A study of efficacy of Nigella sativa in treatment of Meniere's disease: A randomized, placebo controlled clinical trial

Abstract

Purpose

Meniere's disease (MD), first introduced by Prosper Meniere, is characterized mainly by vertigo, tinnitus, aural fullness and sensorineural hearing loss. Though the exact pathophysiology of MD is unknown, immunologic and inflammatory interactions are possible underlying mechanisms involved in MD. This study is aimed to investigate the immunomodulatory and anti-inflammatory effect of Nigella sativa on MD as a therapeutic agent.

Methods

We divided 40 patients with definite MD into two groups of 20 cases. The study group received 1 g of Nigella sativa oil daily for three months and the control group received a placebo. Changes in hearing, tinnitus and vertigo were estimated by pure tone audiometry, tinnitus handicap inventory questionnaire and dizziness handicap inventory questionnaire, respectively.

Results

At the end of the study we did not observe any significant improvement in study's group hearing threshold, tinnitus and vertigo compared to the control group.

Conclusions

In this study, statistical analysis showed that Nigella sativa failed to improve signs and symptoms of MD. However, further investigations with a larger study population are needed to ascertain the current conclusion.

Abbreviations

MD

Meniere's disease

PTA

pure tone audiometry

THI

tinnitus handicap inventory questionnaire

DHI

dizziness handicap inventory questionnaire

MDH

Meniere's disease with high basal levels of IL- 1β

MDL:

Meniere's disease with low basal levels of IL- 1β

RA

rheumatoid arthritis

SLE

systemic lupus erythematosus

AS

ankylosing spondylitis

1. Introduction

Meniere's disease (MD), first introduced by Prosper Meniere in 1861, is characterized mainly by episodes of vertigo, tinnitus, aural fullness and sensorineural hearing loss in which each episode lasts for 20 min to 12 h (Unsal et al., 2019; Lopez-Escamez et al., 2015). The disorder has a prevalence of 50–200 cases per 100 000 populations and the majority of the cases are between the ages of 40 and 60 years, though it can have a prevalence of 3 percent between children. Also, it seems to affect women and white people more. Due to disabling attacks of MD, patients are at risk of falling and major traumas and the disease may interfere with their professional and educational life (Kitahara, 2018; Basura et al., 2020). The underlying etiology of this disorder is still unknown and different hypotheses have been suggested for the pathophysiology of MD. However, the increase of inner ear fluid volumes called endolymphatic hydrops is the most common finding in the ears of MD patients (Kangasniemi and Hietikko, 2018; Eckhard et al., 2019). Besides, many researches have reported genetic, viral infections and immunologic interactions as probable disease etiologies. According to the theory of the role of viral infections in MD, it has been suggested that an irregular immune reaction to a viral threat in an ear with a narrow vestibular duct leads to reduction in endolymphatic drainage and causes endolymphatic hydrops (Greco et al., 2012). This theory is mainly supported by investigations based on antigen and antibody detection against viruses like herpes simplex, Varicella zoster virus, adenovirus and cytomegalovirus. On the other hand, some studies have reported an increase in autoantibodies and inflammatory cytokines in MD patients, while others reported the growth in autoimmune diseases among patients with MD (Greco et al., 2012). As an example, ankylosing spondylitis and rheumatoid arthritis are 2–3 times more frequent in MD patients and systemic lupus erythematosus is eight times more regular between them (Greco et al., 2012). These findings alongside the positive effect of steroid therapy in controlling signs and symptoms of MD suggest the possible role of the immune system in the pathogenesis of MD (Greco et al., 2012). Regardless of the underlying etiology, the first therapeutic line in MD consists of low-salt and low-caffeine diet, diuretics and vasoactive drugs (Manrique-Huarte et al., 2018). If they fail to relieve symptoms, more invasive treatments like labyrinthine toxic drugs or surgical interventions like endolymphatic sac surgery, labyrinthectomy and vestibular neurectomy may be recommended (Manrique-Huarte et al., 2018). Also, supportive treatments like hearing rehabilitation and vestibular rehabilitation can be prescribed if indicated (Manrique-Huarte et al., 2018). However, the current treatments have adverse effects and are not entirely effective. These challenges as well as their invasive method of administration necessitate further investigation to discover new therapies (Öztürk and Ata, 2019; Devantier et al., 2019).

Nigella sativa, also called black seed, is a native plant of southwest Asia and is a member of the Ranunculacea family of plants. Its use as a therapeutic agent goes back more than 2000 years and is used for various of diseases like cardiorespiratory, gastrointestinal, renal and immunologic disorders (Nasuti et al., 2019; Tavakkoli et al., 2017; Soliman et al., 2017). Active components of this plant consist of proteins, fatty acids, alkaloids, saponins and Thymoquinone which is responsible for the majority of pharmacological effects of Nigella sativa. Therapeutic potentials of this plant include anti-cancer, antipyretic, anti-inflammatory, analgesic and immunomodulatory. Thymoquinone and flavonoid components of the plant have a strong antioxidant effect. Thymoqionone prevents lipid peroxidation and improves the enzymatic and non-enzymatic activity of natural antioxidants of the body. This plant inhibits the production of inflammatory mediators, leukotrienes and prostaglandins; thus, it is used to treat a broad range of inflammatory and autoimmune diseases (Kooti et al., 2016). Hence, considering the need for a novel treatment for MD, in this report we aim to study the immunomodulatory, antioxidant and anti-inflammatory effects of Nigella sativa in relieving symptoms of MD.

2. Materials and methods

The study included 40 patients with definite MD and had a single –blind randomized controlled study design. The patients enrolled in the study from February 2021 (first patient, first visit) to October 2021 (last patient, last visit). They had been treated with life style and diet modification and Betahistine 16 mg bid and Triamterene H 50/25 daily for at least six months. Yet, the symptoms had not been controlled. The patients were randomly assigned into two groups of study and control using the balanced block randomization technique, each containing 20 cases. The inclusion criterion was a definite diagnosis of MD according to the 1995 guidelines of the American Academy of Otolaryngology (Committee on Hearing and Equilibrium, 1995). The exclusion criteria were medical history of cardiac, hepatic, renal, psychiatric or hypertensive diseases. The study was approved by Ethics Committee in Research of Amir Alam Hospital Complex (IR.TUMS.AMIRALAM.REC.1399.041) and follow the principles of the Declaration of Helsinki. Also, all the patients filled out written and informative consent forms. The previous treatments of MD continued during the study. The patients in the study group received coated capsules of Nigella sativa oil for three months. Each capsule contained 1 g of the oil and the capsules were taken once a day. Patients in the control group received capsules of placebo similar to capsules of Nigella sativa oil and were taken daily for three months.

Changes in tinnitus, hearing and vertigo were estimated by the tinnitus handicap inventory questionnaire (THI), pure tone audiometry (PTA) and dizziness handicap inventory questionnaire (DHI), respectively (Mahmoudian et al., 2011; Jafarzadeh et al., 2014). The bone conduction in PTA was used in thresholds at 0.25, 0.5, 1, 2 and 4 kHz to study hearing changes (as suggested by similar studies) (Adrion et al., 2016; Lyu et al., 2020). PTA, DHI and THI were estimated once before the administration of the drug and once at the end of the study. The SPSS 16.0 software was used for data analysis. Categorical variables were analyzed by chi-square tests and were shown by a percentage, while numerical variables were compared with independent sample t-tests and were expressed as mean ± standard deviation (SD). P-value ≤0.05 was defined as statistically significant. The current report follows the principles of CONSORT guidelines and the entire trial protocol can be accessed in the Iranian Registry of Clinical Trials by the registration code IRCT20201102049238N1. The major limitation of this study was the low sample size which should be addressed in further studies.

3. Results and analysis

Among a total of 44 patients screened for eligibility, four patients (9%) could not pass the screening due to exclusion criteria (3 cases) or allergy to Nigella sativa (1 case). The 40 eligible patients were randomly assigned into two groups of study and control. Fig. 1 shows the flow of the participants during the study. Age and sex were distributed similarly in both groups (p-value ≥0.05). Also, the two groups’ baseline DHI, THI and hearing threshold were not significantly different (p value ≥ 0.05). Table 1 illustrates the baseline characteristics of participants. During the application of Nigella sativa oil no severe side effects were reported. This study was conducted during covid-19 pandemic. Hence, 14 patients failed to remain in the study due to being affected by the virus or the quarantine of the cities. In the end, changes in the severity of tinnitus were assessed by comparing THI score before and after consumption of Nigella sativa oil and showed no significant difference between the two groups of study and control (p-value ≥0.05). Similarly, comparing changes in vertigo attacks using DHI score did not show any significant difference between the two groups (p-value ≥0.05). PTA was used to monitor hearing changes at thresholds of 0.5, 1, 2 and 4 kHz. However, the results demonstrated no significant change in hearing thresholds after the application of Nigella sativa oil in comparison with the placebo group (p value ≥ 0.05). Table 2 displays differences in the studied variables between the two groups.

4. Discussion

Different etiologies have been proposed for the MD (Unsal et al., 2019; Basura et al., 2020). In this regard, many studies have mentioned the role of immunologic interactions in the initiation of MD (Yang and Brook, 2017). Bystander damage, cross-reactions, intolerance and presence of cytokines (IL-1α, TNF-α, NF-kβ P65, P50, and Ikβα) in cochlea and the production of autoantibodies in the sera against inner ear proteins are possible mechanisms through which inflammations and immune system may cause MD (Frejo and Lopez-Escamez, 2022). As an example, in a study by Flook et al. the cytokine profile (containing fourteen cytokines (IFN-γ,IFNα-2, IL-10, IL-1β, IL-1rα, IL-4, IL-12p40, IL-6, IL-12p70, IL-17, IL-13, TNFα, and IL-28 A), and 11 chemokines (IL-8, CCL2, CXCL10, CCL3, CCL4, CD40LG, CCL5, CXCL1, CXCL5, CCL22, and CCL8)) of 129 patients with MD were examined. The group declared that MD could be classified based on the amount of serologic IL-1β into two subgroups of MD with high basal levels of IL- 1β (MDH) and with low basal levels of IL- 1β (MDL). Finally, the study concluded that MDH patients had higher levels of cytokines and chemokines (Flook et al., 2019). Another study by Gottschlich et al. assessed 50 patients with MD serum antibodies. They reported that a significantly high number of patients with MD (30%) had anti-bodies that can react with 68 kd Antigen (inner-ear material antigen) when compared with the control group (Gottschlich et al., 1995). Also, a study by Moleon et al. showed an increase in cytokine profile (CCL18, CCL3, and CXCL4) of patients with MD compared to controls (Moleon et al., 2021). On the other hand, Gazquez et al. in a case series of 690 patients with MD reported that the prevalence of autoimmune diseases like rheumatoid arthritis (RA), ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE) in MD patients is higher than observed in the general population (Gazquez et al., 2011). Similarly, Tyrrell et al. reported a higher prevalence of allergic reactions and immune or autoimmune dysfunction in MD patients when studying 1376 cases of the disease (Tyrrell et al., 2014). Altogether, the role of immunologic and inflammatory reactions should be considered when discovering a treatment for MD.

Although different therapeutic strategies have been proposed for MD, there needs to be a completely effective treatment for the disease necessitates further investigations in this regard (Basura et al., 2020). Considering the possible role of inflammatory and immunologic reactions in the pathophysiology of MD, Nigella sativa can be investigated as a candidate for the treatment of MD; since this plant has been proven to have anti-inflammatory and immunomodulatory effects by many researchers. For instance, Culhaoglu and colleagues caused noise-induced hearing loss in 20 rats by exposing them to acoustic trauma. They further used the anti-oxidant and anti-inflammatory effects of Nigella sativa to improve hearing loss, considering the inflammatory mechanisms involved in acoustic trauma, and announced that the hearing threshold of the rats treated with Nigella sativa was lower than the control group (Culhaoglu et al., 2017). Also, a similar study was performed by Aksoy et al. on 32 rats and reported that thymoquinone has reparative effect in noise-induced hearing loss (Aksoy et al., 2015). Hence, in this study we aimed to investigate the immunomodulatory and anti-inflammatory effects of Nigella sativa on MD.

Our study showed no significant improvement in the study group's hearing threshold, tinnitus and vertigo samples compared to the control group. However, the current study was performed over a small population of MD patients. It was conducted during the pandemic of covid-19 which largely affected the enrollment of the patients and the maintenance of the enrolled cases in the study. Thus, further investigations on larger populations are necessary to determine whether or not Nigella sativa is effective as a therapy for MD.

Disclosure of interest

None.

Appendices.

Fig. 1.

Flowchart of the participants during the study.

Table 1.

Baseline characteristics of participants

characteristics	Control group (n = 16)	Study group (n = 10)
Age	45 ± 13	40 ± 10
Male gender	6 (30%)	3 (15%)
History of migraine	2 (12%)	2 (20%)
History of Autoimmune conditions	2 (12%)	0 (0%)
Duration (years)	5.3 ± 3.3	3.6 ± 2.9
Family history of Meniere's disease	0 (0%)	1 (10%)
Affected ear
Right	4 (25%)	2 (20%)
Left	3 (18%)	1 (10%)
Both	9 (57%)	7 (70%

Table 2.

Differences in tinnitus, vertigo and hearing loss between the two groups of placebo and study

variables	Study group	Control group	Confidence interval (95%)		P value
			Lower	Upper
DHI difference	−19.8 ± 19.5	−4 ± 19.3	−31.9	0.3	0.055
THI difference	−14.4 ± 28.7	−3.3 ± 22.3	−31.6	9.6	0.28
Hearing change (dB)	−0.9 ± 5.6	−0.2 ± 5.8	−4.3	3	0.71

DHI: dizziness handicap inventory questionnaire, THI: tinnitus handicap inventory questionnaire.