer (n=35)6.94 ± 2.463.21 ± 2.37-3.73 ± 2.18 (<0.0001)-1.54
      NT-APA (n=31)6.07 ± 1.715.24 ± 2.44-0.83 ± 2.55 (<0.0001)-0.39
      Pain InterferenceT-APA-Back (n=30)2.26 ± 0.462.60 ± 1.88-0.38 ± 0.47 (<0.0001)-0.640.23 ± 0.57 (0.12)0.41
      T-APA-Cancer (n=35)3.26 ± 2.374.36 ± 1.97-1.29 ± 1.69 (<0.0001)-0.61
      NT-APA (n=31)2.12 ± 0.402.35 ± 1.51-0.61 ± 0.66 (<0.0001)-0.91
      a Between-group effect size= (Mt-Ms)/σpooled. Mt mean change score for T-APA-Back group, Ms mean change score for NT-APA group (or th. σpooled = √[((nt-1)σt2+(ns-1)σs2)/(nt+ns)-2], nt = the sample size for T-APA-Back group, ns = the sample size for NT-APA group, σt = standard deviation of change score for T-APA-Back group, σs = standard deviation of change sccore for NT-APA group.
      b Within-group effect size= (Mpost-Mpre)/σpooled. Mpost mean score of post-, Mpre mean score of pre- (or σpooled = √[((npost-1)σpost2+(npre-1)σpre2)/(npost+npre)-2], npost = the sample size for post-, npre = the sample size for the pre-, σpost = standard deviation of post-, σpre = standard deviation of of the post-.APA = auricular point acupressure; T-APA = targeted-point APA; NT-APA = non-targeted-point APA; SD = standard deviation; CGRP = calcitonin gene-related peptide; p = Mann-Whitney U Test (between T-APA-Back and NT-APA) and Wilcoxon signed rank test (within-group differences).

      Within-group Changes in Biomarkers After Intervention

      Within-subject analyses revealed statistically significant changes in three biomarkers: TNF-α (cancer pain in the T-APA group, p = .03), β-endorphin (low back pain in the T-APA group, p = .04), and IL-2 (low back pain in the NT-APA group, p = .002). Four biomarkers achieved the change with borderline significance (p value between .05-.10): IL-2 (cancer pain in the T-APA group, p = 0.06), IL-10 (low back pain in the T-APA group, p = 0.08), IL-1β (low back pain in the NT-APA group, p = .08), and β-endorphin (low back pain in the NT-APA group, p = 0.08). IL-6 had an effect size of –0.25 while the p value was .27 in the cancer pain APA group.

      Between-group Differences

      Using the within-group changes in biomarker scores (pre- and post-intervention) between the T-APA and NT-APA groups in the low back pain groups, IL-4 had the largest effect size (0.35), followed by TNF-α (0.29). Three biomarkers had effect sizes greater than 0.10 (IL-1β = 0.15; IL-10 = 0.13; and CGRP = 0.11). Other biomarkers had an effect size smaller than 0.10.

      Correlations Among Biomarkers, Pain Intensity, and Pain Interference

      Table 3 shows the Spearman's rank correlation coefficients among pain intensity, pain interference, and inflammatory biomarkers on the change in scores after treatment for all subjects. A strong positive monotonic relationship was detected between IL-1β and IL-2 (Spearman's ρ = 0.66). Moderate positive monotonic relationships were detected between IL-1β and IL-6 (Spearman's ρ = 0.41), between IL-1β and CGRP (Spearman's ρ = 0.41), between IL-2 and IL-6 (Spearman's ρ = 0.48), between IL-2 and IL-10 (Spearman's ρ = 0.43), between IL-6 and IL-10 (Spearman's ρ = 0.57), and between TNF-α and IL-10 (Spearman's ρ = 0.41). Figure 1 presents the scatter plot for outcome measures with statistically significant Spearman's rank correlation coefficients.
      Table 3Spearman Rank Correlation among Pain Intensity, Pain Interference, and Inflammatory Biomarkers.
      OutcomesIL-2IL-6TNF-αIL-4IL-10CGRPEndorphinPain IntensityInterference
      IL-1β0.66
      p value < 0.0001.
      0.41
      p value < 0.01.
      0.090.24
      p value < 0.05.
      0.35
      p value < 0.01.
      0.41
      p value < 0.01.
      -.08-0.090.04
      IL-20.48a0.31
      p value < 0.01.
      0.31
      p value < 0.01.
      0.43a0.26-.09-0.110.05
      IL-60.29
      p value < 0.01.
      0.170.57a0.080.18-0.060.09
      TNF-α0.190.41a-.220.09-0.09-0.09
      IL-40.25
      p value < 0.05.
      -.05-.18-0.02-0.04
      IL-10-.010.040.05-0.02
      CGRP0.12-0.11-0.17
      Endorphin0.040.06
      Pain Intensity0.08
      a p value < 0.0001.
      b p value < 0.01.
      c p value < 0.05.
      Figure 1
      Figure 1Scatter Plot for Outcome Measures with Statistically Significant Spearman's Rank Correlation. r = Spearman's Rank Correlation Coefficient.

      Discussion

      The findings of this secondary data analysis from our three pilot studies showed significant improvements in self-reported data (pain intensity and pain interference), significant changes in levels of TNF-α, β-endorphin, and IL-2 from pre- to post-intervention (within-group differences), significant between-group differences in IL-4 and TNF-α (changes from pre- to post-intervention between the T-APA group and NT-APA group), and strong correlations between IL-1β and IL-2, thereby contributing to a better understanding of the role of APA in pain relief via the inflammatory pathway.
      The current findings from different chronic pain conditions support the notion that APA may modulate inflammatory biomarkers and consequently lead to the reduction of pain intensity and pain interference.Consistent with other findings, we speculate that APA may affect pain by modulating the type 1 helper T cells and macrophages to reduce pro-inflammatory cytokines that augment pain signals in many chronic pain conditions (
      • Laumet G.
      • Ma J.
      • Robison A.J.
      • Kumari S.
      • Heijnen C.J.
      • Kavelaars A.
      T cells as an emerging target for chronic pain therapy.
      ). Peripherally released cytokines also modulate pain signaling and play an important role in the advancement of chronic pain (
      • Andrade P.
      • Hoogland G.
      • Garcia M.A.
      • Steinbusch H.W.
      • Daemen M.A.
      • Visser-Vandewalle V.
      Elevated IL-1beta and IL-6 levels in lumbar herniated discs in patients with sciatic pain.
      ;
      • Austin P.J.
      • Moalem-Taylor G.
      The neuro-immune balance in neuropathic pain: Involvement of inflammatory immune cells, immune-like glial cells and cytokines.
      ). Inhibitors of pro-inflammatory cytokines, such as TNF-α inhibitors (
      • Ohtori S.
      • Miyagi M.
      • Eguchi Y.
      • Inoue G.
      • Orita S.
      • Ochiai N.
      • Kishida S.
      • Kuniyoshi K.
      • Nakamura J.
      • Aoki Y.
      • Ishikawa T.
      • Arai G.
      • Kamoda H.
      • Suzuki M.
      • Takaso M.
      • Furuya T.
      • Toyone T.
      • Takahashi K.
      Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: A prospective randomized study.
      ) and IL-6 (
      • Ohtori S.
      • Miyagi M.
      • Eguchi Y.
      • Inoue G.
      • Orita S.
      • Ochiai N.
      • Kishida S.
      • Kuniyoshi K.
      • Nakamura J.
      • Aoki Y.
      • Ishikawa T.
      • Arai G.
      • Kamoda H.
      • Suzuki M.
      • Takaso M.
      • Furuya T.
      • Kubota G.
      • Sakuma Y.
      • Oikawa Y.
      • Toyone T.
      • Takahashi K.
      Efficacy of epidural administration of anti-interleukin-6 receptor antibody onto spinal nerve for treatment of sciatica.
      ) that reduce cytokine expression, have been used to block chronic pain associated with spinal stenosis (
      • Ohtori S.
      • Miyagi M.
      • Eguchi Y.
      • Inoue G.
      • Orita S.
      • Ochiai N.
      • Kishida S.
      • Kuniyoshi K.
      • Nakamura J.
      • Aoki Y.
      • Ishikawa T.
      • Arai G.
      • Kamoda H.
      • Suzuki M.
      • Takaso M.
      • Furuya T.
      • Toyone T.
      • Takahashi K.
      Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis: A prospective randomized study.
      ). While the mechanism of APA on reducing pro-inflammatory cytokines is unclear, we speculate that ear point stimulation causes vasodilation effects via the release of neuropeptide-induced local anti-inflammatory cytokines that could lead to the reduction of pro-inflammatory cytokines. These responses are modulated by mediators of inflammatory biomarkers and could explain the analgesic effects of APA on chronic pain.
      While the current analysis enhances our understanding of the effect of APA on inflammatory biomarkers, why the stimulation of the ear points leads to pain relief remains unclear. Recent advances in functional magnetic resonance imaging (fMRI) have provided a useful tool to understand this knowledge gap. For example, stimulation of the ear thumb point produced significant fMRI activity in the thumb region of the somatosensory cortex (
      • Alimi D.
      • Geissmann A.
      • Gardeur D.
      Auricular acupuncture stimulation measured on functional magnetic resonance imaging.
      ;
      • Romoli M.
      • Allais G.
      • Airola G.
      • Benedetto C.
      • Mana O.
      • Giacobbe M.
      • Pugliese A.M.
      • Battistella G.
      • Fornari E.
      Ear acupuncture and fMRI: A pilot study for assessing the specificity of auricular points.
      ), whereas stimulation of a different area of the external ear did not produce the change (
      • Alimi D.
      • Geissmann A.
      • Gardeur D.
      Auricular acupuncture stimulation measured on functional magnetic resonance imaging.
      ), suggesting the existence of a neurophysiological connection between ear points, corresponding body areas, and the brain (
      • Alimi D.
      • Geissmann A.
      • Gardeur D.
      Auricular acupuncture stimulation measured on functional magnetic resonance imaging.
      ;
      • Romoli M.
      • Allais G.
      • Airola G.
      • Benedetto C.
      • Mana O.
      • Giacobbe M.
      • Pugliese A.M.
      • Battistella G.
      • Fornari E.
      Ear acupuncture and fMRI: A pilot study for assessing the specificity of auricular points.
      ).
      Compared with the pain treatments currently available (
      • Qaseem A.
      • McLean R.M.
      • O'Gurek D.
      • Batur P.
      • Lin K.
      • Kansagara D.L.
      Nonpharmacologic and pharmacologic management of acute pain from non-low back, musculoskeletal injuries in adults: A clinical guideline from the American College of Physicians and American Academy of Family Physicians.
      ), patients can feel immediate (one-two minutes) pain relief after ear point stimulation (
      • Yeh C.H.
      • Chien L.C.
      • Chiang Y.C.
      • Huang L.C.
      Auricular point acupressure for chronic low back pain: A feasibility study for 1-week treatment.
      ), making APA an attractive pain treatment. The immediate pain relief from APA has yet to be clearly explained. We previously conducted an fMRI study to observe brain activity after APA stimulation (
      • Yeh C.H.
      • Caswell K.
      • Pandiri S.
      • Sair H.
      • Lukkahatai N.
      • Campbell C.M.
      • Stearns V.
      • Van de Castle B.
      • Perrin N.
      • Smith T.J.
      • Saligan L.N.
      Dynamic brain activity change after auricular point acupressure on patients with chemotherapy-induced peripheral neuropathy: A pilot longitudinal functional magnetic resonance imaging study.
      ). The results showed that APA can modulate the brain connectivity of the salience network (a brain network for the integration of sensory, emotional, and cognitive information) (
      • Uddin L.Q.
      Salience Network of the Human Brain.
      ), the executive control network (a key network in top-down cognitive control processes, such as decision making and emotion regulation) (
      • Goldman-Rakic P.S.
      Architecture of the prefrontal cortex and the central executive.
      ), and the basal ganglia network (a crucial network for a variety of motor and cognitive functions) (
      • Afifi A.K.
      The basal ganglia: A neural network with more than motor function.
      ). These findings provide a theoretical basis for the neural mechanism of APA in pain processing. We speculate that overlapped cutaneous nerves in the outer ear (i.e., auricular branch of the vagus nerve, the auriculotemporal nerve, and the great auricular nerve) correspond to specific areas of the brain to confer immediate pain relief from ear point stimulation. Specifically, we posit that these areas have a reflex connection with specific parts of the body, and that stimulating ear points provides therapeutic effects.

      Implications for Nursing and Pain Management

      The current findings advance our basic scientific understanding of the inflammatory pathway underlying the effects of APA on pain relief and could facilitate the acceptance of APA by mainstream healthcare providers. Unlike acupuncture, which is a passive treatment, APA is a noninvasive, low-cost technique and engages patients to apply pressure to points on their ears to self-manage pain anywhere, anytime. Moreover, compared to acupuncture, APA is more accessible to patients because it can be administered by health practitioners with brief training and is feasible to scale up. APA is not yet widely available in U.S. healthcare systems, and we received an overwhelming number of requests from former study participants for further APA treatment. To scale up, maximizing the usability and accessibility of APA, we have conducted pilot studies using a smartphone app to support self-administered APA for pain, which featured instructional and demonstrational videos (
      • Kawi J.
      • Yeh C.H.
      • Li M.C.
      • Caswell K.
      • Mazraani M.
      • Lukkahatain N.
      • Mensah S.
      • Taylor J.
      • Budhathoki C.
      • Christo P.
      Auricular point acupressure smartphone application to manage chronic musculoskeletal pain: A longitudinal, one-group, open pilot trial.
      ;
      • Yeh C.H.
      • Kawi J.
      • Ni A.
      • Christo P.
      Evaluating auricular point acupressure for chronic low back pain self-management using technology: A feasibility study.
      ). The four-week intervention demonstrated the feasibility of APA to support self-management of pain among patients with chronic pain (
      • Kawi J.
      • Yeh C.H.
      • Li M.C.
      • Caswell K.
      • Mazraani M.
      • Lukkahatain N.
      • Mensah S.
      • Taylor J.
      • Budhathoki C.
      • Christo P.
      Auricular point acupressure smartphone application to manage chronic musculoskeletal pain: A longitudinal, one-group, open pilot trial.
      ;
      • Yeh C.H.
      • Kawi J.
      • Ni A.
      • Christo P.
      Evaluating auricular point acupressure for chronic low back pain self-management using technology: A feasibility study.
      ). The current study sets the foundation for future work to test the endogenous biomarkers and critically elucidate the mechanism of APA on pain relief.

      Limitations

      Because of the complex interaction among inflammatory biomarkers in chronic pain (
      • Iyengar S.
      • Ossipov M.H.
      • Johnson K.W.
      The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine.
      ;
      • Mizher H.
      • Zin C.S.
      • Helal Uddin A.B.
      • Mohamed A.H.
      • Ling T.H.
      • Izzat M.
      Plasma concentrations of pro-inflammatory cytokine IL-6 and anti-inflammatory cytokine IL-10 in short- and long-term opioid users with noncancer pain.
      ;
      • Schou W.S.
      • Ashina S.
      • Amin F.M.
      • Goadsby P.J.
      • Ashina M.
      Calcitonin gene-related peptide and pain: A systematic review.
      ;
      • Uceyler N.
      • Valenza R.
      • Stock M.
      • Schedel R.
      • Sprotte G.
      • Sommer C.
      Reduced levels of anti-inflammatory cytokines in patients with chronic widespread pain.
      ), the study findings should be interpreted in light of limitations, including the nature of the secondary data analysis (i.e., the combination of data from different chronic pain conditions), a lack of comparison of APA data in the cancer pain group, a lack of long-term follow-up data (i.e., only pre- and post-intervention data were included), and a lack of the control of confounding in inflammatory biomarkers. For example, cytokines and chemokines have short half-lives that vary from two-six hours (
      • Oda S.
      • Hirasawa H.
      • Shiga H.
      • Nakanishi K.
      • Matsuda K.
      • Nakamua M.
      Sequential measurement of IL-6 blood levels in patients with systemic inflammatory response syndrome (SIRS)/sepsis.
      ), and information regarding circadian rhythms and other clinical characteristics (e.g., acute illness/ trauma, immune disease, medication use, nutrition, endocrine/metabolic disease) was not available.

      Conclusions

      Based on our findings, APA shows great promise to reverse chronic pain through an inflammatory mechanism, i.e., it exhibits anti-inflammatory efficacy by blocking pro-inflammatory cytokines (TNF-α, IL-2) or releasing anti-inflammatory cytokines (IL-4) or β-endorphins. More work is needed to understand the complex nature of these biological, psychophysiological, and genetic relationships. Future larger-scale research should investigate the effect of these biomarkers on the analgesic effects of APA in a rigorous mechanism study using a randomized control trial and ear point specificity-control.

      Declaration of interests

      None.

      Acknowledgements

      Research reported in this publication was supported by grants to Dr. Chao Hsing Yeh from Under Armour Women's Health & Breast Cancer Innovation Grant, Johns Hopkins Medicine, and the National Institute on Aging of the National Institutes of Health (R01AG056587).

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