Content of this journal is licensed under a Abstract
Background:
To analyze the overall response of eszopiclone plus acupuncture therapy by dispersing the stagnated liver-qi and regulating the spirit (the acupuncture therapy) for treating chronic fatigue syndrome (CFS)–related sleep disorders.
Methods:
A retrospective analysis was conducted on 107 patients with CFS-induced sleep disorders treated at the Hainan Provincial People's Hospital from February 2021 to February 2023. Among these, 50 patients who received eszopiclone tablets were collected as the control group. The remaining 57 patients who received the acupuncture therapy in addition to the treatment in the control group were collected as the observation group. The Pittsburgh Sleep Quality Index (PSQI) was adopted for evaluating sleep quality before and after treatment in both groups. Clinical overall response rate was compared between the 2 groups. An enzyme-linked immunosorbent assay was conducted for measuring fasting serum levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) prior to and post treatment. Adverse reactions in both groups were also recorded.
Results:
The observation group got significantly lower PSQI scores than the control group (P < .05). The overall response rate of the observation group seemed to be higher than that of the control group (P = .063). The observation group showed significantly higher post-treatment 5-HT and BDNF levels than the control group (both P < .05). Safety profiles favored the observation group, with fewer adverse reactions reported (7.02% vs 22.00%) (P = .026).
Conclusion:
Eszopiclone plus the acupuncture therapy enhances the efficacy of treating CFS-induced sleep disorders, effectively improves serum 5-HT and BDNF levels in patients, and reduces adverse reactions.
Main Points
The study explores using eszopiclone combined with acupuncture to treat sleep disorders linked to chronic fatigue syndrome (CFS).
Results show this combination improves sleep quality and raises serum 5-hydroxytryptamine and brain-derived neurotrophic factor levels in CFS patients.
The treatment also reduces adverse reactions compared to using eszopiclone alone.
Study limitations include its retrospective nature and small sample size, highlighting the need for further research.
Introduction
Chronic fatigue syndrome (CFS) was first proposed by the Centers for Disease Control and Prevention (CDC), USA, and was revised in 1994.1 It is characterized by a series of symptoms primarily manifested as fatigue, accompanied by muscle pain, joint pain, sleep disorders, depression, and anxiety, among other physical and mental health issues.2 The primary symptom, fatigue, persists or recurs for more than 6 months, while secondary symptoms appear no less than 6 months after the onset of fatigue.3 Although CFS is primarily characterized by fatigue, clinical epidemiological investigations show that severe and unrelenting sleep disorders are prominent symptoms that compel CFS patients to seek medical attention. Sleep disorders are one of the core symptoms of CFS, with 81.4% of CFS patients exhibiting at least 1 abnormal sleep factor.
Due to the unclear pathogenesis of CFS, specific treatment methods are still being explored. The management of the disease primarily focuses on symptomatic treatment, which often only alleviates clinical symptoms without fundamentally eliminating the underlying causes of the disease. Commonly used medications include immunosuppressants, antibiotics, and hormones.4 Cognitive behavioral therapy and graded exercise therapy have shown satisfactory efficacy; however, their side effects and high costs hinder their widespread adoption. The CDC, USA, believes that the primary goal for CFS at present is to alleviate symptoms and improve the quality of life for patients, with improving sleep quality being a key aspect of correcting fatigue states.
Research indicates that zopiclone can extend sleep duration and enhance sleep quality in CFS patients, thereby improving their mental state.5 However, the long-term efficacy of this medication is unstable, and common side effects such as hepatotoxicity, nephrotoxicity, and reduced neuro-excitability often make it difficult for patients to maintain treatment.6 According to traditional Chinese medicine (TCM) theory, CFS falls under the category of “deficiency syndrome,” primarily affecting the heart, liver, spleen, and kidneys. Conditions such as liver-qi stagnation, kidney essence deficiency, insufficient qi and blood, and inadequate nourishment of the heart vessels are the main reasons for patients’ fatigue and unrefreshing rest and sleep. Chronic fatigue syndrome–induced sleep disorders can be categorized under TCM concepts such as “insomnia” and “restlessness.” They are strongly bound up with the dysfunction of the heart, liver, and spleen in regulating the “shen” (spirit). The instability of the “shen” is a primary cause of insomnia.7 In TCM, the concept of “shen” encompasses a wide range of aspects, including spirit, consciousness, emotions, and sleep, all of which influence one another. Clinical research has also shown that many insomnia-related conditions are often accompanied by anxiety and depression, while negative emotions can exacerbate sleep disorders, creating a vicious cycle that worsens insomnia.8
Modern TCM pays particular attention to the role of liver-qi stagnation in the onset of CFS, as the liver is responsible for regulating the flow of qi and emotions. In today’s competitive and complex social environment, work and life pressures can easily trigger feelings of tension, anger, and depression, resulting in damage to the internal organs and eventually leading to symptoms of “deficiency syndrome,” “fatigue,” and “insomnia.” The proposed acupuncture therapy, by dispersing the stagnated liver-qi and regulating the spirit (the acupuncture therapy), is an effective method for treating anxiety, depression, and sleep disorders. However, it remains unclear whether the combined application of this method with eszopiclone can enhance the treatment effects for CFS-induced sleep disorders.
This study aimed to analyze the efficacy of eszopiclone plus acupuncture therapy in treating CFS-induced sleep disorders, so as to provide new solutions for clinical treatment.
Material and Methods
Clinical Baseline Data
A retrospective analysis was conducted on 107 patients with CFS-induced sleep disorders treated at the Hainan Provincial People's Hospital from February 2021 to February 2023. Among these, 50 patients who received eszopiclone tablets were collected as the control group. The remaining 57 patients who received the acupuncture therapy in addition to the treatment in the control group were collected as the observation group. In this study, 107 patients with CFS-induced sleep disorders were treated at the Hainan Provincial People's Hospital in the survey. The study was approved by the Ethics Committee of Hainan Provincial People's Hospital (Approval No.: [2021]159, Approval Date: June 23, 2021). Informed consent for publication was obtained from all participants in the study.
Inclusion and Exclusion Criteria
Inclusion criteria: patients who met the Diagnosis of CFS based on the revised diagnostic criteria from the CDC in 1994 and the diagnosis of deficiency syndrome according to “Traditional Chinese Internal Medicine”; patients between 18 and 75 years old; patients with Pittsburgh Sleep Quality Index (PSQI) score of 8 or higher9; patients who had not received any medication or acupuncture therapy in the past 14 days; patients who had not participated in other clinical trials recently.
Exclusion criteria: patients with malignant tumors, endocrine metabolic diseases, or other chronic wasting diseases; patients with drug or alcohol dependence. Patients with severe organic lesions, infectious diseases, or contagious diseases; individuals with known psychiatric disorders, including individuals with a history of psychiatric illnesses and those diagnosed with depression; women who were pregnant, breastfeeding, or planning to conceive within the next 3 months.
Treatment Methods
Control group: The control group received eszopiclone tablets (Itaning, Chengdu Kanghong Pharmaceutical Group Co., Ltd.; SFDA approval no.: H20100074, specification: 3 mg), with a dosage of 3 mg per administration, taken once daily before bedtime.
Observation group: The observation group received the acupuncture therapy in addition to the treatment in the control group. The acupuncture points included: Baihui, Taichong, Neiguan, Yintang, Hegu, Qimen, Xinshu, Ganshu, Sanyinjiao, and Zusanli.10,11 Acupuncture method: The acupuncture was performed using a balanced tonification and reduction technique, aiming to obtain qi. After needling, manipulation was performed once after 20 minutes, with needles retained for 40 minutes. Treatment was administered once daily, with a total of 6 acupuncture sessions per week for 5 consecutive weeks.
The acupuncture therapy referred to the 7th edition of Acupuncture compiled by Shi Xuemin et al. All acupuncturists were standardized in their approach and adhered to the same needling techniques.
In addition, assessors of PSQI scores and biochemical markers were not blinded to treatment groups.
Data Collection
Data collection involves gathering patients’ clinical baseline information and laboratory-related data from the electronic medical record system, including age, gender, disease duration, smoking history, alcohol consumption history, monthly family income, education level, PSQI score, serum 5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF) levels, treatment outcomes, and occurrences of adverse reactions.
Outcome Measures
Primary outcome measures: The PSQI was adopted for evaluating the sleep quality of both groups before and after treatment.12 The assessment consists of 7 components, each scored from 0 to 3, resulting in a total score ranging from 0 to 21. A PSQI score of ≥ 8 indicates sleep disorders, with higher scores reflecting poorer sleep quality. The clinical overall response rate of the 2 groups was compared as follows: (1) Basic recovery: Main symptoms of fatigue have largely disappeared, with good sleep quality (0 < PSQI score ≤ 5), and the patient can generally adapt to daily activities and work; (2) significant improvement: Main symptoms of fatigue have noticeably improved, with acceptable sleep quality (5 < PSQI score ≤ 10), allowing the patient to maintain daily activities and work; (3) some improvement: Main symptoms of fatigue are partially improved, with average sleep quality (10 < PSQI score ≤ 15), enabling the patient to perform light daily activities and work; (4) no change: Main symptoms of fatigue show no improvement, with very poor sleep quality (15 < PSQI score ≤ 20), rendering the patient unable to engage in normal daily activities and work.
Secondary outcome measures: The clinical data of both groups were compared. The enzyme-linked immunosorbent assay was conducted for measuring fasting serum levels of 5-HT and BDNF before and after treatment in both groups. 5-hydroxytryptamine and BDNF levels play a crucial role as key biological markers, not only involved in regulating emotions, cognitive functions, and neuroprotection but also impacting the modulation of sleep patterns. By monitoring changes in 5-HT and BDNF levels, a deeper understanding of the pathophysiology of CFS and its related sleep disorders can be acquired. Adverse reactions in both groups were also recorded.
Statistical Analysis
Data were processed using SPSS 26.0 (IBM SPSS Corp.; Armonk, NY, USA) statistical software. The measurement data were normally distributed and presented as mean ± SD. They were analyzed using the independent samples t-test. The counting data were presented as the number of cases and percentages. If there was an expected value problem, Fisher’s exact test was performed for 2 × 2 tables, and Fisher–Freeman–Halton test was performed for 2 × k or k × k (k > 2) tables; otherwise, the chi-square test was used. A statistically significant difference was observed when P < .05.
Results
Comparative Analysis of Baseline Demographic and Clinical Characteristics Between Study Groups
A comparison of baseline characteristics between the control group (n = 50) and observation group (n = 57) showed no statistically significant differences in demographic or clinical characteristics between the 2 groups (all P-values > .05). In terms of age distribution, 38.00% of the control group and 29.82% of the observation group were aged ≥40 years. The gender distribution was similar, with males accounting for 40.00% in the control group and 50.88% in the observation group (P = .260). (Table 1).
Table 1.
Baseline Data Comparison [n(%)]
| Factors | Control Group (n = 50), n (%) | Observation Group (n = 57), n (%) | P | |
|---|---|---|---|---|
| Age | .372 | |||
| ≥40 years | 19 (38.00) | 17 (29.82) | ||
| <40 years | 31 (62.00) | 40 (70.18) | ||
| Sex | .260 | |||
| Male | 20 (40.00) | 29 (50.88) | ||
| Female | 30 (60.00) | 28 (49.12) | ||
| Course of disease |
.519 | |||
| ≥15 months | 18 (36.00) | 24 (42.11) | ||
| <15 months | 32 (64.00) | 33 (57.89) | ||
| Smoking history | .260 | |||
| Yes | 20 (40.00) | 29 (50.88) | ||
| No | 30 (60.00) | 28 (49.12) | ||
| Alcohol history | .686 | |||
| Yes | 2 (4.00) | 4 (7.02) | ||
| No | 48 (96.00) | 53 (92.98) | ||
| Monthly family income | .546 | |||
| ≥5000 Yuan | 13 (26.00) | 12 (21.05) | ||
| <5000 Yuan | 37 (74.00) | 45 (78.95) | ||
| Education level | .426 | |||
| ≥Senior high school | 19 (38.00) | 26 (45.61) | ||
| <Senior high school | 31 (62.00) | 31 (54.39) | ||
Sleep Quality Assessment
The comparison revealed no notable difference in PSQI scores between the control and observation groups before treatment (P > .05). After treatment, PSQI scores significantly decreased in both groups (P < .05). Significantly, the observation group showed significantly lower post-treatment PSQI scores than the control group (P < .05, Figure 1 and Tables 2 and 3).
Figure 1.
Sleep quality assessment (PSQI score). Notes: ns: non-significant; ****P < .001.
Table 2.
Intra-Group Comparisons of Sleep Quality (Mean ± SD)
| Before | After | P | ||
|---|---|---|---|---|
| PSQI score | Control group (n = 50) | 12.28 ± 2.79 | 7.28 ± 3.82 | <.001 |
| Observation group (n = 57) | 12.26 ± 2.82 | 4.28 ± 2.22 | <.001 |
PSQI, Pittsburgh Sleep Quality Index.
Table 3.
Inter-Group Comparisons of Sleep Quality Based on Percentage Change
| Percent Change According to Baseline | P | ||
|---|---|---|---|
| Control Group (n = 50) (%) (Mean ± SD) | Observation Group (n = 57) (%) (Mean ± SD) | ||
| PSQI score | −37.50 ± 16.89 | −55.59 ± 20.04 | .002 |
Percent change (%) = [(after-before)/before)]*100.
PSQI, Pittsburgh Sleep Quality Index; SD, standart deviation.
Clinical Overall Response Rate Assessment
The clinical overall response rate differed significantly between the 2 groups (P = .063). In the observation group (n = 57), 61.40% of patients achieved basic recovery, which was notably higher than the 38.00% in the control group (n = 50). The control group had a higher proportion of patients with significant improvement (46.00% vs. 31.58% in the observation group). A smaller percentage of patients in the observation group experienced some improvement (7.02%) or no change compared to the control group (14.00% and 2.00%, respectively). These results suggest that the intervention in the observation group tended to be associated with a higher rate of basic recovery (P = .063, Table 4).
Table 4.
Clinical Overall Response Rate [n(%)]
| Grouping | Basic Recovery | Significant Improvement | Some Improvement | No Change |
|---|---|---|---|---|
| Control group (n = 50), n (%) | 19 (38.00) | 23 (46.00) | 7 (14.00) | 1 (2.00) |
| Observation group (n = 57), n (%) | 35 (61.40) | 18 (31.58) | 4 (7.02) | 0 (0.00) |
| P | .063 | |||
Comparative Analysis of Serum 5-Hydroxytryptamine and Brain-Derived Neurotrophic Factor Level
Both the control and observation groups showed significant increases in serum 5-HT and BDNF levels after treatment compared to baseline (P < .001 for all comparisons, Table 5). However, the observation group demonstrated a more pronounced improvement. For 5-HT, the observation group exhibited a greater post-treatment increase (110.54 ± 8.97) compared to the control group (100.56 ± 12.55). Similarly, BDNF levels rose more substantially in the observation group (35.78 ± 3.7) than in the control group (30.24 ± 3.86). When assessing percent changes from baseline (Table 6 and Figure 2), the observation group had a significantly higher increase in BDNF (17.47 ± 9.95%) compared to the control group (51.19 ± 23.61%, P < .001). Conversely, the 5-HT percent change was lower in the observation group (−46.56 ± 24.27%) than in the control group (56.22 ± 21.98%, P = .033).
Table 5.
Comparisons of Serum 5-HT and BDNF Within the Group (Mean ± SD)
| Before | After | P | ||
|---|---|---|---|---|
| 5-HT | Control group (n = 50) | 69.38 ± 7.6 | 100.56 ± 12.55 | <.001 |
| Observation group (n = 57) | 71.67 ± 7.89 | 110.54 ± 8.97 | <.001 | |
| BDNF | Control group (n = 50) | 24.57 ± 4.36 | 30.24 ± 3.86 | <.001 |
| Observation group (n = 57) | 24.37 ± 3.75 | 35.78 ± 3.7 | <.001 |
5-HT, 5-hydroxytryptamine; BDNF, brain-derived neurotrophic factor.
Table 6.
Changes in serum 5-Hydroxytryptamine and Brain-Derived Neurotrophic Factor Before and After Treatment
| Percent Change According to Baseline | P | ||
|---|---|---|---|
| Control Group (n = 50) (%) (Mean ± SD) | Observation Group (n = 57) (%) (Mean ± SD) | ||
| 5-HT | 56.22 ± 21.98 | −46.56 ± 24.27 | .033 |
| BDNF | 51.19 ± 23.61 | 17.47 ± 9.95 | <.001 |
Percent change (%) = [(after-before)/before]*100.
5-HT, 5-hydroxytryptamine; BDNF, brain-derived neurotrophic factor.
Figure 2.
Changes in serum 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) before and after treatment. A. Changes in 5-HT levels before and after treatment in both groups. B. Changes in BDNF levels before and after treatment in both groups. Notes: ns: non-significant; ****P < .001.
Comparison of Adverse Reactions
The incidence of total adverse reactions was lower in the observation group (7.02%) compared to the control group (22.00%) (P = .026). In the control group (n = 50), the most common adverse reaction was decreased appetite (8.00%), followed by headache (6.00%), while fatigue and dry mouth each occurred in 4.00% of patients. In contrast, the observation group (n = 57) reported fewer adverse events, with fatigue, dry mouth, headache, and decreased appetite each occurring in only 1.75% of patients. There was no statistical difference in the incidence of headache, fatigue, dry mouth, or decreased appetite (P > .05).
Discussion
Sleep is a crucial factor for human health. In today’s competitive and complex social environment, the incidence of insomnia continues to rise due to increasing work and life pressures.13 Insomnia, also known as a sleep disorder, is a common symptom of neurological diseases, characterized by persistent difficulties in sleeping, trouble falling asleep, waking up feeling fatigued, and experiencing shallow sleep. The medical community believes that the causes of insomnia include various factors such as environmental and emotional influences, physical illnesses, and lifestyle choices.10 Moreover, long-term insomnia can trigger negative emotions in patients, such as depression and anxiety. These adverse mindsets can further worsen sleep quality, creating a vicious cycle. Additionally, it has been reported that some insomnia patients may experience decreased attention and weakened immune function, leading to a reduced ability to resist diseases. They may also suffer from symptoms such as memory decline and headaches. In severe cases, this can result in the onset of primary diseases such as hypertension and cardiovascular diseases, threatening the patients’ quality of life and health safety.13-15 Therefore, to prevent these situations, early, effective, and appropriate clinical treatment for insomnia is crucial.
Chronic fatigue syndrome is a troubling condition where patients often feel that their physical strength cannot be restored, even after adequate rest.16 In addition, patients may experience various symptoms due to reduced immune function, such as muscle pain, poor sleep quality, headaches, and memory decline.17 To date, the mechanisms behind CFS remain unclear, and pharmacological treatments are widely used for managing the condition. Eszopiclone, a non-benzodiazepine hypnotic, is used for the treatment of insomnia.18 Its mechanism involves binding to Gamma-Aminobutyric Acid (GABA) receptors in the brain, thereby inhibiting neural activity and helping patients fall asleep more quickly and maintain sleep. Although eszopiclone has shown significant effects in alleviating insomnia, it may bring side effects such as dizziness, drowsiness, headaches, dry mouth, and palpitations. In rare cases, it may also lead to mood swings, memory issues, and even actions taken while insufficiently alert.19
In TCM, CFS is classified as “deficiency syndrome.” Traditional acupuncture treatment has shown significant advantages in alleviating CFS and accompanying insomnia symptoms.20 In this study, the combined application of acupuncture and eszopiclone significantly improved patients’ sleep quality. 5-hydroxytryptamine is an important inhibitory neurotransmitter in the human body related to anxiety and depression, playing a role in regulating brain activities such as emotions, memory, energy, and worldview. It is closely associated with insomnia. The synthesis of 5-HT begins with tryptophan, a precursor that can cross the blood-brain barrier. Acupuncture can increase tryptophan levels in the peripheral system, elevate blood 5-HT levels, accelerate the transport of tryptophan across the blood-brain barrier, thereby promoting the synthesis of 5-HT in the brain, ultimately improving the patient’s sleep.21 Brain-derived neurotrophic factor is a neurotrophic factor that exerts a broad effect on peripheral and central neurons, playing a crucial role in maintaining neuron growth, survival, differentiation, and physiological functions. Following a cerebral infarction, the expression of BDNF significantly increases in the ischemic area, aiding in the protection of neurons, inhibiting delayed neuronal death, reducing the infarct area, and minimizing neural functional damage.22 Acupuncture treatment can enhance BDNF expression, promote endothelial cell proliferation and differentiation, stimulate neurovascular regeneration, accelerate the reconstruction of neural physiological functions, while also delaying neuronal necrosis and apoptosis in the ischemic region, stimulating axon formation, thereby facilitating the recovery of neurological functions in patients.23 In this study, after acupuncture treatment, the serum levels of 5-HT and BDNF in patients increased significantly. 5-hydroxytryptamine is crucial in the pathogenesis of CFS, as its levels can directly affect patients’ emotions and sleep. Brain-derived neurotrophic factor, a neurotrophic protein, regulates neuronal activity and facilitates synaptic regeneration and plasticity. These results indicate that the combined application of eszopiclone and acupuncture can improve CFS fatigue symptoms and enhance patients’ sleep quality by modulating serum 5-HT and BDNF levels. It is noteworthy that acupuncture treatment can reduce adverse reactions in patients (Table 7), demonstrating that this combined therapy can minimize the risk of side effects.
Table 7.
Statistics of Adverse Reactions [n(%)]
| Grouping | Fatigue | Dry Mouth | Headache | Decreased Appetite | Total |
|---|---|---|---|---|---|
| Control group (n = 50), n (%) | 2 (4.00) | 2 (4.00) | 3 (6.00) | 4 (8.00) | 11 (22.00) |
| Observation group (n = 57), n (%) | 1 (1.75) | 1 (1.75) | 1 (1.75) | 1 (1.75) | 4 (7.02) |
| P | .598 | .598 | .338 | .183 | .026 |
1: Adverse events were counted by “unique patients” (not events); patients reporting multiple symptoms were counted only once in the “Total” row.
Total incidence = Patients with ≥1 symptom / group size (Control: 11/50 = 22.00%; Observation: 4/57 = 7.02%).
Through this research analysis, it was determined that the combined application of eszopiclone and acupuncture therapy can enhance sleep quality in CFS patients. However, this study has certain limitations. First, the limitations of the retrospective study include the inability to establish causality. Secondly, the small sample size may lead to bias in the results. Thirdly, no follow-ups were conducted, which leaves the long-term overall response rate for patients unclear. Therefore, the hope is to conduct a prospective experiment in future research to refine the conclusions. Moreover, when addressing the limitations of this study, it is important to acknowledge that the concept of liver-qi remains contentious.
In summary, the combined application of eszopiclone and acupuncture therapy can significantly enhance the overall response rate of treating CFS-induced sleep disorders and effectively improve serum 5-HT and BDNF levels, without increasing the incidence of adverse reactions.
Funding Statement
This work was supported by the Hainan Province Health Industry Research Project (Grant No. 21A200150) and Hainan Provincial Natural Science Foundation of China (Grant No. 8210N0985).
Footnotes
Ethics Committee Approval: Ethical committee approval was received from the Ethics Committee of Hainan Provincial People’'s Hospital (Approval Number [2021]159; Date: June 23, 2021).
Informed Consent: Verbal and written informed consent was obtained from the patients who agreed to take part in the study.
Peer-review: Externally peer-reviewed.
Author Contributions: Concept – H.B., L.L.; Design – H.B., L.L.; Supervision – H.B., L.L.; Resources – H.B., L.L.; Materials – H.B., L.L.; Data Collection and/or Processing – H.B., Y.N.G.; Analysis and/or Interpretation – H.B., Y.N.G.; Literature Search – H.B.; Writing – H.B., L.L., Y.N.G.; Critical Review – H.B., L.L., Y.N.G.; Final Approval – All authors.
Acknowledgements: The authors would like to thank all the team members who contributed to this study.
Declaration of Interests: The authors have no conflicts of interest to declare.
Data Availability Statement:
The data that support the findings of this study are available on request from the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author.