Comparative Evaluation of the Effects of Diclofenac Sodium and Vitamin D Supplementation on Symptoms in Individuals With Myofascial Pain and Vitamin D Deficiency

doi:10.21203/rs.3.rs-5294906/v1

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Comparative Evaluation of the Effects of Diclofenac Sodium and Vitamin D Supplementation on Symptoms in Individuals With Myofascial Pain and Vitamin D Deficiency

https://doi.org/10.21203/rs.3.rs-5294906/v1

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Background: Temporomandibular joint disorders are significant health issues characterized by dysfunctions in the masticatory muscles and the temporomandibular joint. These disorders are often associated with stress, oral parafunctions, and habits such as bruxism. Treating bruxism and other parafunctional habits can reduce symptoms of myofascial pain. While the etiology of bruxism remains unclear, psychological factors like stress and anxiety, along with central nervous system, are thought that it will provoke. Additionally, a significant relationship has been reported between low serum vitamin D levels and bruxism.

Methods: The aim of this study is to comparatively evaluate the effectiveness of nonsteroidal anti-inflammatory drug treatment and vitamin D supplementation on symptoms in individuals with myofascial pain and vitamin D deficiency. Two different treatment methods were applied to the patients. One group received medical treatment with diclofenac sodium and an occlusal splint. The other group received vitamin D supplementation and an occlusal splint. The patients' mouth opening and pain scores were evaluated.

Results: The results obtained are homogeneous in both groups.

Conclusions: Vitamin D may serve as an alternative with anti-inflammatory and analgesic effects compared to NSAIDs.

Trial registration: This study was approved by the Van Yüzüncü Yıl University Faculty of Medicine Clinical Research Ethics Committee (May 18, 2022, decision no: 05).

Temporomandibular joint disorders (TMD) are a significant contemporary health issue that can be defined as clinical problems characterized by dysfunctions of the masticatory muscles, the temporomandibular joint (TMJ), and related structures, sometimes affecting all of these parts simultaneously (1). Various publications on painful musculoskeletal disorders of the jaw have often indicated that stress, oral parafunction, or a combination of both contribute to these disorders (2, 3). Studies have established a strong link between myofascial pain in the masticatory muscles and parafunctional habits such as bruxism (4–6), and, in line with these findings, it has been reported that treatment of parafunctional habits could reduce the symptoms of myofascial pain (7). Although the etiology of bruxism remains unclear or controversial, it is thought to be influenced by various factors, such as psychological factors like stress and anxiety and central mechanisms involving brain neurotransmitters or basal ganglia (8). Current literature reports a significant relationship between bruxism and low serum vitamin D levels (9, 10). Vitamin D plays an important role in the musculoskeletal and cardiovascular systems (11, 12). A deficiency of Vitamin D has been associated with poor physical performance and reduced muscle strength (13). Numerous studies have examined the relationship between TMJ disorders and serum vitamin D levels, revealing that vitamin D deficiency can induce TMJ disorders (14–16). In addition to regulating calcium homeostasis and bone turnover, vitamin D has antiproliferative, pro-differentiation, antibacterial, immunomodulatory, and anti-inflammatory properties in various cells and tissues across the body (17, 18). Although there is insufficient clinical evidence on the effectiveness of vitamin D supplementation for chronic pain, the use of vitamin D is generally considered to be a low-risk, well-tolerated, and inexpensive treatment option, with no contraindications for its use in patients with chronic pain (19, 20). In cases where vitamin D levels are insufficient or deficient due to additional risk factors (e.g., current medications, obesity levels, and inadequate sun exposure), appropriate vitamin D supplementation can be beneficial. The aim of this study is to comparatively evaluate the effectiveness of diclofenac sodium treatment as a nonsteroidal anti-inflammatory drug (NSAID) and vitamin D supplementation in alleviating symptoms in individuals with myofascial pain and vitamin D deficiency.

This prospective, randomized, and single-blind clinical study was conducted between June 1, 2022, and October 1, 2023, at the Department of Oral, Dental, and Maxillofacial Surgery, Faculty of Dentistry, Van Yüzüncü Yıl University. The study included patients aged 18–40 who experienced myofascial pain (MP) and were diagnosed with myofascial pain in accordance with DC/TMD criteria.

Ethics:

The study was approved by the Van Yüzüncü Yıl University Faculty of Medicine Clinical Research Ethics Committee on May 18, 2022 (decision no. 05).

Controlled Trial Registration:

The trial was registered with the Clinical Trial Registry. ClinicalTrials ID: NCT06111573.

Selection of Patients:

Table 1

Inclusion And Exclusion Criteria For Trial Participants
Inclusion criteria	Exclusion criteria
Individuals aged 18 and over	Individuals who have undergone invasive or surgical procedures related to the temporomandibular joint
Individuals with vitamin D deficiency (25(OH)D level below 20)	Individuals with temporomandibular joint pathology
Individuals without systemic disorders	Pregnant and breastfeeding individuals
Individuals with myofascial pain complaints	Individuals who did not attend postoperative follow-up appointments
Individuals with chronic pain	Individuals using medications other than those recommended
Individuals who have not received treatment for myofascial pain in the last 3 months	Individuals allergic to the study medications and materials
Individuals who have not used any medication in the last two weeks
Individuals without missing teeth
Individuals without an open bite and/or crossbite

Sample Size:

To ascertain whether the size of the study group was statistically significant, an a priori calculation of the sample size necessary for this investigation was done. For the parameters to be compared, a 5% error margin, a 95% confidence level, an effect size of 0.5, and a theoretical power of 80% were used for the calculation. Based on these parameters, it was determined that at least 20 participants were needed, with 10 participants in each group. The study ultimately included 40 participants (37 female, 3 male), with 20 patients per group. Six patients were excluded from the study due to non-attendance at follow-up appointments.

Randomization and Blinding:

Patients were randomly divided into 2 groups using the closed-envelope technique managed by an assistant to ensure unbiased randomization and efficacy. In the randomization procedure, combinations of treatments (vitamin D or diclofenac sodium and occlusal splint) were secured inside closed envelopes. Patients were asked to select an envelope and hand it over to the assistant, who would then determine the treatment to be performed. Follow-ups were conducted by the study coordinator (NHK), who also provided treatment prescriptions to participants (NHK).

Study Procedures:

Two different treatment methods were administered to the patients. One group received medical treatment with diclofenac sodium (Voltaren 75 mg, 2x1, for 2 weeks) and an occlusal splint (Group A). The other group received vitamin D supplementation (10,000 IU, 1x1, for 8 weeks) and an occlusal splint (Group B). The occlusal splints were made of 3 mm thick, flat-surfaced, hard acrylic and were worn for 8 hours each night during sleep over the period of three months. Participants were prescribed 500 mg paracetamol tablets as a rescue pain reliever if needed. Patients were instructed to continue using the occlusal splints and take paracetamol as needed.

Examination:

Patients were examined at 4 stages: before starting the treatment, 1 week after starting treatment, at 4 weeks of treatment, and 12 weeks after treatment. The following parameters were recorded at each time point: mouth opening measurements (in mm), including Pain-Free Comfortable Opening (MCO), Maximum Unassisted Opening (MUO), Maximum Assisted Opening (MAO), and VAS pain scores.

Statistical Analysis:

The normality of the variables was assessed using the Shapiro-Wilk and/or Kolmogorov-Smirnov tests due to the sample sizes. Differences between groups were analyzed using the Mann-Whitney U test because the variables did not follow a normal distribution. For the analysis of more than two dependent variables, the Friedman test was used due to abnormal distribution; if significant differences were found, Multiple Comparison Tests were conducted to identify the groups with differences.

The study included participants aged between 18 and 40, with a mean age of 24.8 years. Of the participants, 3 (7.5%) were male and 37 (92.5%) were female.

There were no significant differences between the groups in terms of Maximum Comfortable Opening (MCO) values measured before treatment, on the 7th day, after the 1st month, and after the 3rd month. However, the Maximum Unassisted Opening (MUO) value at the 7th day and the Maximum Assisted Opening (MAO) values at the 7th day and 1st month were significantly higher in Group B compared to Group A (Table 2) (Table 3).

Table 2

Analysis of Differences Between Groups Based on Maximum Unassisted Mouth Opening Values
		Group						Mann Whitney U Test
		n	Mean	Median	Min	Max	Sd	Mean Rank	Z	P
Pre-Treatment MUO	A	20	38,05	38,5	23	50	7,66	17,65	-1,54	0,12
	B	20	41,55	43	20	57	9,02	23,35
	Total	40	39,8	40	20	57	8,45
Day 7 of MUO	A	20	36,65	36,5	22	50	8,95	16,25	-2,30	0,02 *
	B	20	43,35	45	27	60	8,89	24,75
	Total	40	40	40	22	60	9,44
1 Month of MUO	A	20	40,2	40	22	53	8,07	17,48	-1,64	0,10
	B	20	44,45	45	29	60	8,26	23,53
	Total	40	42,33	42	22	60	8,34
3 Months of MUO	A	20	42,3	43	27	54	7,32	18,23	-1,23	0,21
	B	20	44,9	46	31	60	7,71	22,78
	Total	40	43,6	44,5	27	60	7,54

Table 3

Analysis of Differences Between Groups Based on Maximum Assisted Mouth Opening (MAO) Measurement Values
		Grup						Mann Whitney U Testi
		n	Mean	Median	Min	Max	Sd	Mean Rank	Z	P
Pre-Treatment MAO	A	20	42,5	42,5	30	54	6,74	17,2	-1,79	0,07
	B	20	46,7	50	30	60	8	23,7
	Total	40	44,6	45	30	60	7,61
Day 7 of MAO	A	20	40,0	40	27	50	6,93	15,1	-2,93	0,00 *
	B	20	47,2	50	35	61	7,3	25,9
	Total	40	43,6	43	27	61	7,91
1 Month of MAO	A	20	43,6	43	30	55	6,56	16,5	-2,15	0,03 *
	B	20	48,5	48,5	36	61	6,72	24,4
	Total	40	46,1	46	30	61	7,01
3 Months of MAO	A	20	45,3	45,5	30	55	6,4	16,9	-1,94	0,05
	B	20	49,4	51	37	62	6,39	24,0
	Total	40	47,3	48,5	30	62	6,65

In Group A, the VAS values on the 7th day, 1st month, and 3rd month are significantly lower as compared to the baseline VAS values. In Group B, the VAS values are significantly lower on the 7th day, 1st month, and 3rd month as compared to the baseline VAS values. Additionally, the VAS value during the 3rd month is significantly lower than the VAS value on the 7th day.

Table 4

Analysis of Differences Between Time Points in VAS Measurement Values for the Groups
								Friedman Test			Multiple Comparisons
		n	Mean	Median	Min	Max	Sd	Mean Rank	Chi-Square	P
	Pre-Treatment VAS	20	7,6	7	5	10	1,7	3,75
A	Day 7 of VAS	20	4,65	5	0	8	2,6	2,48	36,394	0,001	4 − 1 3 − 1 2 − 1
	1 Month of Vas	20	4,15	3,5	0	10	3,12	2,3
	3 Months of Vas	20	3,1	2	0	10	3,11	1,48
	Pre-Treatment VAS	20	7,55	7,5	5	10	1,64	3,8
											4 − 2
B	Day 7 of VAS	20	5	5	0	10	2,79	2,7	38,038	0,001	4 − 1 3 − 1
											2 − 1
	1 Month of Vas	20	3,3	3	0	9	2,41	1,93
	3 Months of Vas	20	2,8	2	0	10	3	1,58

In conclusion, the changes in MCO, MUO, MAO, and VAS are homogeneous in both groups. Comparisons between these groups in terms of change (difference) values are shown in Table 5.

Table 5

Comparisons Between Groups in Terms of Change (Difference) Values
		Group						Mann Whitney U Test
		n	Mean	Median	Min	Max	Sd	Mean Rank	z	P
MCO Change	A	20	9,05	7	-5	33	9,68	23,03	-1,368	0,171
	B	20	5,2	4	-13	28	11,18	17,98
	Total	40	7,12	6	-13	33	10,5
MUO Change	A	20	4,25	5	-6	15	5,91	21,75	-0,679	0,497
	B	20	3,35	2,5	-5	17	5,15	19,25
	Total	40	3,8	3	-6	17	5,49
MAO Change	A	20	2,8	2,5	-5	12	4,31	21,1	-0,326	0,744
	B	20	2,65	2	-7	13	5,09	19,9
	Total	40	2,72	2	-7	13	4,66
VAS Change	A	20	-4,5	-4,5	-9	0	2,72	20,95	-0,245	0,806
	B	20	-4,75	-4,5	-10	0	2,47	20,05
	Total	40	-4,63	-4,5	-10	0	2,57

TMD (Temporomandibular Disorders) is most commonly seen in young and middle-aged adults with an average age range of 30–40 and has been reported to have a higher prevalence in women (21, 22). In this study, the average age of participants was 24.8 years, and 92.5% of participants were women. This finding confirms that female gender and age are key risk factors for TMD. It is thought that TMDs in women may be related to hormonal changes. It has been noted that the menstrual cycle can exacerbate pain and that estrogen may trigger inflammation in the TMJ (23–26). Additionally, a study by LeResche reported that 80% of female patients sought medical help for treatment (24). In this study, most of the patients presenting to our clinic with pain complaints were women, and out of the six patients excluded from the study for non-attendance at follow-up visits, four were males. This finding suggests that gender is an influential factor in patients' motivation to seek and continue treatment. We believe that female patients may experience higher motivation to participate in treatment due to the severity of their pain, which could be related to their hormonal status.

In this study, we used the 'Diagnostic Criteria for TMD' (27) for patient diagnosis. After completing the DC/TMD questionnaires, participants reported an increased awareness of TMD and were more motivated to participate in the treatment.

Occlusal splints are a widely accepted and well-known treatment for TMD due to their alleviating effects on TMD symptoms (28–31). In this study, all participants, being bruxists, used occlusal splints throughout the treatment period.

Previous studies (32, 33) have indicated that a rigid or soft appliance can be successfully used to alleviate muscle pain in TMD patients. However, the use of soft occlusal splints has been associated with minimal changes in occlusion (34, 35). Although soft splints are superior in terms of patient tolerance (32), rigid splints made from PMMA (Polymethylmethacrylate) have been noted as a more suitable option for bruxism patients and long-term treatment due to their superior wear resistance and surface hardness (36, 37). Considering the 3-month follow-up period for participants in this study, rigid occlusal splints were used throughout the follow-up period to ensure durability.

All participants in this study presented with severe pain complaints. Research indicates that 50–70% of individuals with TMD experience pain in the masticatory muscles, and in 25% of these patients, pain in the masticatory muscles originates in the muscles themselves (38). This pain is localized in the masticatory muscles, worsens with muscle palpation, and intensifies during functional activities (38–40). Repetitive loading or macro- or micro-trauma to the masticatory muscles leads to micro-lesions in the muscle fibers. This results in the release of local inflammatory mediators such as prostaglandins, bradykinin, histamine, and substance P. These mediators can induce nociceptive afferent impulse transmission to the central nervous system, leading to peripheral and central sensitization (41). NSAIDs may alleviate pain by reducing peripheral sensitivity associated with a decrease in the release of inflammatory components in the masticatory muscles and TMJ (42). NSAIDs are also known to reduce pain and inflammation through the inhibition of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2). COX-2 is important in the synthesis of prostaglandin E2 (PGE2), which is associated with joint pain (43). Given their analgesic and anti-inflammatory properties, NSAIDs are a reasonable choice for such pain. In this study, diclofenac sodium, frequently prescribed for TMD treatment, was administered to the control group.

While the etiology of TMD remains uncertain, it is widely known to be multifactorial, with functional, structural, and psychological factors and parafunctional habits contributing to its development (24, 44, 45). All participants in this study exhibited bruxism, supporting the idea that bruxism is an etiological factor in individuals with myofascial pain. Bruxism is commonly accepted to have a multifactorial etiology, and these factors may complicate the intervention aimed at addressing the etiology (46). It has been reported that individuals with sleep bruxism have statistically significantly higher anxiety and depression scores compared to those without sleep bruxism (47). Ahlberg et al. (48) demonstrated that individuals with severe anxiety are more likely to have sleep bruxism. Muscle tension is considered a common symptom of anxiety that increases pressure on the muscles and can lead to musculoskeletal symptoms such as pain over time (49, 50).

Recently, vitamin D has garnered significant attention due to observational studies showing relationships between serum 25(OH)D concentrations and individuals' psychological well-being (51). Previous studies have reported correlations between vitamin D deficiency, low dietary calcium intake, anxiety, depression, and musculoskeletal function (52–57).

Alkhatatbeh et al. showed in a case-control study that individuals with sleep bruxism had higher rates of anxiety and depression and significantly lower vitamin D levels (57). Allaf et al. found a significant relationship between bruxism and serum 25-hydroxyvitamin D levels, noticing that bruxism activity increases with vitamin D deficiency and is categorized into five different levels (58). The association between vitamin D deficiency and psychological symptoms, including anxiety that can lead to sleep bruxism, can be justified by vitamin D's role in maintaining mental health (52, 53, 59). Vitamin D exerts neuroprotective effects on neurotrophin production, neurotransmitter synthesis, regulation of intracellular calcium levels, and reduction of oxidative damage in the central nervous system (60). Thus, low vitamin D levels may disrupt calcium homeostasis in the brain, affecting neuronal excitability (60) and potentially increasing the risk of psychiatric issues such as dementia, schizophrenia, anxiety, and depression (61). Additionally, the traditional function of vitamin D is to maintain calcium homeostasis, so low vitamin D levels can lead to low serum calcium levels commonly referred to as hypocalcemia (62). Hypocalcemia directly affects neuromuscular function, potentially causing muscle spasms and cramps (63). Since sleep bruxism involves repeated hyperactivity of the jaw muscles, vitamin D deficiency, and associated hypocalcemia may contribute to the development of sleep bruxism through their effects on neuromuscular function. Aguilera et al. suggested that correcting magnesium and calcium deficiencies might be a potential treatment for sleep bruxism (64).

However, some researchers have proposed a hypothesis that sleep disorders have become epidemic due to vitamin D deficiency. The relationship between the brain's sleep-wake regulation areas and vitamin D target neurons in the diencephalon suggests that vitamin D may have direct effects on sleep (65).

In this study, there was no statistically significant difference between treatment groups in MCO values before treatment, after 1 week, after 1 month, and after 3 months of treatment. There were also no statistical differences in MUO values before treatment, 1 month, and 3 months after treatment. However, the 1-week post-treatment values for patients using diclofenac sodium were significantly lower compared to those using vitamin D. For MAO, there were no statistical differences between groups in pre-treatment and 3 months post-treatment values, but 1-week and 1-month post-treatment values were significantly lower in patients using diclofenac sodium compared to those using vitamin D. We believe that the effects of vitamin D on mouth opening may be due to its rapid entry into bloodstream, enhancing calcium absorption, and positively affecting musculoskeletal function.

Studies on the efficacy of NSAIDs for TMD have shown improvement in maximum mouth-opening values (66–68). Considering that mandibular movement restriction is often described in temporomandibular dysfunctions and is a clear cause of discomfort for patients, evaluating mouth opening becomes quite important. Both treatment groups had a similar effect on mouth-opening changes in the long term, which we attribute to the impact of prolonged use of the hard splint.

There was no statistically significant difference between the treatment groups in VAS scores before treatment, 1 week, 1 month, and 3 months after treatment. Based on this result, we believe that vitamin D has similar effects on myofascial pain as diclofenac sodium. Diclofenac sodium is well known for its analgesic and anti-inflammatory properties and its efficacy in TMD treatment (69, 70). Our results support the idea that vitamin D may have anti-inflammatory (71) and analgesic (72) effects.

Additionally, there were no statistically significant differences between the groups in terms of changes in pain-free maximum mouth opening, maximum unassisted mouth opening, and maximum assisted mouth opening. Similarly, there were no statistically significant differences in VAS change values between the study groups. This can be explained by the pain originating from tension in the masticatory muscles and the contribution of vitamin D to muscle relaxation through various mechanisms. Overall, changes in mouth-opening values and VAS scores were homogeneous across both groups.

This study had several limitations, including the presence of muscle pain along with other TMD internal disorders (reduced disc displacement, non-reduced disc displacement) among participants, the initiation of follow-ups in different seasons (due to temperature and sun exposure), the short duration of follow-up, and the lack of monitoring of 25OHD levels at the end of the study.

The majority of patients who presented to our clinic with myofascial pain during the study period were women and bruxists. Blood tests were conducted for all those who met the inclusion criteria, and generally, vitamin D deficiency was observed. We believe that lifestyle factors such as women spending less time outdoors, specific clothing styles, and the use of UV-filtered sunscreen products by women may contribute to this deficiency.

Women in Group B who received vitamin D supplementation reported feeling generally better and noticed a reduction in chronic pain in other areas of their bodies. It is suggested that in patients with myofascial pain living in regions with significant seasonal temperature and sun exposure differences, different mechanisms might be at play, directly or indirectly influencing outcomes. Although there are various treatment options for TMD, there is a need for more advanced and specific long-term randomized clinical trials. Vitamin D, used in the treatment of patients with myofascial pain, has been found to be as effective as other pharmacological treatments. It is concluded that vitamin D may serve as a viable alternative with anti-inflammatory and analgesic benefits compared to NSAIDs.

Author Contribution

NHK and SKT designed and directed the study. NHK performed the measurements, collected the data.SKT helped to contribute to the interpretation of the results. NHK and SKT draft the manuscript andwrote the manuscript. All authors read and approved the final manuscript.

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Comparative Evaluation of the Effects of Diclofenac Sodium and Vitamin D Supplementation on Symptoms in Individuals With Myofascial Pain and Vitamin D Deficiency

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