Efficacy of ozone therapy as an add-on treatment in fibromyalgia: A randomized double-blind placebo-controlled study

Abstract

BACKGROUND:

Fibromyalgia (FM) is a chronic disease that causes widespread pain, fatigue, and sleep disturbance. There is still no effective definitive treatment method; therefore, the search for treatment continues.

OBJECTIVE:

The purpose of this study is to investigate the effectiveness of ozone therapy (OT), which has been used in FM treatment in recent years, as an additional treatment.

METHODS:

The patients were divided into OT ( $n=$ 26) and placebo control (PC) ( $n=$ 28) groups. Both groups received OT in the form of major autohemotherapy (MaAHT) and minor autohemotherapy (MiAHT) for two sessions per week for a total of 10 sessions. The fibromyalgia impact questionnaire (FIQ), Pittsburgh sleep quality index (PSQI), and 12-item short-form health survey (SF-12) were used for evaluation pre- and post-intervention.

RESULTS:

In the between-group comparison, the OT group showed significant post-treatment improvements in FIQ subscales (feel good, fatigue) and PSQI total score and subscales (subjective sleep quality, sleep latency and sleep disturbances) compared to the PC group ( $p<$ 0.05). Although there were improvements in the FIQ total score post-treatment in both groups, there was no significant difference between the groups ( $p>$ 0.05).

CONCLUSION:

OT, which is applied as an additional treatment with the autohemotherapy method, simultaneously improves the subscale scores (feel good and fatigue) of FM and sleep quality in the treatment period. However, changes in the post-treatment FIQ total score were not different in the ozone therapy group from the placebo control group.

Keywords

Autohemotherapy fibromyalgia ozone quality of life sleep

1. Introduction

Fibromyalgia (FM) is a chronic disease with multiple and complex clinical symptoms. While the primary complaint in FM is widespread pain, sleep disturbances, chronic fatigue, mood disorders, and other somatic complaints may occur [1, 2]. Although its etiopathogenesis is unclear, genetic and environmental factors and peripheral and central mechanisms play a role in FM development [3, 4, 5]. Oxidative stress increases in FM; however, it is not known whether this increase is the cause or an outcome of the disease [6, 7, 8]. In these patients, antioxidant enzymes such as catalase, glutathione peroxidase, and superoxide dismutase have been reported in low concentrations [8, 9].

Ozone is an unstable molecule; when it comes into contact with tissues, it reacts with unsaturated fatty acids, thus forming reactive oxygen derivatives and lipid oxidation products. These reactive oxygen species stimulate the antioxidant enzyme system, and ozone creates a mild, temporary, and controlled oxidative stress when applied in therapeutic doses [8, 10]. Ozone therapy (OT) acts by upregulating the antioxidant system, thus modulating the immune system and stimulating the suppression of inflammatory processes [10, 11, 12]. Ozone therapy (OT), which has several local (intraarticular, paravertebral, and intradermal) and systemic (major or minor autohemotherapy [AHT] and rectal insufflation) application methods, is used in treating various diseases, such as cardiovascular, inflammatory and infectious diseases [10, 11, 12].

It has been assumed that OT can be useful in FM treatment based on these mechanisms of action, and it has been shown to be effective in certain case studies [8, 12, 13, 14]. However, in these uncontrolled studies, the possible placebo effect of OT was ignored. Whereas, we think that more accurate results about the treatment efficacy of OT can be reached with a placebo-controlled study. Therefore, this randomized, placebo-controlled study, which will be the first in the literature, aims to evaluate the effectiveness of OT compared to placebo as an additional treatment in FM.

There is still no definite effective treatment method in FM [3, 13]. The drugs administered in symptomatic treatment, however, have many side effects, which leads to problems regarding their use [2, 3, 4]. Consequently, the search for treatment in FM is still ongoing. In this respect, we thought that OT could contribute as an additional treatment in FM and we aimed to investigate its effect on pain, fatigue, sleep disturbance, and daily life quality.

2. Materials and methods

2.1 Study design and participants

The study protocol was prospective, randomized, and placebo-controlled. The study was performed in the physical therapy and rehabilitation department of the Private Nisa Hospital between April 2019 and February 2020. Patients aged over 18 years diagnosed with FM were included in the study based on the criteria determined by the American College of Rheumatology [15]. The exclusion criteria were pregnancy, breastfeeding, hyperthyroidism, favism (glucose-6-phosphate dehydrogenase deficiency), sickle cell anemia, hypoglycemia, hypotension and exogenous antioxidant vitamin use (vitamins A, C, E and B9). Because ozone was administered as an add-on therapy, patients continued to receive their ongoing medical treatments during the study period.

2.2 Ethical considerations

This study was approved by the Research Ethics Committee of Istanbul Gelisim University (Meeting date: March 26, 2019, Decision no.: 8-6). The study was conducted in accordance with the rules of the Declaration of Helsinki, and all individuals provided written informed consent prior to participation.

2.3 Randomization and blinding

Patients were randomized to groups by a physiatrist who did not participate in the recruitment and treatment of participants. They were asked to select a number between 1 and 10, with those selecting even numbers assigned to the OT group and those selecting odd numbers assigned to the placebo control (PC) group (Fig. 1).

Figure 1.

Study flowchart. Abbreviations: ACR: American College of Rheumatology; MaAHT: Major autohemotherapy; MiAHT: Minor autohemotherapy.

Patients and the physician performing the intervention were blinded to ozone concentrations. An independent different physician performed the ozone concentration adjustment from the generator and drew it into the injector, and only this physician was aware of the ozone dose to be administered to the patient.

2.4 Interventions

The number of sessions, ozone dosage, and ozone concentration in the OT interventions were determined by considering the recommendations of the Madrid Declaration on Ozone Therapy (MDOT) [16]. In our study, both groups underwent a total of 10 OT sessions, two sessions per week for five consecutive weeks using the major autohemotherapy (MaAHT) and minor autohemotherapy (MiAHT) methods of application. MaAHT and MiAHT applications were applied in the same session. The ozone concentration (ozone/oxygen gas) in MaAHT and MiAHT applications was 15 $\mu$ g/ml in the first two sessions, 20 $\mu$ g/ml in the next four sessions, and 25 $\mu$ g/ml in the final four sessions in the OT group and 0.1 $\mu$ g/ml for all sessions in the PC group. The ozone generator used was Turkozone Blue S (Ozon Health Services Co. Ltd., Istanbul, Turkey), which was approved by the Ministry of National Health.

MaAHT was administered as follows: 100 ml of autologous blood was collected from the patient’s intravenous vein into a vacuum glass bottle containing 10 ml of citrate. After drawing 100 ml of ozone at the desired concentration into the injector, it was transferred to the same vacuum bottle. The ozonation process of the blood was completed in 5 min under gentle mixing. Ozone, unlike oxygen, immediately reacts and dissolves in plasma. In this manner, blood is ozonated. Ozonated blood was then reinfused into the patient in approximately 15 min via a suitable blood filter tube [16].

MiAHT was administered as follows: 5 ml of ozone with the desired ozone concentration was drawn to a syringe and the same volume of autologous blood was drawn into the same injector through the vascular route. The ozonation process of the blood was completed under gentle mixing. Ozonated blood was injected to the musculus gluteus maximus through an intramuscular injection [16].

Sterile, disposable and ozone-resistant materials (glass, silicon, polypropylene, and polyethylene) were used, and antiseptic conditions were observed for OT. Patients and the physician performing the intervention were blinded to ozone concentrations.

OT applications were performed by a 15-year physical medicine and rehabilitation specialist with 5 years of ozone therapy experience.

2.5 Evaluations

Demographic and clinical characteristics (age, sex, duration of the disease, and current treatments for FM) were recorded for all patients. Patients were evaluated using the Turkish-approved versions of the fibromyalgia impact questionnaire (FIQ) [17], Pittsburgh sleep quality index (PSQI) [18] and the 12-item short-form health survey (SF-12) [19] scales. These measurements were performed twice: before therapy (pre-intervention $=$ 1 day before initiation of ozone administration) and after therapy (post-intervention $=$ day following treatment completion). Moreover, OT side effects were recorded. Evaluations were made by face-to-face interviews. The patient and the physician who performed the assessment were blinded to the ozone doses.

2.5.1 FIQ

The FIQ measures 10 subscales, including physical impairment, feel good, missed work, do work, pain, fatigue, rested, stiffness, anxiety, and depression. The maximum score of each subscale is 10, and the total obtainable maximum score is 100. High scores show that the disease affects the person more [20].

2.5.2 PSQI

PSQI, which assesses sleep quality in the past one month, comprises 24 questions, and the 18 items included in the scoring are grouped into seven components. These components are subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The addition of the points of these components yields the total PSQI score. Each component is evaluated over 0–3 points, and the total PSQI score ranges between 0 and 21. High scores in the components and a total PSQI score of $\geqslant$ 5 indicate poor sleep quality [21].

2.5.3 SF-12

SF-12 is a questionnaire that assesses quality of life. It comprises 12 questions by which physical component score (PCS) and mental component score (MCS) subscales are calculated. Scores between 0 and 100 are obtained on the subscales, and higher scores indicate better quality of life [22, 23].

2.6 Statistical analyses

All statistical analyses were performed using the Statistical Package for the Social Sciences, version 20.0 (SPSS, Chicago, IL, USA). Descriptive statistics were presented as the mean $\pm$ standard deviation (SD). Categorical variables were presented as number (n) and percentage (%). Normality of the data was assessed using the Shapiro-Wilk test. All continuous variables were observed to be normally distributed. The independent samples $t$ -test was used to compare groups in pre- and post-intervention measures (comparison between OT and PC groups). The paired-samples $t$ -test was used to compare the results of tests performed pre- and post-intervention (within-group comparisons of OT and PC groups). A Chi-square test was used to compare the nominal data (gender and current treatment). For all analyses, $P<$ 0.05 was considered to be statistically significant.

Intention-to-treat analysis was performed concurrently with per-protocol analysis to reduce the risk of bias in data analysis and to further predict the efficacy of the intervention in real conditions. The “last value carried forward” was accepted as the recommended method for missing observations. Statistically significant differences were found the same in both analyzes. Tables were created with the data obtained according to intention-to-treat analysis.

Power analysis was performed using the G*Power version 3.1.9.7 software (Heinrich-Heine Universität, Dusseldorf, Germany). Sample size was calculated with respect to FIQ total score. The difference between the means of two independent groups was evaluated with the $t$ -test. An effect size of 0.76 was calculated based on the FIQ total score and SD of a previous study using ozone therapy in the treatment of FM [13], and 14, which was considered the minimally important clinical difference for the FIQ as the mean difference between the two groups [24]. A sample size of 26 patients per group was needed to achieve a 5% significance level and 80% power while accounting for a maximum loss rate of 20%.

3. Results

Of the 60 patients evaluated in this study, 54 meeting the inclusion criteria were randomized. Twenty-six patients were included in the OT group and 28 patients in the PC group (Fig. 1). Of these 54 patients, 35 (65%) were female, with ages of 34–69 years (mean [SD]: 48.1 [8.3]), and the duration of disease was 1–15 years (mean [SD]: 4.5 [2.3]). In both groups, 76% of patients used pregabalin, and there was no significant difference in age, sex, duration of the disease, and current treatments between the two groups ( $p>$ 0.05) (Table 1).

Table 1
Comparison of demographic characteristics and current treatments between the ozone therapy and placebo control groups ${}^{***}$

Variables	Total ( $n=$ 54)		Ozone therapy group ( $n=$ 26)		Placebo control group ( $n=$ 28)		$p$ value
Age (years), mean (SD)	48.1	(8.3)	48.4	(8.7)	47.8	(8.1)	0.771 ${}^{*}$
Duration of the disease (years), mean (SD)	4.5	(2.3)	4.3	(2.1)	4.2	(2.2)	0.644 ${}^{*}$
Gender, $n$ (%)							0.627 ${}^{**}$
Female	35	(65%)	16	(61%)	19	(68%)
Male	19	(35%)	10	(39%)	9	(32%)
Current treatments, $n$ (%)
Pregabalin	41	(76%)	20	(77%)	21	(75%)	0.869 ${}^{**}$
Gabapentin	11	(20%)	4	(15%)	7	(25%)	0.381 ${}^{**}$
Duloxetine	25	(46%)	14	(54%)	11	(39%)	0.284 ${}^{**}$
Amitriptyline	4	(7%)	3	(11%)	1	(3%)	0.264 ${}^{**}$
Sertraline	3	(5%)	2	(8%)	1	(3%)	0.509 ${}^{**}$

$n$ : number of patients; SD: standard deviation; %: percentage; ${}^{*}$ : independent samples $t$ -test; ${}^{**}$ : Chi-square test; ${}^{***}$ : Intention-to-treat analysis.

Table 2

Results and comparison of FIQ scores pre- and post-intervention in the ozone therapy and placebo control groups ${}^{***}$

	Variables		Ozone therapy group ( $n=$ 26) Mean (SD)	Placebo control group ( $n=$ 28) Mean (SD)	$p$ value
FIQ	Physical impairment	Pre	5.4 (1.6)	5.6 (1.6)	0.697
		Post	5.3 (1.7)	5.6 (1.5)	0.526
		MD	0.1 (0.5)	0 (0.2)
		P value	0.188	0.488
	Feel good	Pre	6.2 (1.2)	5.7 (1.3)	0.200
		Post	4.5 (1.3)	5.4 (1.2)	0.011
		MD	1.6 (1.3)	0.3 (0.9)
		P value	$<$ 0.001	0.083
	Missed work	Pre	0.8 (0.8)	0.8 (0.7)	0.985
		Post	0.7 (0.8)	0.7 (0.7)	0.985
		MD	0 (1.0)	0 (0.8)
		P value	1.00	1.000
	Do work	Pre	4.3 (1.8)	4.0 (1.3)	0.432
		Post	3.7 (1.5)	3.9 (1.2)	0.593
		MD	0.6 (1.6)	0.1 (0.5)
		P value	0.069	0.424
	Pain	Pre	6.1 (1.6)	5.7 (1.3)	0.329
		Post	5.2 (1.5)	5.6 (1.3)	0.292
		MD	1.0 (1.5)	0.1 (0.4)
		P value	0.004	0.184
	Fatigue	Pre	5.9 (1.5)	5.3 (1.3)	0.085
		Post	4.0 (1.7)	5.1 (1.4)	0.048
		MD	1.6 (1.5)	0.2 (0.5)
		P value	$<$ 0.001	0.096
	Rested	Pre	5.9 (1.7)	5.4 (1.3)	0.277
		Post	4.7 (1.6)	5.3 (1.3)	0.188
		MD	1.2 (1.3)	0.2 (0.5)
		P value	$<$ 0.001	0.057
	Stiffness	Pre	5.5 (2.1)	5.2 (1.4)	0.613
		Post	4.8 (1.8)	5.1 (1.3)	0.496
		MD	0.7 (1.3)	0.1 (0.4)
		P value	0.015	0.103
	Anxiety	Pre	4.5 (1.5)	4.4 (1.0)	0.675
		Post	4.2 (1.4)	4.4 (0.9)	0.606
		MD	0.3 (1.3)	0.1 (0.6)
		P value	0.195	0.745
	Depression	Pre	4.2 (1.4)	4.3 (1.3)	0.850
		Post	4.1 (1.7)	4.3 (1.4)	0.771
		MD	0.2 (0.9)	0.1 (0.4)
		P value	0.404	0.663
	Total	Pre	48.8 (8.7)	46.3 (7.4)	0.959
		Post	41.6 (9.7)	45.1 (7.4)	0.627
		MD	7.3 (8.9)	1.0 (1.4)
		P value	$<$ 0.001	0.002

FIQ: Fibromyalgia Impact Questionnaire; $n$ : number of patients; SD: standard deviation; pre: Pre-intervention; post: Post-intervention; MD: mean difference. ${}^{***}$ (Intention-to-treat analysis): The independent-samples $t$ -test was used to compare groups at pre- and post-intervention measures (comparisons between OT and PC groups). The paired-samples $t$ -test was used to compare the results of tests performed pre- and post-intervention (within-group comparisons of ozone therapy and placebo control groups). Bold-face indicates the value is statistically significant ( $p<$ 0.05).

Table 3

Results and comparison of PSQI and SF-12 scores pre- and post-intervention in the ozone therapy and placebo control groups ${}^{***}$

	Variables		Ozone therapy group ( $n=$ 26) Mean (SD)	Placebo control group ( $n=$ 28) Mean (SD)	$p$ value
PSQI	Subjective sleep quality	Pre	1.5 (0.8)	1.6 (0.8)	0.634
		Post	0.9 (0.7)	1.5 (0.8)	0.010
		MD	0.6 (0.6)	0.1 (0.6)
		P value	$<$ 0.001	0.326
	Sleep latency	Pre	0.8 (0.7)	1.1 (0.8)	0.067
		Post	0.7 (0.7)	1.1 (0.7)	0.016
		MD	1.0 (0.4)	0 (0.5)
		P value	0.327	1.000
	Sleep duration	Pre	0.6 (0.7)	0.9 (0.8)	0.337
		Post	0.6 (0.7)	0.8 (0.7)	0.387
		MD	0 (0.4)	0.1 (0.5)
		P value	1.000	0.713
	Habitual sleep efficiency	Pre	1.0 (0.9)	1.1 (1.0)	0.671
		Post	0.8 (0.9)	1.1 (0.9)	0.291
		MD	0.1 (0.4)	0.1 (0.4)
		P value	0.185	0.663
	Sleep disturbances	Pre	1.4 (0.6)	1.4 (0.6)	0.972
		Post	0.8 (0.7)	1.4 (0.6)	0.002
		MD	0.6 (0.6)	0.1 (0.6)
		P value	$<$ 0.001	0.769
	Use of sleeping medication	Pre	0.1Â (0.3)	0.3 (0.4)	0.206
		Post	0.2 (0.4)	0.3 (0.4)	0.617
		MD	0.1 (0.3)	0 (0.4)
		P value	0.161	1.000
	Daytime dysfunction	Pre	1.0 (0.8)	1.2 (0.9)	0.347
		Post	0.8 (0.7)	1.1 (0.7)	0.175
		MD	0.2 (0.5)	0.1 (0.6)
		P value	0.161	0.326
	Total	Pre	6.3 (2.9)	7.4 (2.9)	0.181
		Post	4.9 (2.9)	7.1 (2.8)	0.004
		MD	1.4 (1.6)	0.3 (1.8)
		P value	$<$ 0.001	0.458
SF-12	PCS	Pre	35.7 (5.8)	36.0 (6.2)	0.880
		Post	36.4 (6.0)	36.2 (5.8)	0.913
		MD	0.7 (2.2)	0.3 (1.4)
		P value	0.115	0.298
	MCS	Pre	36.6 (6.9)	37.3 (8.1)	0.714
		Post	37.8 (7.6)	37.9 (7.9)	0.936
		MD	1.2 (4.9)	0.6 (2.5)
		P value	0.221	0.191

PSQI: Pittsburgh Sleep Quality Index; SF-12: 12-item Short Form Survey; $n$ : number of patients; SD: standard deviation; pre: Pre-intervention; post: Post-intervention; PCS: physical component score; MCS: mental component score; MD: mean difference. ${}^{***}$ (Intention-to-treat analysis): The independent-samples $t$ -test was used to compare groups at pre- and post-intervention measures (comparisons between OT and PC groups). The paired-samples $t$ -test was used to compare the results of tests performed pre- and post-intervention (within-group comparisons of ozone therapy and placebo control groups). Bold-face indicates the value is statistically significant ( $p<$ 0.05).

Table 2 shows the FIQ pre-and post-intervention total score and subscores for the OT and PC groups. There was no significant difference in pre-intervention FIQ scores between the two groups. However, in the OT group, there were significant improvements in the post-intervention feel good, pain, fatigue, rested, stiffness, and total FIQ scores ( $p<$ 0.05). In post-intervention, there was a significant difference between the two groups in favor of the OT group in the feel good and fatigue scores ( $p<$ 0.05). There was no significant difference in the pre- and post-intervention depression and anxiety subscores of the FIQ between the two groups ( $p>$ 0.05).

Table 3 shows the PSQI pre-and post-intervention total score and subscores and SF-12 subscores for the OT and PC groups. There was no significant difference in pre-intervention PSQI scores between the two groups. In the OT group, there were significant improvements in the post-intervention subjective sleep quality, sleep disturbances, and total PSQI scores ( $p<$ 0.05). However, in addition to significant improvements in the same post-intervention scores, the OT group showed a significant improvement in the sleep latency score compared with the PC group ( $p<$ 0.05).

In the SF-12, MCS, and PCS scores, there was no statistically significant difference in pre- and post-intervention evaluations between the two groups ( $p>$ 0.05) (Table 3).

Moreover, our study showed no other negative effects other than mild and temporary ecchymosis and blood extravasation in the intravenous injection site in four patients in the OT group and three patients in the PC group.

4. Discussion

The search for potentially effective treatments in FM still continues. In this respect, we aimed to investigate the effectiveness of OT in FM in this study. Some results supporting the efficacy of OT applied with autohemotherapy method on widespread pain, fatigue, and sleep disturbance in FM concurrent with the treatment duration were obtained.

Increased oxidative stress, decreased antioxidant enzyme levels, and increased inflammatory cytokine (tumor necrosis factor- $\alpha$ , interleukin [IL]-1, IL-6, and IL-8) levels are known to play a role in FM pathogenesis [6, 9, 25]. OT induces mild and controlled oxidative stress, leading to the upregulation of the antioxidant system, modulation of the immune system, and stimulation of the suppression of inflammatory processes [8, 12]. Based on these mechanisms, OT may be useful in FM treatment [8, 12, 13]. Therefore, we designed this placebo-controlled study assuming that certain therapeutic effects of OT may be associated with the abovementioned pathogenetic mechanisms of FM.

The most commonly accepted application method of OT in treating systemic diseases is MaAHT [8, 11]. No precise methodology has been reported in the literature because OT application methods, number of sessions, and ozone doses can be adjusted as per different protocols and recommendations. Tirelli et al. [12] used MaAHT and OT twice a week for a month and then twice a month as maintenance therapy. Moreno-Fernández et al. [13] used an ozone concentration of 30 $\mu$ g/ml for the first three sessions, 40 $\mu$ g/ml for the fourth session, 50 $\mu$ g/ml for the fifth session and 60 $\mu$ g/ml for the final five sessions, for a total of 10 sessions of MaAHT application performed twice a week. In our study, the OT method, the number of sessions, and ozone concentration were determined by considering MDOT recommendations [16]. In this declaration, it is considered that clinical benefit will be achieved by the tenth session with MaAHT and MiAHT applications, which will be held as two sessions per week. Furthermore, the therapeutic concentration of ozone recommended for the AHT method has been determined to be between 5 and 40 $\mu$ g/ml, and lower doses have been reported to have no therapeutic effect, whereas higher doses may have toxic effects. FM is considered to be in the first category among OT-sensitive diseases, and treatment with low-dose ozone concentrations (10–25 $\mu$ g/ml) is recommended. Based on these recommendations, in MaAHT and MiAHT applications performed in two sessions per week for a total of 10 sessions, we used a therapeutic effective ozone concentration of 15–25 $\mu$ g/ml in the study group and a nontherapeutic effective ozone concentration of 0.1 $\mu$ g/ml in the placebo group.

In the literature, trials that use OT in FM treatment are open-label studies with no control groups [8, 12, 13]. In these studies, OT was performed as a systemic application with rectal insufflation and MaAHT methods [8, 12, 13, 25]. To our knowledge, after Borrelli and Bocci [26] reported beneficial effects of OT with MaAHT in four of five patients with FM in 2002, Hidalgo-Tallon et al. [8] evaluated the potential effect of OT in FM with rectal insufflation. They reported that with the rectal application of ozone, clinically significant improvements in the physical symptoms of FM, total FIQ and pain scores and depression were observed [8]. Tirelli et al. [12] reported that after applying rectal insufflation to 10 of 65 patients with FM and MaAHT to 55 patients, 70% of patients had a significant improvement in their symptoms and OT could be recommended as a complementary method in FM treatment. Moreno-Fernández et al. [13] used OT via MaAHT application for 20 patients with FM, evaluated the clinical response of the disease with FIQ, and investigated biochemical oxidative stress factors and serum serotonin levels in blood samples. They reported an improvement in the total FIQ score, a moderate increase in serotonin levels, and a decrease in oxidative stress levels in all patients treated with OT. In addition, improvement of antioxidant defense prevents insomnia progression [27]. Low serum levels of BDNF and GABA are important indicators in the patients with insomnia [28]. It has been shown that ozone therapy can increase the serum BNDF and GABA levels by increasing the antioxidant capacity and thus improve sleep quality [29]. To our knowledge, our study is the first placebo-controlled research in which OT was applied to AHT as an add-on treatment in FM. In this study, there were significant improvements in feel good, fatigue, rested, stiffness and pain scores and sleep quality in patients with FM. However, there was no significant difference in the psychological parameters (anxiety and depression) of patients. In this respect, OT can be recommended as a complementary method in the treatment of symptoms such as pain, fatigue, and sleep disturbance rather than psychological symptoms in FM.

The side effects of OT applications are very rare, mostly temporary and mild [8]. Ecchymosis and blood extravasation, which may occur in MaAHT because of repeated intravenous injections, may last for a few days, and phlebitis may rarely occur [8, 11]. In this study, in addition to mild and transient ecchymosis in a small number of patients, no other side effects were observed during the follow-up period.

4.1 Study limitations

The most important limitations of the study were the relatively low number of cases and a short follow-up time. The fact that the last evaluation was made the day after the last treatment allows the study results to be interpreted only simultaneously with the treatment. It is not possible to draw a conclusion beyond this period. Although the differences in ozone concentrations can be interpreted as another additional limitation, the number and frequency of OT sessions are similar to those reported in previous studies.

5. Conclusion

OT administered as an additional treatment with MaAHT and MiAHT for the number of sessions and the ozone doses used in this study may simultaneously provide beneficial improvements with ongoing treatment in FM. These improvements may be achieved especially in the feel good, fatigue subscales of FM and in the sleep quality, sleep latency, and sleep disturbances subscales of sleep. However, there was no significant difference between the two groups in the post-treatment FIQ total score. However, additional randomized controlled clinical trials with higher patient numbers and longer follow-up times are warranted.

Ethical approval

This study was approved by the Research Ethics Committee of Istanbul Gelisim University (Meeting date: March 26, 2019, Decision no.: 8-6).

Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Informed consent

All individuals provided written informed consent prior to participation.

Acknowledgements

The authors would like to thank all patients. They also thank Enago for their assistance in manuscript translation and editing.

Author contributions

HS: Conceptualization, Methodology, Data curation, Writing-Original draft preparation, Investigation, Validation, Writing-Reviewing and Editing. NS: Data curation, Investigation, Reviewing and Editing.

Footnotes

Conflict of interest

None of the authors have any conflict of interest to declare.

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Efficacy of ozone therapy as an add-on treatment in fibromyalgia: A randomized double-blind placebo-controlled study

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Materials and methods

2.1 Study design and participants

2.2 Ethical considerations

2.3 Randomization and blinding

2.5 Evaluations

2.5.1 FIQ

2.5.2 PSQI

2.5.3 SF-12

2.6 Statistical analyses

3. Results

Table 1 Comparison of demographic characteristics and current treatments between the ozone therapy and placebo control groups * ⁣ * *

4.1 Study limitations

5. Conclusion

Ethical approval

Funding

Informed consent

Acknowledgements

Author contributions

Footnotes

Conflict of interest

References

Table 1
Comparison of demographic characteristics and current treatments between the ozone therapy and placebo control groups ${}^{***}$