Auricular Vagus Nerve Acupressure For Patients With Emotional Distress Under The COVID-19 Pandemic: A Smartphone-based, Randomized Controlled Trial
Mar 15, 2022
For more information:ali.ma@wecistanche.com
Abstract
Objective: To confirm whether self-administered AVNA treatment is effective in improving emotional distress under the COVID-19 pandemic. Methods: A smartphone-based online, randomized, controlled trial was designed from 26 February 2020 to 28 April 2020 in four study sites, including Wuhan, Beijing, Shenyang, and Guangzhou of China. Local residents who had considerable emotional distress with a score of the Hospital Anxiety and Depression Scale (HADS) ≥ 9 were recruited. Participants were randomly assigned to three times AVNA (n = 191) per day, in the morning, around noon, and in the evening or usual care (UC, n = 215) once daily for 14 days. The primary outcome was the response rate, which was the proportion of participants whose Hospital Anxiety and Depression Scale (HADS) score reduced from baseline by ≥ 50%. The assessment was conducted at baseline, 3 days, and 14 days. Results: The AVNA group had a markedly higher response rate than the UC group at 3 days (35.6% vs. 24.9%, P = 0.02) and at 14 days (70.7% vs. 60.6%, P = 0.02). The AVNA group showed a significantly greater reduction in scores of HADS at the two measurement points and BAI at 3 days (P ≤ 0.03), with an average respective effect size of 0.217 and 0.195. Participants with AVNA spent less time falling asleep and rated their sleep quality as remarkably higher than those with UC at the endpoint. Conclusion: During the COVID-19 pandemic period, treatment with self-administrated AVNA was more effective than UC in reducing the emotional distress of isolated populations. These findings support self-administered AVNA as a treatment option for patients with emotional distress under the COVID-19 pandemic or other emergent events.
Keywords: Neurology, Psychiatry, Emotional distress, Auricular vagus nerve stimulation, COVID- 19
Background
The global spread of the 2019 coronavirus disease (COVID-19) has become a public health emergency of international concern. Although infectious disease management measures, including city lockdown and household isolation, have reduced the risk of viral transmission, it has also produced a considerable number of patients with emotional distress, such as anxiety, depression, and poor sleep [1. Therefore, therapeutic approaches that show effectiveness and convenience will hold considerable promise for the treatment of emotional distress under COVID-19.
Several studies have confirmed the efficacy of acupressure in relieving insomnia of patients and the emotional distress of caregivers [2-4]. The external ear is a specific anatomic region where nerve fibers and terminals from the auricular branch of the vagus nerve (ABVN) are abundantly distributed in the concha and surrounding areas(Figure 1A)[5-8]. Accumulating evidence from clinical studies has confirmed that stimulation of auricular acupoints is effective in improving sleep quality, and in reducing anxiety and depressed mood with low side effects [9-12]. We have also demonstrated the efficacy of a non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) in patients with emotional distress [13, 14]. These studies have led to the hypothesis that self-administered auricular vagus nerve acupressure (AVNA)might be an effective management intervention of emotional distress under the COVID-19 pandemic.
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To test this hypothesis, a randomized controlled trial was conducted via a smartphone-based online mini-program. We compared the efficacy of self-administered AVNA treatment with usual care (UC) in reducing the emotional distress of local residents during COVID-19lockdown and household isolation in China. Breathing-focused and home-based exercise, the most frequently recommended activities at home during the COVID-19 pandemic, were included as major UC interventions [15, 16].
Methods
Inclusion and exclusion criteria
Patients were included if they met the diagnosis of emotional distress, using a Hospital Anxiety and Depression Scale (HADS).
Inclusion criteria included:(1)subjects aged between 18 and 75 years;(2)HADS scores29 points during the baseline phase,(3)living in the study cities for at least half a year.
Those who had been diagnosed with a psychiatric illness, who had taken antipsychotic drugs, who was
illiterate or who could not use WeChat, who had unstable medical conditions, infection or cutaneous lesions of the external ear, or were not able to conduct acupressure themselves were excluded.
Randomization and blinding
Eligible patients were randomly assigned to receive either self-administered AVNA or UC in a ratio of roughly 1:1. The randomization sequence was generated in the mini-program, Massage on Auricular Acupuncture Points and Get Rid of Insomnia and Stress, and stratified by sites. The event that the participant clicked the button triggered to generate the seed of a random number. The timestamp of the trigger button was millisecond precision, which was triggered by the user who approached the real random process.
All investigators with at least five years of acupuncture practice were not allowed to get access to participants' information during the study period except for one technician (Junying Wang) who was responsible for maintaining the mini-program and daily operating records. All assessments were done by participants themselves on the mini-program without investigator involvement. Such design ensured complete blindness of investigators to the group allocation.
Interventions and assurance of compliance
Participants in the AVNA group were instructed and trained to have three times of self-administered AVNA per day, in the morning, around noon, and in the evening for 14 days. This length of the intervention was consistent with the mandatory self-isolation period. They were also instructed to receive one session of the UC intervention per day during the same days. To ensure compliance, participants in the group were instructed to receive the UC intervention as done in the AVNA group; meanwhile, they were informed that self-administered AVNA would be instructed after 14 days of the UC intervention. The AVNA procedures were established based on the distribution of the auricular branch of the vagus nerve [6-8] and agreed upon by consensus after consulting senior acupuncturists and traditional Chinese medicine practitioners.
The self-administered AVNA consists of 3 steps (Figure 1B-D). Step 1:using the index fingertip pads to gently press and knead the cavity of concha in both clockwise and anticlockwise directions for 25-30 times in each direction; Step 2:using the index fingertip pads to gently massage the cymbal concha forward and backward 25-30 times in each direction. Step 3:using the index fingertip pads to firmly press Shenmen, Sub-cortex, Occipital, and Stomach, the 4 auricular acupoints that have particular effects in alleviating emotional symptoms and insomnia according to TCM practice[16], 1 minute for each point. Participants were advised to practice each step until a specific sensation, commonly soreness, numbness, or heaviness, should be fel, but the forces could not be too strong otherwise the skin of the ears would be injured. About 6-7 min were needed to finish all three steps.
For the UC group, all participants received hygiene, personal protection, dietary, and sleep education at their entry into the study. The consultation was further provided upon request. Meanwhile, all participants were instructed to practice breath-focused and indoor at-home exercises. The detailed procedure of breath-focused exercise is provided in the mini-program. The indoor at-home exercise included jogging around the house and bare hand exercises, such as pushups, squats, abdominal crunches, leg lifting, side bending, and muscle stretching. Participants practiced breath-focused exercise for 5 min and the indoor at-home exercise for 30 min per day.
The evaluation scale was uploaded in the form of an electronic scale in the mini-program. At the corresponding time point, patients were reminded by the mini-program to complete the scale. Participants were required to record their daily interventions and activity on the online platform. To ensure complete compliance and quality of interventions, designated site investigators (Lei Wang in Beijing, Lingling Yu in Wuhan, Chunzhi Tang in Guangzhou, Jiazi Dong in Shenyang)monitored participants' activities via WeChat video or voice call on a daily basis.
Outcome Assessments
The primary outcome was the response rate, which was the proportion of participants whose HADS score reduced from baseline by 之 50%. Non-response means HADS scores reduced by<50%. The worst response means a greater score after randomization. These definitions were based on the distribution of normative values for HADS score in the general population [17].
Secondary outcomes, including the Hospital Anxiety and Depression Scale(HADS)[17, Beck Anxiety Inventory (BAI)[18], Patient Health Questionnaire(PHQ-9)[19] and Impact emergent scale-revised (IES-R)[20], were additionally used to measure the severity of anxiety, depression, and stress response to the COVID-19, respectively. Participants were also asked to record total sleep hours, time to fall asleep, number of wakeups, and sleep quality per night during the past week, which was modified from the Pittsburgh Sleep Quality Index [21]. The sleep quality was measured using a 5-point Likert self-rating scale where higher scores indicate worse sleep quality. The assessment was conducted at baseline.3 days, and 14 days after randomization. The purpose of assessment at 3 days was to detect the short-term effects of AVNA as previous studies have suggested that acupressure could rapidly improve anxiety and insomnia [2-4].In addition, participants were required to report adverse events on the daily basis.
Sample size estimation and statistical analysis The primary objective of this study was to determine whether self-administered AVNA treatment could produce a clinically greater efficacy response rate than UC, Our preliminary study revealed an efficacy response rate of 76% in the AVNA group versus 59%in the UC group. A sample size of 204 in each group would be sufficient to detect a 17% difference in efficacy response rate between the two groups at an 80%power and a statistical level of 0.05, with the consideration of an estimated dropout rate of 20%.
The outcome analysis was carried out based on an intent-to-treat(ITT)data set, defined as the subset of participants who completed at least one session of intervention, baseline, and at least one post-baseline evaluation. Interim and stopping analysis was conducted only when home isolation was canceled according to the governmental epidemic prevention policy.
The primary outcome, HADS-defined response, non-response, and exacerbation rate, was analyzed using a multinomial generalized estimating equation model. The linear mixed-effect model for repeated measures analysis was used to analyze secondary outcomes with the study site and isolation days as covariates. Treatment, visit, and treatment × visit interaction served as a fixed effect. Site and interaction between site and treatment served as random effects accounting for center differences. Baseline differences in demographic and clinical characteristics were analyzed using Chi-square （y²） test or t-test
Between-group effect size was calculated by dividing the between group difference in post-treatment means with the pooled standard deviation. The effect sizes of 0.20,0.50,0.80,and 1.30represent "small","medium","large",and"very large"effect, respectively [22].
All data were collected autonomically from the mini-program and reorganized by Yufeng Zhao. Statistical analysis was performed by independent statisticians (Yufeng Zhao, Zongshi Qin) using SAS statistical software, version 9.4 (SAS Institute Inc., Cary, NC). The significance level was set at an a2-sided P<0.05.
Results
Baseline characteristics of study participants Among 975 local residents who attended screening via the mini-program from February 26, 2020, to April 28, 2020,406 who met the inclusion criteria and were willing to participate in the study were randomly assigned to AVNA(n=191)and UC(n=215)groups, 404 (99.5%) completed all assessments and interventions as per protocol(Figure 2). Two participants who were lost to follow-up without any assessment and intervention after randomization were excluded from the data analysis. All baseline variables were well balanced between the two groups(Table 1), but significant differences in baseline outcome variables were observed across the four sites (Supplementary materials). Site hence served as a covariate in the outcome analysis.
Primary outcome: HADS-defined response rate
The results of HADS-defined response, non-response, and exacerbation rate are illustrated in Table 2 and Figure 3. At 3 days, the response rate of the AVNA group was significantly greater than that of the UC group [35.6%(68/191) vs.24.9%(53213).P=0.02]. At 14 days, the AVNA group had a markedly higher response than the UC group[70.7%(135/191)vs. 60.6%(129/213), P = 0.02], with a remarkably lower exacerbation rate than the UC group [3.7%(7191)vs. 9.4% (20213), P= 0.02].
Secondary outcomes: continuous variables
Continuous outcome variables are summarized in Table 3. In within-group comparisons, striking reductions were observed in scores of HADS.PHO-9, BAI. IES-R, number of wakeups, and sleep quality scale at 3 days and 14 days compared to baseline (P≤.0015)in each group. Total sleep hours per night were markedly greater at 14 days than baseline in both groups(P ≤.0046). Time to fall asleep was unchanged over time in both groups.
In between-group comparisons, the AVNA group had a significant reduction of HADS score at 3 days(P =.01)and 14 days(P=.02)compared to the group, with effect sizes of 0.217and 0.218, respectively. The Bal score of the AVNA group was also markedly lower than that of the UC group at 3 days(P=.03), with an effect size of 0.195. The AVNA group took a much shorter time to fall asleep(P=.02)and rated their sleep quality as being remarkably higher(P=,04)than the UC group at 14 days, with effect sizes of0.214 and 0.234, respectively.
Discussion
This study for the first time applied self-administered AVNA to the management of emotional distress during the COVID-19 pandemic period. We revealed that self-administered AVNA was superior to UC in improving distress-related symptoms. The AVNA group reported an approximately 10%higher response rate than the UC group, while the exacerbation rate was nearly 6-7%lower than that of the UC group across the two post-baseline measurement points. Self-administered AVNA produced a significantly greater reduction in the mean scores of HADS after three days and 14 days of treatment and in the mean scores of Bal after three days of treatment. The greater reduction of PHQ scores of the AVNA group at 3 days also reached a margin at the statistical significance level. Furthermore, participants in the AVNA group spent much less time falling asleep and with better self-rated sleep quality than the UC group. No adverse events were reported between the two groups. These results indicate that the self-administered AVNA could rapidly relieve anxiousness and depressed mood and largely improve sleep disturbance. This situation of self-massage provides convenience for patients who cannot get medical assistance during isolation.
AVNA is easier to learn and practice independently than other non-drug measures recommended to alleviate anxiety and depression, such as body acupuncture, biofeedback therapy, meditation relaxation therapy, game therapy, art therapy, NaiKan therapy, Taiji therapy, yoga therapy, and repeated transcranial magnetic stimulation, especially during city lockdown and by Social isolation caused pandemics.
Although the positive effects of AVNA observed were small, with an average effect size of approximately 2.1, considering the rapid response, practicality, and safety, AVNA deserves to be recommended for patients with emotional distress under the current COVID-19 pandemic and other emergent events. In fact, auricular acupressure has been introduced to those who were experiencing mental distress in nursing students, cancer patients, women under in vitro fertilization, and post-cesarean section [9-12].
Unlike conventional vagus nerve stimulation(VNS), in which a VNS device is embedded beneath the chest wall and the electrodes are implanted on the cervical vagal trunk via surgical procedure [23], transcutaneous auricular vagus nerve stimulations(taVNS)is non-invasive, safer, and more practicable. In a non-randomized clinical study [24] with 160 patients with major depressive disorders (MDD), the efficacy of taVNS was investigated by training the patients to apply bilateral taVNS at home. The intervention of taVNS was administered to the first cohort of patients(n=91)for 12 weeks. Patients (n=69)in the second cohort were offered sham taVNS for 4 weeks and then 8 weeks of real taVNS.Patients in the taVNS group had more reduction of the 24-item Hamilton Depression (HAMD)score than those of the sham taVNS group after the fourth week. The effect of the reduction of HAMD in both groups continued at the endpoint. Kong et al [14] found that compared with sham taVNS, taVNS treatment for one month can also alleviate anxiety, sleep disturbance, and hopelessness in patients with MDD. The technique of taVNS has been growingly introduced into the treatment of neurological and psychiatric disorders, including epilepsy, pain, stroke, depression, insomnia, and dementia[8]. ABVN mainly consists of thick-myelinated afferents that transmit mechanoreceptive sensations, such as touch, pressure, and movement, from the external ear to the brain [8,25]. The ABVN fibers and their terminals are distributed in the cavity of the concha and the cymbal concha with the highest density and in the surrounding areas with a related high density as shown in Figure 1 [7,8]. It is evidenced that the activation of thick-myelinated, afferent fibers of ABVN is essential to achieving the therapeutic efficacy of taVNS[26,271. A large body of neuroimaging evidence confirms that taVNS broadly modulate a widespread brain network, including the nucleus of the solitary tract, locus coeruleus, dorsal nucleus, parabrachial nucleus, hypothalamus, hippocampus, amygdala, cingulate and prefrontal cortex, all the brain regions that are directly or indirectly involved in the processing of emotional information and the sleep/wake cycle [8]. It thus appears that the anti-distress effects of AVNA observed in this study may be largely attributed to its broad modulation of the vagal brain network by activating mechanoreceptors via acupressure on ABVN-rich auricular areas.
Compared to traditional, in-person visit-required clinical trials, the smartphone-based design could enhance the subject recruitment from all demographics, improve participants' compliance with the intervention, and diminish assessor bias. It hence offered a greater convenience with a time-saving course. Our experience that the completion of the entire study only took two months, with a negligible dropout rate reflects such advantages of smartphone-based clinical trial design.
Limitations
Several limitations of this study should be considered. First, the durationofAVNA intervention was somewhat short, with only 14 days. Further studies are warranted to evaluate the therapeutic value of long-term AVNA intervention. Second, it perhaps has a greater chance of causing large heterogeneity in intervention procedures and outcome measures due to the absence of onsite investigators' guidance 28]. This study that showed site differences in outcome variables echoed such weakness. In this study, trends of changes in outcome variables over time were consistent in the four sites. The site also served as a covariate included in the outcome analysis. Finally, due to the fact that participants were not blinded to their interventions, the influences of participant expectation on the outcomes appear not to be excluded.
Conclusion
During the COVID-19 pandemic period, treatment with self-administrated AVNA was more effective than UC in reducing the emotional distress of isolated populations. These findings support self-administered AVNA as a treatment option for patients with emotional distress under the COVID-19 pandemic or other emergent events.
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