Complementary Therapies in Medicine (2015) 23, 226—232
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Efficacy of adjuvant Chinese herbal formula treatment for chronic tinnitus: A retrospective observational study Chia-Hui Lin a,b,1, Chun-En Kuo c,1, Hao-Chang Yu b,d, Yu-Kai Lai d, Yu-Chuen Huang e, Ming-Yen Tsai b,c,∗ a
Department of Psychiatry, Yuli Hospital, Ministry of Health and Welfare, Hualien 981, Taiwan Graduate Institute of Integrated Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan c Department of Traditional Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan d Departments of Otolaryngology and Chinese Medicine, Chi Mei Medical Center, Liouying 73663, Taiwan e Department of Medical Research, China Medical University Hospital and School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan Available online 7 February 2015 b
KEYWORDS Chinese herbal medicine; Chai-Hu-Jia-Long-GuMu-Li-Tang; Tinnitus; Retrospective study
Summary Background: The aim of this study was to evaluate the clinical efficacy of using western antitinnitus therapy with or without Chai-Hu-Jia-Long-Gu-Mu-Li-Tang (CHJLGMLT) to treat patients with chronic tinnitus. Methods: A descriptive case series with chart review was established to compare patients with chronic tinnitus who had received CHJLGMLT with western anti-tinnitus therapy (the CHJLGMIT group) with those who received western anti-tinnitus therapy alone (the non-CHJLGMIT group). We included 21 patients, 10 patients in the CHJLGMIT group with CHJLGMLT and 11 patients in the non-CHJLGMIT group. Both groups were comparable in terms of patient demographics and clinical characteristics. The follow-up examinations included the assessment of Tinnitus Handicap Inventory (THI), Pittsburgh Sleep Quality Index (PSQI), Visual Analogue Scale (VAS) of 0—10 for tinnitus intensity, pure tone audiometry (PTA), and speech reception threshold (SRT). Results: After 2 months of treatment, THI and PSQI scores were reduced significantly more in the CHJLGMIT group (p < 0.05) than in the non-CHJLGMIT group. Scores on the emotional subscale
Abbreviations: CHJLGMLT, Chai-Hu-Jia-Long-Gu-Mu-Li-Tang; CHM, Chinese herbal medicine; FDA, Food and Drug Administration; GABA, ␥-aminobutyric acid; GMP, good manufacturing procedures; PSQI, Pittsburgh Sleep Quality Index; PTA, pure tone audiometry; SRT, speech reception threshold; TCM, traditional Chinese medicine; THI, tinnitus handicap inventory; VAS, Visual Analogue Scale. ∗ Corresponding author at: Department of Chinese Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan. Tel.: +886 77317123x2332; fax: +886 77317123x2335. E-mail address: [email protected] (M.-Y. Tsai). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.ctim.2015.01.002 0965-2299/© 2015 Elsevier Ltd. All rights reserved.
Efficacy of Chinese herbal formula for chronic tinnitus
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of the THI were significantly reduced in the CHJLGMIT group (p < 0.05) after treatment, but the effects on the seven PSQI subscales did not differ significantly between the two groups (p > 0.05). Scores on the VAS for tinnitus loudness were significantly reduced in both groups (p < 0.05). No significant differences between the two groups were found on the binaural hearing tests (PTA and SRT). Conclusions: Our study found that adjuvant CHJLGMLT therapy for chronic tinnitus may exert additional efficacy by improving psychological sensation of tinnitus and sleep quality. Future randomized controlled double-blind studies should be performed to elucidate its efficacy. © 2015 Elsevier Ltd. All rights reserved.
Background
Methods
Chronic tinnitus is a bothersome health problem that can affect 10—15% of the general population.1 Most cases of chronic tinnitus are subjective, meaning that only the patient can hear the sounds.2 The disorder may be accompanied by otological, orthopaedic, metabolic, neurological, cardiovascular, dental, and pharmacological conditions, more than one of which may be present in the same individual.3,4 Chronic tinnitus can even be a devastating concern; a significant proportion of suffers develop sleep disturbances, anxiety, depression, and other psychiatric comorbidities, and a small fraction commit suicide.5,6 Numerous drug regimens, retraining therapy, behavioural therapies, or noise-masking devices have been tried, with an overall disappointing lack of universal efficacy.1,7 Since there is currently no satisfactory treatment for tinnitus, the condition of these patients may be especially distressing. In order to improve the therapeutic efficacy, many chronic tinnitus patients seek herbal medicine and other alternative and complementary therapies.8,9 This is particularly apparent in Asian patients, who have wellestablished preconceptions about Chinese herbal medicine (CHM). The use of Chai-Hu-Jia-Long-Gu-Mu-Li-Tang (CHJLGMLT), which has a long history as part of the traditional Chinese pharmacopoeia, was first documented in the classical Chinese text Shang Han Lun (On Cold Damage) circa 210 A.D. by Zhong-Jing Zhang.10 In the classical literature, CHJLGMLT is prescribed to reconcile the qi of Shaoyang syndrome, relieve rigidity of the muscles and active collaterals, and tranquilize and allay excitement. TCM practitioners, who use CHJLGMLT to treat many difficult and complicated diseases, rely on traditional Chinese medicine (TCM) theory.11 Several studies in China have shown that treatment with CHJLGMLT effectively improves debilitating conditions such as resistant hypertension, insomnia, neurosis, and tinnitus, and that patients treated with this herbal medicine typically exhibit fewer side effects than those treated with western medicines.12—15 Animal studies have also shown that CHJLGMLT has anti-depressive, stress relief, and sedative effects.16,17 Despite this documented research, questions regarding the beneficial effects of this TCM persist, and the exact mechanism by which CHJLGMLT improve chronic tinnitus remains unknown. The purpose of this study was to review and explore the effects of combining CHJLGMLT with western anti-tinnitus therapies on patients with chronic tinnitus.
Patients We performed a retrospective observational study of adult outpatients with chronic tinnitus treated by an otolaryngologist at Liouying Chi-Mei Hospital, Tainan City, Taiwan, between June 2011 and January 2012. The eligibility criteria for inclusion were: (1) diagnosis of chronic tinnitus defined as a perceived noise of varying intensity, loudness, and pitch in the absence of an external sound lasting longer than 3 months;18 (2) no conductive hearing loss; (3) no major cognitive impairment or psychiatric disorders; and (4) no severe comorbidities (e.g., heart failure, unstable diabetes). This study protocol was ethically approved in case No. 10206-L02 of the Chi-Mei Institutional Review Board (CMHIRB-10206-L02).
Treatment The study, included patients with chronic tinnitus who had undergone current anti-tinnitus therapies. The patients were categorized into two groups. Each patient in CHJLGMIT group had been provided with adjuvant the CHJLGMLT formula for the 2-month period examined for the study. Patients in the non-CHJLGMIT group had received only anti-tinnitus therapies. The western medicine for chronic tinnitus are oral peripheral vasodilators (nicametate citrate 50 mg and thiamine 100 mg three times a day), which are
Table 1 Components of Chai-Hu-Jia-Long-Gu-Mu-Li-Tang (every 4 g of dry extract was derived from 23.8 g of the raw materials). Pharmaceutical name
Chinese Pinyin
Ratio (g)
Radix Bupleuri Fossilia Ossis Mastodi Rhizoma Zingiberisrecens Radix Ginseng Poria Radix Scutellariae Concha Ostreae Ramulus Cinnamomi Rhizoma Pinelliae Fructus Jujubae Rhizoma Rhei
Chaihut Longku Shengjiang Renshen Fuling Huangqin Muli Guizhi Banxia Dazao Dahuang
2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.8
228 frequently suggested as a possible treatment for tinnitus in the press, and many people with tinnitus use a variety of products on the basis of limited evidence.19 The CHJLGMLT formula used was an herbal extract powder made according to the good manufacturing procedures (GMP) of the certified company Kaiser Pharmaceutical Co., Ltd. (Taiwan), for the purpose of meeting international market standards of quality and uniformity. The composition of the CHJLGMLT formula is shown in Table 1. This medication was administered at a treatment dose of 3 g three times per day, after each meal. All treatments were administered by both an otolaryngologist and a TCM practitioner who had at least 6 years of clinical experience in their professional fields.
Outcome measurements To assess the efficacy of treatment, the severity of chronic tinnitus was evaluated using comprehensive audiologic examinations both before and after 2 months of treatment by an assistant specializing in otolaryngology. At the same time, it was confirmed that none of the patients had received other herbal medicines, and the western medicines were modified during the period. As part of the treatment, the primary outcome was assessed by using the Tinnitus Handicap Inventory (THI) and Pittsburgh Sleep Quality Index (PSQI) at the baseline visit and after the 2 months of treatment. The THI, which consists of 25 items scored as 0 = no, 2 = sometimes, and 4 = yes, permits description of the perceived aspects of function (difficulties with concentration and anti-social trends), emotion (anger, frustration, irritability, depression), and catastrophe (despair, feelings of hopelessness, fear of a ‘‘severe disease’’, loss of control, and inability to cooperate).20 The questionnaire was developed to gain further insights into each person’s physiological changes and the psychological impacts commonly experienced by tinnitus patients. The composite scores for each of the subscales are based on
C.-H. Lin et al. adding up the scores of the items of the respective dimensions. The composite score (total score) is the sum of the dimension scores. Useful categories for describing clinical relevance of the index were as follows: slight (0—16), mild (18—36), moderate (38—56), severe (58—76), or catastrophic (78—100).21 The PSQI is a simple, non-invasive, self-report measure that provides night-to-night information on sleep patterns, sleep quality, and relevant daytime behaviour.22 It comprises seven subscales, and each subscale is rated on a scale of 0—3, with higher scores reflecting more severe sleep complaints. The sum of all the scores permits analysis of the patient’s overall sleep experience. A global PSQI score greater than 5 indicates poor sleep. The measure has been shown to have adequate internal reliability, validity, and consistency for clinical and community samples of the tinnitus population.23 Other subjective parameters were evaluated during the treatment period with a Visual Analogue Scale (VAS) on a scale of 0 to 10 for tinnitus intensity, such as tinnitus loudness and annoyance.24 The objective parameters were evaluated by pure tone audiometry (PTA) and speech reception threshold (SRT) (MADSEN Astera; GN Otometrics A/S, Denmark), both of which were assessed by two senior audiologists. PTA was evaluated according to the average of four frequencies (0.5, 1, 2, and 4 kHz).
Statistical analysis All data were analyzed using the SPSS 17.0 software. The continuous variables were presented as mean ± standard deviation (SD). The Fisher’s exact test was used for categorical variables such as gender and improvement of tinnitus symptoms. The data of symptomatic scores and audiometry for the pre- and post-tests were assessed by Wilcoxon signed-rank test. Differences in efficacy between the two groups were determined by Mann—Whitney U-test. A p < 0.05 was considered statistically significant.
Figure 1 Flow chart of subject recruitment at Liouying Chi-Mei Hospital, from June 2011 to January 2012 in Taiwan. CHJLGMLT: Chai-Hu-Jia-Long-Gu-Mu-Li-Tang.
Efficacy of Chinese herbal formula for chronic tinnitus Table 2
229
Characteristics of patients.
Baseline data
CHJLGMLT group (n = 10)
Non-CHJLGMLT group (n = 11)
p-value*
Sex (M/F) Age (years) Duration of tinnitus (years) Weight (kg) Height (cm) BMI (kg/m2 ) THI PSQI VAS for tinnitus loudness VAS for tinnitus annoyance
4/6 61.1 ± 8.7 10.0 ± 8.3 64.1 ± 9.9 165.0 ± 9.2 23.41 ± 2.18 37.60 ± 14.10 10.80 ± 4.10 5.85 ± 1.41 4.80 ± 1.73
7/4 65.0 ± 8.8 10.1 ± 8.3 67.1 ± 8.9 167.5 ± 6.3 23.81 ± 2.10 36.91 ± 20.48 9.00 ± 1.48 5.40 ± 1.06 5.00 ± 1.64
0.306** 0.306 0.512 0.525 0.571 0.573 0.860 0.054 0.371 0.520
* **
Mann—Whitney U-test. Fisher’s exact test was used.
Results In sum, 46 patients with a diagnosis of chronic tinnitus were identified from the outpatient records (Fig. 1). Among them, 21 patients met the criteria and had complete outpatient records. Data were collected for a 7-month period, from June 2011 to January 2012. Clinical data were investigated for 21 patients, of which 10 were in the CHJLGMIT group and 11 in the non-CHJLGMIT group. The patients’ backgrounds (e.g. age, sex, baseline questionnaire scores of tinnitus) in the two groups were almost homogenous, as shown in Table 2. No conclusive evidence of adverse effects was found in patients treated with CHJLGMIT and western medicine. As shown in Fig. 2, after treatment for 2 months, THI scores decreased significantly in both groups (CHJLGMIT group p = 0.014; non-CHJLGMIT group p = 0.030, Wilcoxon signed-rank test). Worthy of special mention is that the scores of the CHJLGMIT group were reduced more than those of the non-CHJLGMIT group (p = 0.002, Mann—Whitney U test). PSQI scores were reduced in the CHJLGMIT group at 2 months after baseline administration (p = 0.015, Wilcoxon signed-rank test); furthermore, the response was more efficacious in that group than in the non-CHJLGMIT group (p = 0.040, Mann—Whitney U-test). Both groups exhibited similar significant changes in VAS for tinnitus loudness (CHJLGMIT group p = 0.018; non-CHJLGMIT group p = 0.034, Wilcoxon signed-rank test). However, there were no significant differences between groups on the VAS for tinnitus loudness or tinnitus annoyance (p > 0.05, Mann—Whitney U-test). After 2 months of treatment, the CHJLGMIT group showed improvements on both the functional (p = 0.011) and emotional subscales (p = 0.015) (Table 3). In contrast, the non-CHJLGMIT group showed improvement on only the functional subscale (p = 0.046). Thus, the only significant difference between the two groups was on the emotional subscale (p = 0.003). Scores on the PSQI subscales were similar in both groups and were not significantly different after the 2 months of treatment. No significant changes were detected in the levels of PTA and SRT in the two groups at the end of the treatment period. However, the decrement in
the left SRT of the CHJLGMIT group was significantly greater (p = 0.028) than that of the non-CHJLGMIT group.
Discussion Tinnitus is a common otologic disorder that can have a serious impact on working performance, social relations, and sleep, and thus it can affect quality of life.25 No FDAapproved drug to treat tinnitus specifically is available, and few drugs reliably eradicate chronic tinnitus in the majority of patients.26,27 Obstacles to the identification of good candidates for an effective pharmacological treatment for tinnitus include the heterogeneity of tinnitus and our limited knowledge of the varied pathophysiology of tinnitus.28,29 Therefore, the goals for treatment of tinnitus are primarily directed towards alleviating or managing the accompanying symptoms by making the tinnitus less intrusive or less distressing.30 Significant advances have been made in recent years in the management of tinnitus. Several researchers have suggested that anticonvulsants, anxiolytics, or antidepressants could modulate neurotransmitters such as dopamine, serotonin, ␥-aminobutyric acid (GABA), and glutamate within the auditory system and remodel neural activity in the temporal lobe and inferior colliculus to reduce phantom auditory sensations.31—33 Based on reviews of randomized clinical trials, only nortriptyline, amitriptyline, alprazolam, clonazepam, and oxazepam are more beneficial than placebo.34 Currently, a combination of daily doses of antidepressants and psychological therapy is the most effective way to manage chronic tinnitus.35 However, the adverse effects and withdrawal syndromes from antidepressants are common factors that lead to decreased compliance.36 CHJLGMLT, a well-known herbal medicine, has traditionally been used as therapy in neuropsychiatric disorders;12 however, the effects on tinnitus have not been elucidated. Iizuka et al. 16 investigated the use of CHJLGMLT in epilepsy-susceptible mice and found that the formula could ameliorate sleep disorders by reducing excitation. Tamano et al. 37 evaluated the anxiolytic effects of CHJLGMLT in vivo and found that the glutamate concentration in
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C.-H. Lin et al.
Figure 2 Comparison of THI score (A), global PSQ score (B), and VAS scores for tinnitus loudness (C) and tinnitus annoyance (D) before and after treatment with both CHJLGMLT and western medicine (CHJLGMLT group) and western medicine alone (nonCHJLGMLT group) on chronic tinnitus patients for 2 months. *p < 0.05 using Wilcoxon signed-rank test; †p < 0.05 using Wilcoxon rank-sum test. Table 3 Changes in major variables of the measurements, and hearing test scores before and after 2 months of treatment in both groups. CHJLGMLT group
THI subscale (Mean ± SD) Functional subscale Emotional subscale Catastrophic subscale PSQI subscale (Mean ± SD) Subjective sleep quality Sleep latency Sleep duration Habitual sleep efficiency Sleep disturbances Use of sleeping medication Daytime dysfunction PTA, dB (Mean) Right ear Left ear SRT, dB (Mean) Right ear Left ear a b *
Pre-test
Post-test
18.80 ± 7.50 14.20 ± 7.57 6.60 ± 2.84
12.60 ± 7.78 8.60 ± 6.40 4.20 ± 3.46
2.10 ± 0.74 2.10 ± 1.10 1.80 ± 1.03 1.40 ± 0.84 1.50 ± 0.53 0.50 ± 1.08 1.40 ± 0.52
1.80 ± 0.63 1.90 ± 1.20 1.60 ± 0.97 1.30 ± 0.82 1.30 ± 0.48 0.30 ± 0.67 1.30 ± 0.48
p-valuea
Non-CHJLGMLT group
p-valuea
p-valueb
Pre-test
Post-test
0.011* 0.015* 0.087
16.18 ± 9.82 14.73 ± 8.55 6.00 ± 3.46
14.73 ± 8.91 14.18 ± 8.07 5.45 ± 3.11
0.046* 0.257 0.257
0.051 0.003* 0.137
0.083 0.157 0.157 0.317 0.157 0.157 0.317
1.82 ± 0.40 1.27 ± 0.79 1.73 ± 0.90 1.27 ± 0.47 1.09 ± 0.30 0.27 ± 0.90 1.55 ± 0.69
1.82 ± 0.40 1.27 ± 0.79 1.63 ± 0.67 1.27 ± 0.47 1.09 ± 0.30 0.27 ± 0.90 1.45 ± 0.52
1.000 1.000 0.564 1.000 1.000 1.000 0.317
0.056 0.303 0.636 0.294 0.128 0.128 0.945
26.80 27.29
25.98 25.97
0.671 0.202
29.82 29.37
29.68 30.28
1.000 0.391
0.858 0.313
23.83 23.33
21.00 22.00
0.084 0.332
26.82 28.18
26.36 29.55
0.705 0.083
0.193 0.028*
Wilcoxon signed-rank test (Within group). Mann—Whitney U-test (Differences in efficacy between two groups). p < 0.05.
Efficacy of Chinese herbal formula for chronic tinnitus the hippocampus was significantly suppressed. In addition, CHJLGMLT has been reported to reduce stress-induced brain monoamine release and may be used to treat depression.17,38 As stated above, most of the researchers who have studied the tranquilizing effects of CHJLGMLT have focused on psychological illnesses such as anxiety, depression, and insomnia. This study is the first to investigate whether the combination of conventional therapy and CHJLGMLT can, like psychoactive drugs, act on the central auditory system and reduce tinnitus directly. Our results demonstrate improvements on the THI and PSQI in chronic tinnitus after 2 months of CHJLGMLT treatment, indicating that the combination of treatments may be superior to treatment with western medicine alone. Although no statistically significant differences between the two groups were found on any of the PSQI subscales, our results illustrate that the subjective sleep quality of patients with chronic tinnitus improved during the CHJLGMLT period. In the patients examined for this retrospective study, the combination of CHJLGMLT and conventional therapy produced significant improvements on the THI subscales of the functional and emotional reactions to tinnitus from baseline to the end of the treatment period 2 months later. Moreover, the scores on the emotional subscale were reduced significantly more in patients treated with CHJLGMLT than in patients treated with conventional medicine. On the VAS for loudness, both groups showed significant improvements from baseline to the end of the treatment period; however, scores on the THI showed no statistically significant differences between the groups. Although the precise mechanism by which CHJLGMLT ameliorate chronic tinnitus remains unknown, the results of the present study may imply the hypothesis that CHJLGMLT, as mentioned before, has a simultaneous effect on both the psychological disturbance and the tinnitus by altering the secretion of neurotransmitters. The audiologic examinations (PTA and SRT) showed no significant improvements at the end of treatment in either group. Interestingly, there was a statistically significant difference between the group treated with CHJLGMLT and the non-CHJLGMIT group in the left SRT. Because participants with conductive hearing loss were excluded due to their hearing level, which could have an influence on the severity of tinnitus,39 it is difficult to confirm whether CHJLGMLT would be effective for SRT or not. Despite being limited by its retrospective design and execution in a single institution, this study nevertheless yielded useful conclusions. It showed that a combination of CHJLGMLT and conventional therapy may decrease the intensity of tinnitus and relieve the annoyance associated with tinnitus more effectively than conventional therapy alone. Another limitation is that the small sample size limited the statistical power for subgroup analyses. In consideration of this limitation, we analyzed data using non-parametric methods, such as the Mann—Whitney U-test and Wilcoxon signed rank test, to make the results based on a limited number of patients more convincing. However, since this was an open-label CHM treatment, it follows that the placebo effect, assessor bias, and natural recovery still cannot be ruled out.40 For further study, a prospective, randomized controlled study involving a large number of chronic tinnitus patients is needed to resolve this issue.
231
Conclusion Our study found that adjuvant CHJLGMIT therapy could alleviate subjective symptoms in chronic tinnitus more than conventional therapy. Although more definite conclusions require further large controlled studies, patients may benefit from the use of CHJLGMLT as an additional option in the psychological treatment of chronic tinnitus. Prognosis, adequate therapeutic course, and comparisons with other anti-tinnitus therapies should also be investigated.
Conflict of interest statement The authors declare that there is no conflict of interest.
Authors’ contributions M.-Y. Tsai was responsible for the paper preparation and submission and helped to draft the manuscript with C.-E. Kuo. C.-H. Lin and H.-C. Yu created the study design and was responsible for coordination and patient recruitment, and also conceived of the study. Y.-K. Lai was responsible for data acquisition and obtaining the ethical certification for the study. Y.-C. Huang conducted all statistical analyses and interpreted the data. All authors have read and approved the paper.
Acknowledgments This CHJLGMLT study was supported by the Graduate Institute of Integrated Medicine, School of Chinese Medicine (Taiwan). The authors would like to thank Yung-Hsiang Chen, Ph.D and Wen-Chi Chen, Ph.D. for their professional assistance in supervising the study.
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ScienceDirect journal homepage: www.elsevierhealth.com/journals/ctim
Efficacy of adjuvant Chinese herbal formula treatment for chronic tinnitus: A retrospective observational study Chia-Hui Lin a,b,1, Chun-En Kuo c,1, Hao-Chang Yu b,d, Yu-Kai Lai d, Yu-Chuen Huang e, Ming-Yen Tsai b,c,∗ a
Department of Psychiatry, Yuli Hospital, Ministry of Health and Welfare, Hualien 981, Taiwan Graduate Institute of Integrated Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan c Department of Traditional Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan d Departments of Otolaryngology and Chinese Medicine, Chi Mei Medical Center, Liouying 73663, Taiwan e Department of Medical Research, China Medical University Hospital and School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan Available online 7 February 2015 b
KEYWORDS Chinese herbal medicine; Chai-Hu-Jia-Long-GuMu-Li-Tang; Tinnitus; Retrospective study
Summary Background: The aim of this study was to evaluate the clinical efficacy of using western antitinnitus therapy with or without Chai-Hu-Jia-Long-Gu-Mu-Li-Tang (CHJLGMLT) to treat patients with chronic tinnitus. Methods: A descriptive case series with chart review was established to compare patients with chronic tinnitus who had received CHJLGMLT with western anti-tinnitus therapy (the CHJLGMIT group) with those who received western anti-tinnitus therapy alone (the non-CHJLGMIT group). We included 21 patients, 10 patients in the CHJLGMIT group with CHJLGMLT and 11 patients in the non-CHJLGMIT group. Both groups were comparable in terms of patient demographics and clinical characteristics. The follow-up examinations included the assessment of Tinnitus Handicap Inventory (THI), Pittsburgh Sleep Quality Index (PSQI), Visual Analogue Scale (VAS) of 0—10 for tinnitus intensity, pure tone audiometry (PTA), and speech reception threshold (SRT). Results: After 2 months of treatment, THI and PSQI scores were reduced significantly more in the CHJLGMIT group (p < 0.05) than in the non-CHJLGMIT group. Scores on the emotional subscale
Abbreviations: CHJLGMLT, Chai-Hu-Jia-Long-Gu-Mu-Li-Tang; CHM, Chinese herbal medicine; FDA, Food and Drug Administration; GABA, ␥-aminobutyric acid; GMP, good manufacturing procedures; PSQI, Pittsburgh Sleep Quality Index; PTA, pure tone audiometry; SRT, speech reception threshold; TCM, traditional Chinese medicine; THI, tinnitus handicap inventory; VAS, Visual Analogue Scale. ∗ Corresponding author at: Department of Chinese Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan. Tel.: +886 77317123x2332; fax: +886 77317123x2335. E-mail address: [email protected] (M.-Y. Tsai). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.ctim.2015.01.002 0965-2299/© 2015 Elsevier Ltd. All rights reserved.
Efficacy of Chinese herbal formula for chronic tinnitus
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of the THI were significantly reduced in the CHJLGMIT group (p < 0.05) after treatment, but the effects on the seven PSQI subscales did not differ significantly between the two groups (p > 0.05). Scores on the VAS for tinnitus loudness were significantly reduced in both groups (p < 0.05). No significant differences between the two groups were found on the binaural hearing tests (PTA and SRT). Conclusions: Our study found that adjuvant CHJLGMLT therapy for chronic tinnitus may exert additional efficacy by improving psychological sensation of tinnitus and sleep quality. Future randomized controlled double-blind studies should be performed to elucidate its efficacy. © 2015 Elsevier Ltd. All rights reserved.
Background
Methods
Chronic tinnitus is a bothersome health problem that can affect 10—15% of the general population.1 Most cases of chronic tinnitus are subjective, meaning that only the patient can hear the sounds.2 The disorder may be accompanied by otological, orthopaedic, metabolic, neurological, cardiovascular, dental, and pharmacological conditions, more than one of which may be present in the same individual.3,4 Chronic tinnitus can even be a devastating concern; a significant proportion of suffers develop sleep disturbances, anxiety, depression, and other psychiatric comorbidities, and a small fraction commit suicide.5,6 Numerous drug regimens, retraining therapy, behavioural therapies, or noise-masking devices have been tried, with an overall disappointing lack of universal efficacy.1,7 Since there is currently no satisfactory treatment for tinnitus, the condition of these patients may be especially distressing. In order to improve the therapeutic efficacy, many chronic tinnitus patients seek herbal medicine and other alternative and complementary therapies.8,9 This is particularly apparent in Asian patients, who have wellestablished preconceptions about Chinese herbal medicine (CHM). The use of Chai-Hu-Jia-Long-Gu-Mu-Li-Tang (CHJLGMLT), which has a long history as part of the traditional Chinese pharmacopoeia, was first documented in the classical Chinese text Shang Han Lun (On Cold Damage) circa 210 A.D. by Zhong-Jing Zhang.10 In the classical literature, CHJLGMLT is prescribed to reconcile the qi of Shaoyang syndrome, relieve rigidity of the muscles and active collaterals, and tranquilize and allay excitement. TCM practitioners, who use CHJLGMLT to treat many difficult and complicated diseases, rely on traditional Chinese medicine (TCM) theory.11 Several studies in China have shown that treatment with CHJLGMLT effectively improves debilitating conditions such as resistant hypertension, insomnia, neurosis, and tinnitus, and that patients treated with this herbal medicine typically exhibit fewer side effects than those treated with western medicines.12—15 Animal studies have also shown that CHJLGMLT has anti-depressive, stress relief, and sedative effects.16,17 Despite this documented research, questions regarding the beneficial effects of this TCM persist, and the exact mechanism by which CHJLGMLT improve chronic tinnitus remains unknown. The purpose of this study was to review and explore the effects of combining CHJLGMLT with western anti-tinnitus therapies on patients with chronic tinnitus.
Patients We performed a retrospective observational study of adult outpatients with chronic tinnitus treated by an otolaryngologist at Liouying Chi-Mei Hospital, Tainan City, Taiwan, between June 2011 and January 2012. The eligibility criteria for inclusion were: (1) diagnosis of chronic tinnitus defined as a perceived noise of varying intensity, loudness, and pitch in the absence of an external sound lasting longer than 3 months;18 (2) no conductive hearing loss; (3) no major cognitive impairment or psychiatric disorders; and (4) no severe comorbidities (e.g., heart failure, unstable diabetes). This study protocol was ethically approved in case No. 10206-L02 of the Chi-Mei Institutional Review Board (CMHIRB-10206-L02).
Treatment The study, included patients with chronic tinnitus who had undergone current anti-tinnitus therapies. The patients were categorized into two groups. Each patient in CHJLGMIT group had been provided with adjuvant the CHJLGMLT formula for the 2-month period examined for the study. Patients in the non-CHJLGMIT group had received only anti-tinnitus therapies. The western medicine for chronic tinnitus are oral peripheral vasodilators (nicametate citrate 50 mg and thiamine 100 mg three times a day), which are
Table 1 Components of Chai-Hu-Jia-Long-Gu-Mu-Li-Tang (every 4 g of dry extract was derived from 23.8 g of the raw materials). Pharmaceutical name
Chinese Pinyin
Ratio (g)
Radix Bupleuri Fossilia Ossis Mastodi Rhizoma Zingiberisrecens Radix Ginseng Poria Radix Scutellariae Concha Ostreae Ramulus Cinnamomi Rhizoma Pinelliae Fructus Jujubae Rhizoma Rhei
Chaihut Longku Shengjiang Renshen Fuling Huangqin Muli Guizhi Banxia Dazao Dahuang
2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.8
228 frequently suggested as a possible treatment for tinnitus in the press, and many people with tinnitus use a variety of products on the basis of limited evidence.19 The CHJLGMLT formula used was an herbal extract powder made according to the good manufacturing procedures (GMP) of the certified company Kaiser Pharmaceutical Co., Ltd. (Taiwan), for the purpose of meeting international market standards of quality and uniformity. The composition of the CHJLGMLT formula is shown in Table 1. This medication was administered at a treatment dose of 3 g three times per day, after each meal. All treatments were administered by both an otolaryngologist and a TCM practitioner who had at least 6 years of clinical experience in their professional fields.
Outcome measurements To assess the efficacy of treatment, the severity of chronic tinnitus was evaluated using comprehensive audiologic examinations both before and after 2 months of treatment by an assistant specializing in otolaryngology. At the same time, it was confirmed that none of the patients had received other herbal medicines, and the western medicines were modified during the period. As part of the treatment, the primary outcome was assessed by using the Tinnitus Handicap Inventory (THI) and Pittsburgh Sleep Quality Index (PSQI) at the baseline visit and after the 2 months of treatment. The THI, which consists of 25 items scored as 0 = no, 2 = sometimes, and 4 = yes, permits description of the perceived aspects of function (difficulties with concentration and anti-social trends), emotion (anger, frustration, irritability, depression), and catastrophe (despair, feelings of hopelessness, fear of a ‘‘severe disease’’, loss of control, and inability to cooperate).20 The questionnaire was developed to gain further insights into each person’s physiological changes and the psychological impacts commonly experienced by tinnitus patients. The composite scores for each of the subscales are based on
C.-H. Lin et al. adding up the scores of the items of the respective dimensions. The composite score (total score) is the sum of the dimension scores. Useful categories for describing clinical relevance of the index were as follows: slight (0—16), mild (18—36), moderate (38—56), severe (58—76), or catastrophic (78—100).21 The PSQI is a simple, non-invasive, self-report measure that provides night-to-night information on sleep patterns, sleep quality, and relevant daytime behaviour.22 It comprises seven subscales, and each subscale is rated on a scale of 0—3, with higher scores reflecting more severe sleep complaints. The sum of all the scores permits analysis of the patient’s overall sleep experience. A global PSQI score greater than 5 indicates poor sleep. The measure has been shown to have adequate internal reliability, validity, and consistency for clinical and community samples of the tinnitus population.23 Other subjective parameters were evaluated during the treatment period with a Visual Analogue Scale (VAS) on a scale of 0 to 10 for tinnitus intensity, such as tinnitus loudness and annoyance.24 The objective parameters were evaluated by pure tone audiometry (PTA) and speech reception threshold (SRT) (MADSEN Astera; GN Otometrics A/S, Denmark), both of which were assessed by two senior audiologists. PTA was evaluated according to the average of four frequencies (0.5, 1, 2, and 4 kHz).
Statistical analysis All data were analyzed using the SPSS 17.0 software. The continuous variables were presented as mean ± standard deviation (SD). The Fisher’s exact test was used for categorical variables such as gender and improvement of tinnitus symptoms. The data of symptomatic scores and audiometry for the pre- and post-tests were assessed by Wilcoxon signed-rank test. Differences in efficacy between the two groups were determined by Mann—Whitney U-test. A p < 0.05 was considered statistically significant.
Figure 1 Flow chart of subject recruitment at Liouying Chi-Mei Hospital, from June 2011 to January 2012 in Taiwan. CHJLGMLT: Chai-Hu-Jia-Long-Gu-Mu-Li-Tang.
Efficacy of Chinese herbal formula for chronic tinnitus Table 2
229
Characteristics of patients.
Baseline data
CHJLGMLT group (n = 10)
Non-CHJLGMLT group (n = 11)
p-value*
Sex (M/F) Age (years) Duration of tinnitus (years) Weight (kg) Height (cm) BMI (kg/m2 ) THI PSQI VAS for tinnitus loudness VAS for tinnitus annoyance
4/6 61.1 ± 8.7 10.0 ± 8.3 64.1 ± 9.9 165.0 ± 9.2 23.41 ± 2.18 37.60 ± 14.10 10.80 ± 4.10 5.85 ± 1.41 4.80 ± 1.73
7/4 65.0 ± 8.8 10.1 ± 8.3 67.1 ± 8.9 167.5 ± 6.3 23.81 ± 2.10 36.91 ± 20.48 9.00 ± 1.48 5.40 ± 1.06 5.00 ± 1.64
0.306** 0.306 0.512 0.525 0.571 0.573 0.860 0.054 0.371 0.520
* **
Mann—Whitney U-test. Fisher’s exact test was used.
Results In sum, 46 patients with a diagnosis of chronic tinnitus were identified from the outpatient records (Fig. 1). Among them, 21 patients met the criteria and had complete outpatient records. Data were collected for a 7-month period, from June 2011 to January 2012. Clinical data were investigated for 21 patients, of which 10 were in the CHJLGMIT group and 11 in the non-CHJLGMIT group. The patients’ backgrounds (e.g. age, sex, baseline questionnaire scores of tinnitus) in the two groups were almost homogenous, as shown in Table 2. No conclusive evidence of adverse effects was found in patients treated with CHJLGMIT and western medicine. As shown in Fig. 2, after treatment for 2 months, THI scores decreased significantly in both groups (CHJLGMIT group p = 0.014; non-CHJLGMIT group p = 0.030, Wilcoxon signed-rank test). Worthy of special mention is that the scores of the CHJLGMIT group were reduced more than those of the non-CHJLGMIT group (p = 0.002, Mann—Whitney U test). PSQI scores were reduced in the CHJLGMIT group at 2 months after baseline administration (p = 0.015, Wilcoxon signed-rank test); furthermore, the response was more efficacious in that group than in the non-CHJLGMIT group (p = 0.040, Mann—Whitney U-test). Both groups exhibited similar significant changes in VAS for tinnitus loudness (CHJLGMIT group p = 0.018; non-CHJLGMIT group p = 0.034, Wilcoxon signed-rank test). However, there were no significant differences between groups on the VAS for tinnitus loudness or tinnitus annoyance (p > 0.05, Mann—Whitney U-test). After 2 months of treatment, the CHJLGMIT group showed improvements on both the functional (p = 0.011) and emotional subscales (p = 0.015) (Table 3). In contrast, the non-CHJLGMIT group showed improvement on only the functional subscale (p = 0.046). Thus, the only significant difference between the two groups was on the emotional subscale (p = 0.003). Scores on the PSQI subscales were similar in both groups and were not significantly different after the 2 months of treatment. No significant changes were detected in the levels of PTA and SRT in the two groups at the end of the treatment period. However, the decrement in
the left SRT of the CHJLGMIT group was significantly greater (p = 0.028) than that of the non-CHJLGMIT group.
Discussion Tinnitus is a common otologic disorder that can have a serious impact on working performance, social relations, and sleep, and thus it can affect quality of life.25 No FDAapproved drug to treat tinnitus specifically is available, and few drugs reliably eradicate chronic tinnitus in the majority of patients.26,27 Obstacles to the identification of good candidates for an effective pharmacological treatment for tinnitus include the heterogeneity of tinnitus and our limited knowledge of the varied pathophysiology of tinnitus.28,29 Therefore, the goals for treatment of tinnitus are primarily directed towards alleviating or managing the accompanying symptoms by making the tinnitus less intrusive or less distressing.30 Significant advances have been made in recent years in the management of tinnitus. Several researchers have suggested that anticonvulsants, anxiolytics, or antidepressants could modulate neurotransmitters such as dopamine, serotonin, ␥-aminobutyric acid (GABA), and glutamate within the auditory system and remodel neural activity in the temporal lobe and inferior colliculus to reduce phantom auditory sensations.31—33 Based on reviews of randomized clinical trials, only nortriptyline, amitriptyline, alprazolam, clonazepam, and oxazepam are more beneficial than placebo.34 Currently, a combination of daily doses of antidepressants and psychological therapy is the most effective way to manage chronic tinnitus.35 However, the adverse effects and withdrawal syndromes from antidepressants are common factors that lead to decreased compliance.36 CHJLGMLT, a well-known herbal medicine, has traditionally been used as therapy in neuropsychiatric disorders;12 however, the effects on tinnitus have not been elucidated. Iizuka et al. 16 investigated the use of CHJLGMLT in epilepsy-susceptible mice and found that the formula could ameliorate sleep disorders by reducing excitation. Tamano et al. 37 evaluated the anxiolytic effects of CHJLGMLT in vivo and found that the glutamate concentration in
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C.-H. Lin et al.
Figure 2 Comparison of THI score (A), global PSQ score (B), and VAS scores for tinnitus loudness (C) and tinnitus annoyance (D) before and after treatment with both CHJLGMLT and western medicine (CHJLGMLT group) and western medicine alone (nonCHJLGMLT group) on chronic tinnitus patients for 2 months. *p < 0.05 using Wilcoxon signed-rank test; †p < 0.05 using Wilcoxon rank-sum test. Table 3 Changes in major variables of the measurements, and hearing test scores before and after 2 months of treatment in both groups. CHJLGMLT group
THI subscale (Mean ± SD) Functional subscale Emotional subscale Catastrophic subscale PSQI subscale (Mean ± SD) Subjective sleep quality Sleep latency Sleep duration Habitual sleep efficiency Sleep disturbances Use of sleeping medication Daytime dysfunction PTA, dB (Mean) Right ear Left ear SRT, dB (Mean) Right ear Left ear a b *
Pre-test
Post-test
18.80 ± 7.50 14.20 ± 7.57 6.60 ± 2.84
12.60 ± 7.78 8.60 ± 6.40 4.20 ± 3.46
2.10 ± 0.74 2.10 ± 1.10 1.80 ± 1.03 1.40 ± 0.84 1.50 ± 0.53 0.50 ± 1.08 1.40 ± 0.52
1.80 ± 0.63 1.90 ± 1.20 1.60 ± 0.97 1.30 ± 0.82 1.30 ± 0.48 0.30 ± 0.67 1.30 ± 0.48
p-valuea
Non-CHJLGMLT group
p-valuea
p-valueb
Pre-test
Post-test
0.011* 0.015* 0.087
16.18 ± 9.82 14.73 ± 8.55 6.00 ± 3.46
14.73 ± 8.91 14.18 ± 8.07 5.45 ± 3.11
0.046* 0.257 0.257
0.051 0.003* 0.137
0.083 0.157 0.157 0.317 0.157 0.157 0.317
1.82 ± 0.40 1.27 ± 0.79 1.73 ± 0.90 1.27 ± 0.47 1.09 ± 0.30 0.27 ± 0.90 1.55 ± 0.69
1.82 ± 0.40 1.27 ± 0.79 1.63 ± 0.67 1.27 ± 0.47 1.09 ± 0.30 0.27 ± 0.90 1.45 ± 0.52
1.000 1.000 0.564 1.000 1.000 1.000 0.317
0.056 0.303 0.636 0.294 0.128 0.128 0.945
26.80 27.29
25.98 25.97
0.671 0.202
29.82 29.37
29.68 30.28
1.000 0.391
0.858 0.313
23.83 23.33
21.00 22.00
0.084 0.332
26.82 28.18
26.36 29.55
0.705 0.083
0.193 0.028*
Wilcoxon signed-rank test (Within group). Mann—Whitney U-test (Differences in efficacy between two groups). p < 0.05.
Efficacy of Chinese herbal formula for chronic tinnitus the hippocampus was significantly suppressed. In addition, CHJLGMLT has been reported to reduce stress-induced brain monoamine release and may be used to treat depression.17,38 As stated above, most of the researchers who have studied the tranquilizing effects of CHJLGMLT have focused on psychological illnesses such as anxiety, depression, and insomnia. This study is the first to investigate whether the combination of conventional therapy and CHJLGMLT can, like psychoactive drugs, act on the central auditory system and reduce tinnitus directly. Our results demonstrate improvements on the THI and PSQI in chronic tinnitus after 2 months of CHJLGMLT treatment, indicating that the combination of treatments may be superior to treatment with western medicine alone. Although no statistically significant differences between the two groups were found on any of the PSQI subscales, our results illustrate that the subjective sleep quality of patients with chronic tinnitus improved during the CHJLGMLT period. In the patients examined for this retrospective study, the combination of CHJLGMLT and conventional therapy produced significant improvements on the THI subscales of the functional and emotional reactions to tinnitus from baseline to the end of the treatment period 2 months later. Moreover, the scores on the emotional subscale were reduced significantly more in patients treated with CHJLGMLT than in patients treated with conventional medicine. On the VAS for loudness, both groups showed significant improvements from baseline to the end of the treatment period; however, scores on the THI showed no statistically significant differences between the groups. Although the precise mechanism by which CHJLGMLT ameliorate chronic tinnitus remains unknown, the results of the present study may imply the hypothesis that CHJLGMLT, as mentioned before, has a simultaneous effect on both the psychological disturbance and the tinnitus by altering the secretion of neurotransmitters. The audiologic examinations (PTA and SRT) showed no significant improvements at the end of treatment in either group. Interestingly, there was a statistically significant difference between the group treated with CHJLGMLT and the non-CHJLGMIT group in the left SRT. Because participants with conductive hearing loss were excluded due to their hearing level, which could have an influence on the severity of tinnitus,39 it is difficult to confirm whether CHJLGMLT would be effective for SRT or not. Despite being limited by its retrospective design and execution in a single institution, this study nevertheless yielded useful conclusions. It showed that a combination of CHJLGMLT and conventional therapy may decrease the intensity of tinnitus and relieve the annoyance associated with tinnitus more effectively than conventional therapy alone. Another limitation is that the small sample size limited the statistical power for subgroup analyses. In consideration of this limitation, we analyzed data using non-parametric methods, such as the Mann—Whitney U-test and Wilcoxon signed rank test, to make the results based on a limited number of patients more convincing. However, since this was an open-label CHM treatment, it follows that the placebo effect, assessor bias, and natural recovery still cannot be ruled out.40 For further study, a prospective, randomized controlled study involving a large number of chronic tinnitus patients is needed to resolve this issue.
231
Conclusion Our study found that adjuvant CHJLGMIT therapy could alleviate subjective symptoms in chronic tinnitus more than conventional therapy. Although more definite conclusions require further large controlled studies, patients may benefit from the use of CHJLGMLT as an additional option in the psychological treatment of chronic tinnitus. Prognosis, adequate therapeutic course, and comparisons with other anti-tinnitus therapies should also be investigated.
Conflict of interest statement The authors declare that there is no conflict of interest.
Authors’ contributions M.-Y. Tsai was responsible for the paper preparation and submission and helped to draft the manuscript with C.-E. Kuo. C.-H. Lin and H.-C. Yu created the study design and was responsible for coordination and patient recruitment, and also conceived of the study. Y.-K. Lai was responsible for data acquisition and obtaining the ethical certification for the study. Y.-C. Huang conducted all statistical analyses and interpreted the data. All authors have read and approved the paper.
Acknowledgments This CHJLGMLT study was supported by the Graduate Institute of Integrated Medicine, School of Chinese Medicine (Taiwan). The authors would like to thank Yung-Hsiang Chen, Ph.D and Wen-Chi Chen, Ph.D. for their professional assistance in supervising the study.
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