Pharmacological Interventions in the Management of Temporomandibular Disorders: A Systematic Review and Meta-analysis

Abstract

Introduction

Temporomandibular Disorders (TMDs) encompass a set of conditions affecting the masticatory muscles and the temporomandibular joint (TMJ), with an impact on both functionality and individuals’ quality of life. Myalgia is a diagnosis of TMD with multifactorial etiology, and treatment strategies aim primarily to relieve pain and restore function. Pharmacological therapy is commonly considered a second-line option, thus complementing conservative measures.

Objectives

Assess the efficacy of pharmacological interventions in the management of myalgia associated with temporomandibular disorders, in adolescents and adults, while exploring differential effects across TMD subtypes through subgroup analyses, using a systematic review and meta-analysis of randomized controlled trials (RCTs).

Materials and Methods

A systematic review with meta-analysis was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and reported following the PRISMA 2020 statement. Seventeen randomized controlled trials (RCTs) published between 2018 and 2024 were included. Pharmacological interventions such as nonsteroidal anti-inflammatory drugs, corticosteroids, muscle relaxants, antidepressants, and intra-articular injectables—were compared with placebo or other active treatments. The primary outcomes were pain intensity (Visual Analog Scale, VAS) and maximum interincisal opening (MIO) unassisted.

Results and Discussion

A total of 1,128 participants were analyzed across 25 treatment arms. Pharmacological interventions were associated with a significant reduction in pain (SMD = –0.68; 95% CI: –1.09 to –0.26; p < 0.001) and an improvement in MIO (SMD = 0.51; 95% CI: 0.20 to 0.82; p < 0.001). Subgroup analyses indicated that interventions were more consistent and effective in arthralgia-only populations, showing lower heterogeneity and a more predictable therapeutic response, whereas myalgia-only populations exhibited smaller and less consistent benefits. Conservative therapies demonstrated a consistent advantage, thus aligning with international recommendations that prioritize such approaches. Subgroup analyses demonstrated more consistent and homogeneous effects in arthralgia-dominant populations, whereas myalgia-only studies showed greater heterogeneity and less predictable responses.

Conclusion

Pharmacological therapy provides a moderate overall beneficial effect in reducing pain and improving mandibular function in TMD, with stronger and more consistent evidence in arthralgia-dominant populations, while myalgia-related outcomes remain more variable, thus indicating the need for tailored treatment strategies. Further high-quality RCTs with standardized protocols are needed.

Introduction

Temporomandibular Disorders (TMDs) are a group of musculoskeletal conditions that can affect the masticatory muscles and the Temporomandibular Joint (TMJ) itself (1). TMDs are more common in individuals between 20 and 40 years of age (2-4).

TMDs affect approximately 5 to 12% of the population, being the second most common musculoskeletal condition (5, 6). They comprise a wide spectrum of clinical entities that should be approached individually. The 12 common TMDs include arthralgia; myalgia, which can be further classified into subtypes such as: local myalgia, myofascial pain, myofascial pain with referral; disc displacement disorders; degenerative joint disease; subluxation; and headache attributed to TMD (7).

According to the Diagnostic Criteria for TMD (DC/TMD), myalgia is defined as muscle-origin pain affected by jaw movement, function, or parafunction, and replication of this pain occurs with provocation testing of the masticatory muscles (7). Myalgia is further subdivided into three mutually exclusive types, such as: local myalgia, defined as pain localized to the site of palpation; myofascial pain, defined as pain spreading beyond the site of palpation but within the boundary of the muscle being palpated and myofascial pain with referral, defined as pain at a site beyond the boundary of the muscle being palpated. The three types of myalgia can be differentiated by palpation testing (2). The diagnostic criteria for myalgia include pain on jaw movements and palpation of the temporalis and masseter muscles, provided that the provoked pain replicates the patient’s complaint (7).

In 2024, the International Network for Orofacial Pain and Related Disorders Methodology, supported by the International Association for Dental Research (INfORM/IADR), published a set of ten key points for good clinical practice in the field of TMDs, thus representing a summary of the current standard of care in TMD treatment and patient needs (8).

TMD treatment may include surgical and non-surgical approaches. Most surgical therapies do not present sufficient scientific evidence (1, 8, 9). Within the scope of non-surgical treatment, the first-line approach involves promoting assisted self-management of the condition and conservative strategies, such as cognitive-behavioral therapy and kinesiotherapy. This type of intervention is effective for approximately 90% of individuals. As a second-line treatment to support self-management, the combination with pharmacological therapy and the use of interocclusal appliances may be considered (1, 10, 11).

Pain associated with TMD is the main reason why patients with this type of condition seek healthcare. It is known that most patients with TMD are able to cope with the pain, however, there are cases of chronic TMD with periods of acute exacerbation (1). Pharmacotherapy helps manage dysfunction and discomfort by controlling pain and inflammation. However, this type of therapy does not cure the dysfunction (9, 12-14).

Various drugs can be used as pharmacological therapy in the treatment of TMD. Among the most commonly used drugs are non-steroidal anti inflammatory drugs (NSAIDs), muscle relaxants, opioid analgesics, and anxiolytics (9, 15, 16). However, the evidence base for the use of pharmacological agents to manage myalgia in people with TMD is limited and empiric (17).

Justification of the study

Despite the increasing number of clinical studies, the evidence regarding pharmacological management of myalgia associated with temporomandibular disorders remains scarce, fragmented, and mostly empirical. Previous reviews, including the Cochrane Review on pharmacological interventions for painful persistent TMD (2021) (1), have highlighted the lack of robust and consistent data. In 2024, the International Network for Orofacial Pain and Related Disorders Methodology (INfORM/IADR) (10) reinforced the priority of conservative management, recognizing pharmacological therapy as a supportive second-line option. In this context, an updated systematic review with meta-analysis is warranted to synthesize the most recent randomized clinical trials and to clarify the effectiveness of pharmacological strategies.

Objective of the study

The objective of this study was to systematically review and quantitatively analyze the efficacy of pharmacological interventions in the management of myalgia associated with temporomandibular disorders in adults, as defined in the registered protocol, with secondary subgroup analyses examining differential responses across TMD phenotypes, including arthralgia, based on randomized controlled trials published between 2018 and 2024.

Methods

This systematic review and meta-analysis were conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (18) and reported according to the PRISMA 2020 statement (19). The review protocol was registered in PROSPERO (registration number CRD42024554300).

Eligibility criteria

Eligibility was defined using the Population, Exposure, Comparator, and Outcomes (PECO) framework:

Population (P): adolescents and adults (≥12 years) diagnosed with myalgia related to TMD (local myalgia, myofascial pain, or myofascial pain with referral);

Exposure (E): pharmacological interventions including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antidepressants, centrally acting muscle relaxants, anticonvulsants, benzodiazepines, local anesthetics, other analgesics, or combination therapies;

Control Group (C): placebo or other active interventions (e.g., saline, occlusal splints, intra-articular injectables), provided they were clearly defined;

Outcomes (O): primary outcomes were pain intensity and maximum interincisal opening (MIO).

Inclusion criteria were restricted to randomized controlled trials (RCTs) that reported at least one quantitative outcome related to myalgia using validated pain scales. Exclusion criteria included: history of trauma to the TMJ; inflammatory, rheumatic, or neoplastic conditions; fibromyalgia; congenital anomalies; animal studies; reviews; case reports; and studies without full-text access.

Information sources and search strategy

A comprehensive electronic search was performed in PubMed, Scopus, the Cochrane Library, and Google Scholar from inception to September 19, 2024, including articles published between 2018 and 2024. The complete search strategies for each database are provided in Table 1. Reference lists of included articles and relevant reviews were hand-searched to identify additional studies.

Table 1. Search protocol used in the systematic review.

Applied filters and MeSH terms	Database/Results
((myalgia related to TMD) OR (myalgia related to temporomandibular disorders) OR (temporomandibular joint disorders) OR (TMD)) AND ((drugs) OR (Nonsteroidal antiinflammatory drugs) OR (corticosteroids) OR (antidepressant drugs) OR (centrally acting muscle relaxants) OR (anticonvulsants) OR (benzodiazepines))	PubMed: 1371 results Cochrane Library: 112 results Google Scholar: 1260 results
((myalgia related to TMD) OR (myalgia related to temporomandibular disorders)) AND ((drugs) OR (Nonsteroidal antiinflammatory drugs) OR (corticosteroids) OR (antidepressant drugs) OR (centrally acting muscle relaxants) OR (anticonvulsants) OR (benzodiazepines))	Scopus: 849 results

Study selection

Two reviewers independently screened titles and abstracts, followed by full-text assessment of potentially eligible articles. Disagreements were resolved by discussion or by consulting a third reviewer. The selection process was documented in a PRISMA flow diagram.

Data Extraction and Management

Data were extracted independently by two reviewers using a standardized data extraction form. Extracted information included: author, year, country, study design, sample size, demographic characteristics (mean age, % female), TMD diagnosis, intervention details (drug, dosage, frequency, route of administration), comparator type, pain scale used, time points, baseline and follow-up mean pain scores (with standard deviations and/or confidence intervals), and adverse events. If necessary, units of drug dosage were converted to ensure comparability. In cases of disagreement, a third reviewer adjudicated.

Risk of bias assessment

The risk of bias was assessed independently by two reviewers using the Cochrane RoB 2.0 tool (Cochrane Risk of Bias tool for randomized trials). Disagreements were resolved by consensus or by consulting a third reviewer. The level of agreement between reviewers was quantified using Cohen’s Kappa coefficient (20).

Outcome measures

Primary outcomes: Change in pain intensity, assessed by validated scales (e.g., Visual Analog Scale, VAS). Change in maximum interincisal opening unassisted, measured in millimeters.

Secondary outcomes: Adverse events associated with pharmacological interventions, such as gastrointestinal discomfort, drowsiness or fatigue, dry mouth and allergic reactions, among others.

Data synthesis and statistical analysis

The effect size was expressed as standardized mean difference (SMD, Cohen’s d) with 95% confidence intervals (CI). Values of 0.2, 0.5, and 0.8 were interpreted as small, medium, and large effects, respectively. Cohen’s and corresponding standard errors were calculated for each study based on reported means, standard deviations, and sample sizes for intervention and control groups.

For studies with multiple post-baseline time points, a multilevel random-effects meta-analysis model was fitted using maximum likelihood estimation, with random intercepts for each study to account for within-study correlations among repeated measurements. Best linear unbiased predictions (BLUP) were extracted as the study-specific estimates for these studies. For studies with only one post-baseline time point, a conventional random-effects meta-analysis was applied.

All study-specific SMD were combined in a meta-analysis using an inverse-variance weighted random-effects model. Heterogeneity was assessed using the statistic.

Subgroup-specific pooled effects were estimated using separate random-effects meta-analyses within each subgroup. To formally test for differences between subgroups, mixed-effects meta-regression models were fitted with the subgroup variable as a categorical moderator, and the likelihood ratio test was used to assess statistical significance. Pairwise comparisons between subgroups were conducted, with p-values adjusted using the Holm method to account for multiple testing. Publication bias was evaluated with funnel plots and the trim-and-fill method. All analyses were performed in R (metafor package) (21). Forest plots and funnel plots were generated using package ggplot2.

A two-sided significance level of 5% was used for all statistical tests.

Results

Study selection

A total of 572 records were retrieved through database searches (PubMed, Scopus, Cochrane Library, and Google Scholar). After removal of 9 duplicates, 563 unique records were screened by title and abstract. Of these, 521 were excluded for not meeting eligibility criteria. Of the 41 articles selected for full-text review, only 37 were available. The full texts of 37 articles were assessed, and 20 were excluded for the following reasons: not a randomized controlled trial (n = 2) (22, 23), insufficient outcome data (n = 11) (24-35), or not focused on pharmacological management of myalgia related to TMD (n = 7) (36-42).

Ultimately, 17 articles met all inclusion criteria and were included in the qualitative synthesis (43-59). Several trials included multiple intervention arms, resulting in a total of 25 comparisons available for quantitative analysis (meta-analysis). The study selection process is illustrated in the PRISMA flow diagram (Figure 1).

Figure 1.

- PRISMA flow diagram

The 25 comparisons included in this review were conducted across nine countries between 2018 and 2024. A total of 1,128 participants were included, with a median sample size of 48 (range: 24–199). The proportion of female participants ranged from 40.9% to 100%, and the mean age ranged from 27.1 to 52.0 years.

Pharmacological interventions evaluated included platelet-rich plasma (PRP), sodium hyaluronate, methylprednisolone acetate, tenoxicam, dexamethasone, nimesulide, injectable platelet-rich fibrin (iPRF), ozone, propranolol, clorzoxazone, dextrose with saline solution, azithromycin, lidocaine, duloxetine, and MESNA.

To allow for exploratory analyses, the selected studies were grouped into four geographic categories. The western countries group includes the United States of America (43), Poland (56), Romania (55), Serbia (48), and Sweden (47), comprising five studies; the Muslim countries group includes three studies from Turkey (44, 50, 54) and three from Egypt (46, 57, 58), Asia includes three studies from India (45, 52, 59) and South America includes three studies from Brazil (49, 51, 53).

Further details of the included studies can be found in Table 2.

Table 2. Descriptive information of the twenty five included studies.

Study characteristics				Population characteristics			Intervention characteristics
Author Year Country	Age Mean (years)	% Female	TMD Diagnostic		Type of pain	TMD Scale	Intervention (n of cases)	Control (n of controls)	Follow-up (n post-baseline)		Measure of effect (VAS scale)	Measure of effect (MIO scale)
Batabyal et al. 2023 India	37,91	55	TMD Symptoms		Arthralgia		Platelet-Rich Plasma (30)	Lidocaíne + Triamcinolone (30)	2	-1,42 (-2,00; -0,84)		1,49 (0,99; 196)
1.Yapıcı-Yavuz et al. 2018 Turkey		86,36	Non-reducing disc displacement of the TMJ		Arthralgia	RDC/TMD	Arthrocentesis + intra-articular injection of sodium hyaluronate (11)	Arthrocentesis (11)	4	-0,19 (-0,73; 0,36)		0,01 (-0,44; 0,46)
2.Yapıcı-Yavuz et al. 2018 Turkey		86,36	Non-reducing disc displacement of the TMJ		Arthralgia	RDC/TMD	Arthrocentesis + intra-articular injection of methylprednisolone acetate (11)	Arthrocentesis (11)	4	0,13 (-0,41; 0,68)		-0,11 (-0,57; 0,34)
3.Yapıcı-Yavuz et al. 2018 Turkey		86,36	Non-reducing disc displacement of the TMJ		Arthralgia	RDC/TMD	Arthrocentesis + intra-articular injection of tenoxicam (11)	Arthrocentesis (11)	4	-0,01 (-0,55; 0,53)		-0,23 (-0,68; 0,22)
1.Martins et al. 2023 Brasil	34,55	91,6	Sintomas de DTM, estadios III ou IV de Wilkes			Wilkes classification	Arthroscopy + intra-articular injection of 2 mg dexamethasone (24)	Arthroscopy (12)	3	-0,47 (-1,05; 0,11)		0,43 (-0,06; 0,92)
2.Martins et al. 2023 Brasil	34,55	91,6	TMD Symptoms, III ou IV stages of Wilkes			Wilkes classification	Arthroscopy + intra-articular injection of 4 mg dexamethasone (24)	Arthroscopy (12)	3	-0,88 (-1,47; -0,29)		0,35 (-0,14; 0,84)
1.Dalewski et al. 2019 Poland	30,73	80	Myofascial pain		Myalgia		Interocclusal splint + nimesulide (30)	Interocclusal splint (30)	1	1,02 (0,56; 1,48)
2.Dalewski et al. 2019 Poland	30,73	80	Myofascial pain		Myalgia		Interocclusal splint + dry needling therapy (30)	Interocclusal splint (30)	1	-0,83 (-1,29; -0,38)
1.Tepecik et al. 2024 Turkey	36,30	100	Disc displacement without reduction		Arthralgia	DC/TMD	Arthrocentesis + intra-articular injection of sodium hyaluronate (29)	Interocclusal splint (30)	2	-0,69 (-1,22; -0,16)		0,11 (-0,33; 0,55)
2.Tepecik et al. 2024 Turkey	36,30	100	Disc displacement without reduction		Arthralgia	DC/TMD	Intra-articular injection of iPRF (29)	Interocclusal splint (30)	2	-0,36 (-0,89; 0,17)		-0,12 (-0,55; 0,32)
Pereira et al. 2021 Brasil	43,91	100	Muscular TMD		Myalgia	DC/TMD	Ozone therapy (25)	Cyclobenzaprine + nimesulide (23)	2	-3,30 (-4,04; -2,55)		1,34 (0,82; 1,87)
Tchivileva et al. 2020 USA	34,05	77,5	Muscular TMD		Myalgia	DC/TMD	Propanolol (100)	Placebo (99)	1	-0,74 (-1,03; -0,45)		-0,02 (-0,30; 0,26)
1.Bechir et al. 2018 Romania	50,50	56,1	Muscular TMD		Myalgia	DC/TMD	Low level laser therapy (42)	Fastum gel + Clorzoxazone (40)	7	-0,59 (-1,04; -0,13)		1,04 (0,68; 1,40)
2.Bechir et al. 2018 Romania	50,50	56,1	Muscular TMD		Myalgia	DC/TMD	Low level laser therapy + Fastum gel + Clorzoxazone (41)	Fastum gel + Clorzoxazone (40)	7	-0,83 (-1,29; -0,37)		1,63 (1,26; 1,99)
Venepally et al. 2018 India	32,43	50	Myofascial pain		Myalgia	Laskin’s criteria, 1969	Transcutaneous Electrical Nerve Stimulation (20)	Aceclofenac + Paracetamol + Tizanidine (20)	4	-0,83 (-1,37; -0,29)
Gibaly et al. 2024 Egypt	31,78	62,5	Temporomandibular joint anterior disc displacement, Wilkes stage II		Artralgia	Wilkes classification	Deep dry needling + Dextrose (20)	Deep dry needling (20)	4	-0,36 (-0,90; 0,17)		0,99 (0,54; 1,44)
Mosleh et al. 2021 Egypt	27,15	70,83	Anteriorly non reducing disc displacement, Wilkes stage III		Arthralgia + Myalgia	Wilkes classification	Arthrocentesis plus intra-articular injection of azithromycin (12)	Arthrocentesis + intra-articular injection of methylprednisolone acetate ednisolona (12)	2	-0,05 (-0,73; 0,64)		-0,21 (-0,80; 0,38)
Chandra et al. 2021 India	30,50	40,90	TMD Symptoms		Arthralgia		Intra-articular injection of PRP (22)	Arthrocentesis (22)	4	-0,46 (-0,98; 0,07)		0,35 (-0,08; 0,78)
1.Đorđević et al. 2019 Serbia	38,30	84,10	TMD Symptoms		Arthralgia		Interocclusal splint (20)	Ibuprofeno (16)	1	-0,34 (-1,00; 0,32)
2.Đorđević et al. 2019 Serbia	38,30	84,10	TMD Symptoms		Arthralgia		Interocclusal splint (20)	Diazepam (8)	1	-0,29 (-1,12; 0,53)
1.Bilici et al. 2018 Turkey			Myofascial pain and Internal Derangement		Arthralgia + Myalgia	RDC/TMD	Interocclusal splint plus intra-articular injection of lidocaine (3 times on alternate days) (12)	Interocclusal splint (29)	2	-2,84 (-3,59; -2,10)
2.Bilici et al. 2018 Turkey			Myofascial pain and Internal Derangement		Arthralgia + Myalgia	RDC/TMD	Interocclusal splint plus intra-articular injection of lidocaine (3 times, once a week) (15)	Interocclusal splint (29)	2	0,35 (-0,27; 0,96)
Isacsson et al. 2018 Sweden	52,00	81,50	TMD Symptoms		Arthralgia	DC/TMD	Arthrocentesis + intra-articular injection of methylprednisolone acetate ednisolona (27)	Saline solution (27)	1	-0,25 (-0,78; 0,29)
Ferreira et al. 2023 Brasil	39,24	96,15	TMD Symptoms		Arthralgia + Myalgia	DC/TMD	Duloxetine (40)	Placebo (38)	1	0,63 (0,18; 1,09)
Mosleh et al. 2024 Egypt		88,33	TMD Symptoms, II, III ou IV stages of Wilkes			Wilkes classification	Arthrocentesis plus intra-articular injection of MESNA (30)	Arthrocentesis + intra-articular injection of sodium hyaluronate (30)	4	-3,62 (-4,23; -3,01)		1,13 (0,72; 1,55)

Abbreviations: iPRF – Injectable Platelet-Rich Fibrin; PRP – Platelet-Rich Plasma; RDC/TMD – Research Diagnostic Criteria for Temporomandibular Disorders; DC/TMD – Diagnostic Criteria for Temporomandibular Disorders; MESNA – Pharmacological agent (Active ingredient: synthetic sulfhydryl compound).

Risk of bias in included studies

Inter-observer validation was calculated using the Cohen’s Kappa coefficient (18) to determine agreement between examiners, resulting in 0.893.

The funnel plot displays a relatively symmetrical distribution of studies around the pooled effect size, with no apparent gaps or asymmetry for both pain and maximum interincisal opening. Moreover, the trim and fill method estimated zero potentially missing studies, thus indicating a low likelihood of significant publication bias in the two meta-analysis (Figure 2).

Figure 2.

- Funnel plot of included studies evaluating the effect on: (A) pain and (B) maximum interincisal opening in temporomandibular disorders. Each point represents an individual study’s effect size plotted against its standard error. The vertical dashed line indicates the pooled mean difference. The blue lines represent pseudo 95% confidence limits. Trim and fill method: (A) no missing studies and (B) no missing studies.

Based on the RoB 2 assessment, four articles were found to have a low risk of bias (low risk – green), ten with a moderate risk (some concerns – yellow), and three with a high risk of bias (high risk – red) (Figure 3).

Figure 3.

– Rob2 Analysis

Effects of interventions

Pain (primary outcome)

Regarding interventions, these were grouped according to treatment strategies into three main categories: conservative treatments (e.g., medications, patient counseling, occlusal splints, physiotherapy, and low-level laser therapy), less invasive treatments (e.g., intra-articular drug injections), and surgical treatment, which includes minimally invasive arthroscopic procedures or invasive open surgeries such as arthroplasty.

For the meta-analysis, the following variables were assessed: sex, age, country group, type of pain, presence of dysfunction, the TMD scale used for diagnosis, type of treatment strategy, specific treatment strategy, and active pharmacological agent. For each group, pain (VAS) and maximum mouth opening (MIO measurement) were evaluated.

In the VAS pain assessment, regarding the type of intervention, no significant differences were observed. However, conservative interventions produced the greatest pain reduction, followed by less invasive interventions and combined surgery/injection modalities. Studies including participants with a mean age of 40 years or older tended to report greater pain reduction (SMD = -1.21; 95% CI: -2.36 to -0.07), although the difference between age subgroups was not statistically significant (p = 0.073). No statistically significant effect modifiers were identified in subgroup comparisons.

Pharmacological interventions proved to be more effective in reducing pain associated with myalgia in patients with TMD. Across the 25 studies, the pooled effect size (SMD) for pain showed a favorable effect for the intervention group, with most individual studies reporting negative effect sizes (Figure 4). The overall pooled effect demonstrated a statistically significant reduction in pain (SMD = -0.68; 95% CI: -1.09 to -0.26; p < 0.001), thus suggesting a moderate to high beneficial effect of interventions on myalgia pain. Most of the included studies (n = 18) reported estimates based on multiple follow-up time points. Heterogeneity between studies was very high (I² = 93.4%), which was explored through subgroup analysis (Figure 4, Figure 5.(A) – 5.(I), Table 3).

Figure 4.

- Forest plot of standardized mean differences (SMD) and 95% confidence intervals for the effect of pharmacological interventions on myalgia related to temporomandibular disorders. Each point represents an individual study estimate, with the size of the marker proportional to the study's weight. Circles indicate studies with a single follow-up time point, while squares represent studies with more than one follow-up assessment (BLUP estimates). The red diamond represents the overall pooled effect. Negative values indicate a reduction in pain favoring the intervention group. Vertical dashed line indicates no effect (SMD = 0).

Figure 5.

A) - Subgroup analysis of the type of pain by VAS scale
B) - Subgroup analysis of the presence of dysfunction by VAS scale
C) - Subgroup analysis of the intervention by VAS scale
D) - Subgroup analysis of the type of intervention by VAS scale
E) - Subgroup analysis of the active principle by VAS scale
F) - Subgroup analysis of the TMD scale used by VAS scale
G) - Subgroup analysis of age by VAS scale (<40 years, >=40 years)
H) - Subgroup analysis of sex by VAS scale (<80% Female, >=80% Female)
I) - Subgroup analysis of the country of origin by VAS scale

Table 3. Subgroup analysis of pain by VAS scale.

	Number of studies		Cohen’s d (95% CI)	p-value
Type of pain
Arthralgia	11	44.7	-0.38 (-0.61,-0.15)	0.57
Arthralgia + Myalgia	4	94.8	-0.46 (-1.80,0.89)
Myalgia	7	95.8	-0.85 (-1.68,-0.01)
Presence of dysfunction
Yes	20	91.1	-0.62 (-1.04,-0.20)	0.59
No	5	97.0	-0.91 (-2.09,0.27)
Intervention
Conservative	10	93.9	-0.89 (-1.30,-0.09)	0.90
Less Invasive	4	93.2	-0.72 (-1.11,-0.32)
Surgery + Less Invasive	9	52.4	-0.51 (-1.27,0.24)
Type of intervention
Mechanic	3	74.1	-0.61 (-0.95,-0.27)	0.92
Pharmacology	3	97.8	-1.11 (-2.93,0.71)
Intra-articular injection of drugs	4	52.4	-0.72 (-1.11,-0.32)
Surgery + Intra-articular injection of drugs	7	94.7	-0.72 (-1.62,0.18)
Active Principle
Corticosteroids	4	37.2	-0.35 (-0.70,0.00)	0.81
Others	13	96.6	-0.80 (-1.57,-0.03)
Factor Rich Plasma	3	64.9	-0.73 (-1.26,-0.20)
TMD Scale
DC/TMD	6	95.6	-0.76 (-1.69,0.18)	0.75
RDC/TMD	5	93.1	-0.49 (-1.50,0.51)
Wilkes classification	5	94.5	-1.07 (-2.21,0.06)
Age
<40 years	15	80.9	-0.40 (-0.71,-0.09)	0.073
>=40 years	4	94.6	-1.21 (-2.36,-0.07)
Sex
<80% Female	8	14.2	-0.69 (-0.87,-0.51)	0.90
>=80% Female	15	94.4	-0.62 (-1.22,-0.01)
Group of countries
India	3	48.7	-0.89 (-1.33,-0.45)	0.75
Brazil	4	95.7	-0.98 (-2.37,0.41)
Europe + USA	8	83.1	-0.37 (-0.78,0.05)
Muslims	10	94.5	-0.75 (-1.53,0.03)

Regarding pain type, in cases of arthralgia there was a significant pain reduction (SMD = -0.38; 95% CI: -0.61 to -0.15, I² = 44.7). In the remaining pain types, heterogeneity was high.

In terms of intervention, surgical procedures combined with less invasive treatments did not show a significant effect in reducing pain (SMD = -0.511; 95% CI: -1.27 to 0.24, I² = 52.4). Regarding intervention type, mechanical interventions (SMD = -0.61; 95% CI: -0.95 to -0.27, I² = 74.1) and intra-articular drug injections (SMD = -0.72; 95% CI: -1.11 to -0.32, I² = 52.4) showed significant pain reduction, whereas other subgroups showed high heterogeneity.

For the active agents administered in different studies, corticosteroids (SMD = -0.35; 95% CI: -0.35 to 0.00, I² = 37.2) and platelet-rich factors (SMD = -0.73; 95% CI: -1.26 to -0.20, I² = 64.9) also demonstrated significant pain reduction.

Regarding participant sex, studies with less than 80% female participants showed a significant pain reduction (SMD = -0.69; 95% CI: -0.87 to -0.51, I² = 14.2).

For the country group division, studies conducted in India (SMD = -0.89; 95% CI: -1.33 to -0.45, I² = 48.7) also reported significant pain reduction, while the other groups showed high heterogeneity.

The forest plot of standardized mean differences (SMD) and 95% confidence intervals for the effect of pharmacological interventions on myalgia related to temporomandibular disorders without the high-risk studies, after Rob2 analysis can be found in Figure 6. The global effect decreases to -0.48 (95% CI: -0.82 to -0.14), however, this reduction is not statistically significant.

Figure 6.

- Forest plot of standardized mean differences (SMD) and 95% confidence intervals for the effect of pharmacological interventions on myalgia related to temporomandibular disorders without the high-risk studies, after Rob2 analysis

Maximum interincisal opening (MIO, primary outcome)

In terms of MIO evaluation, interventions were associated with an overall improvement in maximum interincisal opening. The overall pooled effect demonstrated a statistically significant increase in MIO (SMD = 0.51; 95% CI: 0.20 to 0.82; p < 0.001), suggesting a beneficial effect of interventions (Figure 7, Figure 8.(A) – 8.(F), Table 4). The effect was more pronounced in studies with participants aged 40 years or older (SMD = 1.33; 95% CI: 1.02 to 1.64; p < 0.001) as well as in those investigating conservative interventions (SMD = 0.98; 95% CI: 0.47 to 1.49; p = 0.075).

Figure 7.

- Forest plot of standardized mean differences (SMD) and 95% confidence intervals for the maximum interincisal opening outcome. Each point represents an individual study estimate, with the size of the marker proportional to the study's weight. Circles indicate studies with a single follow-up time point, while squares represent studies with more than one follow-up assessment (BLUP estimates). The red diamond represents the overall pooled effect. Negative values indicate a reduction in pain favoring the intervention group. Vertical dashed line indicates no effect (SMD = 0).

Figure 8.

- A) - Subgroup analysis of the type of pain by MIO scale
B) - Subgroup analysis of the intervention by MIO scale
C) - Subgroup analysis of the TMD scale used by MIO scale
D) - Subgroup analysis of age by MIO scale (<40 years, >=40 years)
E) - Subgroup analysis of sex by MIO scale (<80% Female, >=80% Female)
F) - Subgroup analysis of the country of origin by MIO scale

Table 4. Subgroup analysis of MIO.

	Number of studies		Cohen’s d (95% CI)	p-value
Type of pain
Arthralgia	8	83.5	0.31 (-0.08,0.70)	0.08
Myalgia	4	91.5	0.98 (0.35,1.61)
Intervention
Conservative	5	88.9	0.98 (0.47,1.49)	0.075
Less Invasive	7	85.8	0.45 (-0.14,1.04)
Surgery + Less Invasive	4	85.8	0.44 (-0.14,0.56)
TMD Scale
DC/TMD	4	86.5	0.30 (-0.25,0.80)	0.56
RDC/TMD	3	0.00	-0.11 (-0.37,0.15)
Wilkes classification	6	72.4	0.57 (0.16,0.98)
Age
<40 years	9	80.6	0.37 (0.04,0.70)	<0.001
>=40 years	3	42.4	1.33 (1.02,1.64)
Sex
<80% Female	7	90.4	0.76 (0.27,1.25)	0.155
>=80% Female	9	80.3	0.32 (-0.03,0.66)
Group of countries
Brazil	3	66.8	0.70 (0.20,1.20)	0.170
Europe + USA	3	93.9	0.87 (0.09,1.65)
Muslims	8	79.7	0.21 (-0.15,0.56)

In other subgroup categories, such as TMD scale, sex, pain type, and geographic region, no significant differences were observed. Study heterogeneity was again extremely high (I² = 87, 9%), but subgroup analysis explained some of it. The treatment effect was statistically significant for the TMD scale, age, and country groups regarding MIO evaluation.

Regarding the TMD diagnostic scale, the use of the Wilkes Classification was associated with a significant increase in maximum interincisal opening (SMD = 0.57; 95% CI: 0.16 to 0.98, I² = 72.4).

In terms of age, there was a significant increase in maximum interincisal opening in participants aged 40 years or older (SMD = 1.33; 95% CI: 1.02 to 1.64, I² = 42.4). For the country group division, studies conducted in Brazil (SMD = 0.70; 95% CI: 0.20 to 1.20, I² = 66.8) also reported a significant increase in maximum interincisal opening, while the other groups showed high heterogeneity.

The global effect for the MIO outcome, excluding high-risk studies, yields similar values (Figure 9).

Figure 9.

- Forest plot of standardized mean differences (SMD) and 95% confidence intervals for the maximum interincisal opening outcome without the high-risk studies, after Rob2 analysis.

Additional subgroup meta-analyses were performed separately for studies enrolling exclusively patients with arthralgia and those limited to myalgia.

Pain and MIO (Arthralgia-only studies)

Starting by the pain intensity, when compared with the overall pooled estimate (SMD = –0.68; 95% CI: –1.09 to –0.26, I² = 93.4), the magnitude of improvement in arthralgia-only studies was comparable although slightly lower (SMD = –0.38; 95% CI: –0.57 to –0.18, I² = 59.9), but the heterogeneity was markedly reduced, suggesting a more stable therapeutic response.

Among the trials restricted to arthralgia, pharmacological interventions showed a consistent and more homogeneous benefit compared with the global estimates (Table 6). Conservative treatments achieved a significant though modest reduction (SMD = –0.34; 95% CI: –0.64 to –0.05; I² = 0.00), while less invasive, such as intra-articular injection of drugs approaches, produced larger and clinically relevant effects (SMD = –0.64; 95% CI: –0.94 to –0.34; I² = 6.40). In contrast, surgical or combined procedures yielded negligible benefit (SMD = –0.10; 95% CI: –0.30 to 0.10, I² = 0.00), thus pointing to a limited additional value of invasive strategies.

Table 6. Subgroup analysis of pain by VAS_Arthralgia_only.

	Number of studies		Cohen’s d (95% CI)	p-value
Intervention
Conservative	3	0.00	-0.34 (-0.64,-0.05)	0.019
Less Invasive	4	6.40	-0.64 (-0.94,-0.34)
Surgery + Less Invasive	4	0.00	-0.10 (-0.30,0.10)
Type of intervention
Intra-articular injection of drugs	4	6.40	-0.64 (-0.94,-0.34)	0.015
Surgery + Intra-articular injection of drugs	3	0.00	-0.08 (-0.29,0.13)
Active Principle
Factor Rich Plasma	3	73.3	-0.65 (-1.06,-0.24)	0.068
Others	6	32.1	-0.25 (-0.44,-0.06)
TMD Scale
DC/TMD	3	0.00	-0.39 (-0.57,-0.21)	0.029
RDC/TMD	3	0.00	-0.11 (-0.27,0.05)
Sex
<80% Female (1)	3	7.30	-0.65 (-1.06,-0.24)	0.055
>=80% Female (2)	8	2.15	-0.26 (-0.43,-0.08)
Group of countries
Europe + USA	3	0.00	-0.29 (-0.66,0.09)	0.84
Muslims	6	17.5	-0.24 (-0.36,-0.13)

Trials applying DC/TMD diagnostic criteria demonstrated significant pain improvement (SMD = –0.39; 95% CI: –0.57 to –0.21; I² = 0.00), whereas those using RDC/TMD did not show significant changes (SMD = –0.11; 95% CI: –0.27 to 0.05; I² = 0.00).

Regarding MIO, the global effect is non-significant (SMD = 0.19; 95% CI: –0.20 to 0.57, I² = 74.9). Less invasive interventions showed a better performance than combined with surgery however the difference was non-significant (p = 0.138). On the other hand, a sex-related difference was observed. Studies including <80% female participants exhibited a large, significant increase in MIO (SMD = 0.90; 95% CI: 0.39 to 1.41, I² = 66.5), compared with no measurable effect in studies including at least 80% of female participants (SMD = –0.07; 95% CI: –0.30 to 0.15, I² = 0.00) (Table 7).

Table 7. Subgroup analysis of MIO_Arthralgia_only.

	Number of studies		Cohen’s d (95% CI)	p-value
Intervention
Less Invasive	4	80.4	0.42 (-0.15,0.99)	0.138
Surgery + Less Invasive	3	00.0	-0.12 (-0.42,0.17)
Sex
<80% Female	3	66.5	0.90 (0.39,1.41)	0.001
>=80% Female	5	0.00	-0.07 (-0.30,0.15)

Overall, the arthralgia-specific findings point to the fact that pharmacological treatments and minimally invasive treatments are particularly effective in reducing pain, which is consistent with the main meta-analysis but showing reduced heterogeneity.

Pain and MIO (Myalgia-only studies)

Myalgia only studies showed a significant improve of MIO (SMD = 0.96; 95% CI: 0.28 to 1.63, I² = 83.9) although studies were only 4 and very heterogenous. Because of this low number of available studies, a subgroup analysis for the MIO outcome in myalgia-only trials could not be performed. Consequently, the analysis focused exclusively on the pain outcome.

In contrast to arthralgia studies, studies restricted to myalgia displayed more variable and heterogeneous pain result, mirroring the high heterogeneity observed in the overall pooled analysis. The overall effect for the myalgia trials was non- significant (SMD = -0.83; 95% CI: –1.67 to 0.02, I² = 87.9). Subgroup analysis did not reveal any significant differences related to age (p = 0.135) and sex (p = 0.90) (Table 8).

Table 8. Subgroup analysis of pain by VAS_Myalgia_only.

	Number of studies		Cohen’s d (95% CI)	p-value
Age
<40 years	4	91.3	-0.33 (-1.12,0.47)	0.135
>=40 years	3	84.6	-1.56 (-2.95,-0.17)
Sex
<80% Female	4	0.00	-0.74 (-0.99,-0.49)	0.90
>=80% Female	3	97.2	-1.00 (-2.99,0.99)

Discussion

This systematic review with meta-analysis synthesized evidence from 17 randomized controlled trials (25 treatment arms) assessing pharmacological interventions for myalgia related to temporomandibular disorders (TMD). The review included all pharmacological interventions reported in the literature, irrespective of the route of administration, focusing on the active substance rather than the delivery method.

Pharmacological therapy was associated with a statistically significant reduction in pain (SMD = –0.68; 95% CI: –1.09 to –0.26) and improvement in maximum interincisal opening (MIO) (SMD = 0.51; 95% CI: 0.20 to 0.82). Subgroup analyses suggested greater efficacy in patients with arthralgia, in participants ≥40 years, and for specific drug classes (platelet-rich factors and corticosteroids). Conservative interventions consistently demonstrated beneficial effects, whereas surgical interventions did not provide significant additional benefit and should be reserved for refractory cases (10).

The included studies evaluated a broad range of pharmacological agents, including NSAIDs, corticosteroids, muscle relaxants, antidepressants, platelet-rich factors, and intra-articular injectables. However, heterogeneity across studies was very high, mainly due to differences in diagnostic criteria (DC/TMD vs. Wilkes vs. RDC/TMD), outcome measures, treatment protocols, and follow-up periods. The high heterogeneity limited the interpretation of the overall estimate, however, subgroup analysis allowed us to control for this factor. The evidence is therefore most applicable to adult populations with clinically diagnosed myalgia or arthralgia, but less generalizable to pediatric or elderly populations where data remain sparse.

Only few placebo-controlled trials were available, but using active comparators is not a weaker design, it is often a more rigorous benchmark, as therapies must show benefit beyond accepted treatments rather than placebo (60, 61). Although heterogeneity was high, this was expected from differences in diagnoses, populations and interventions; subgroup analyses showed clearer pain reduction with moderate heterogeneity in arthralgia (I² = 44.7%), while myalgia studies were more variable.

Risk of bias assessment showed that only 4 studies were at low risk, with most judged as having “some concerns,” and 3 at high risk. Common methodological limitations included small sample sizes, lack of blinding, inadequate allocation concealment, and heterogeneity in diagnostic classification. The certainty of the evidence, therefore, ranges from low to moderate according to GRADE criteria, limiting confidence in the observed effect sizes (Table 5) (62).

Table 5. Summary of Findings Table with GRADE certainty ratings.

Outcome	Nº of participants (studies)	Effect (SMD, 95% CI)	Absolute effect (interpretation)	Certainty of the evidence (GRADE)	What happens	Comments
Pain intensity (VAS)	1,128 (25 comparisons, 17 RCTs)	SMD = –0.68 (–1.09 to –0.26)	Moderate reduction in pain favoring pharmacological interventions	⭑⭑◯◯ Low to moderate	Patients receiving pharmacological interventions are likely to experience a moderate reduction in pain compared to placebo or control.	High heterogeneity (I2 = 93.4%); subgroup analysis showed consistent benefit in arthralgia and with some injectable agents.
Maximum interincisal opening (MIO)	786 (12 RCTs)	SMD = 0.51 (0.20 to 0.82)	Moderate improvement in mandibular function (≈ +2–4 mm)	⭑⭑◯◯ Low to moderate	Patients treated pharmacologically are likely to achieve moderate improvement in mouth opening.	Effect more pronounced in patients ≥40 years and in trials using Wilkes classification.
Adverse events	568 (8 RCTs)	Not pooled (heterogeneous reporting)	Mostly mild events (e.g., transient local pain, swelling, gastrointestinal upset); no serious adverse events reported	⭑◯◯◯ Very low	Adverse events were mild and self-limiting; no serious harms identified.	Evidence limited by poor reporting and inconsistent definitions.
Subgroup: Arthralgia vs. Myalgia	442 (9 RCTs)	Arthralgia: SMD = –0.38 (–0.61 to –0.15); Myalgia: SMD = –0.85 (–1.68 to –0.01)	Pain reduction greater in arthralgia; myalgia results highly heterogeneous	⭑⭑◯◯ Low	Patients with arthralgia may benefit more consistently from pharmacological therapy than those with myalgia.	Arthralgia may respond better due to clearer inflammatory mechanisms; myalgia remains multifactorial.

A comprehensive search was performed across multiple databases, and grey literature was partially explored via Google Scholar. Funnel plots did not reveal any evidence of publication bias. Nonetheless, the possibility of missing unpublished negative trials cannot be excluded. Furthermore, the inclusion of multi-arm studies may have introduced some unit-of-analysis issues, although these were handled using multilevel models where possible.

Our findings align with previous reviews. The Cochrane Review on pharmacological interventions for persistent TMD pain (2021) (8), highlighted insufficient evidence, while more recent reviews (e.g., Christidis et al., 2024) (17) suggested potential benefit for botulinum toxin and muscle relaxants in myogenous TMD. The present synthesis corroborates the role of corticosteroids, particularly in arthralgia, while reinforcing the limited efficacy of surgical approaches (10). Regarding platelet-rich factors, there were heterogeneous outcomes across trials, with both positive and null effects reported. Therefore, the evidence should not be interpreted as uniformly favorable, but rather as preliminary and requiring further high-quality investigation (63). These findings are consistent with the 2024 INfORM/IADR consensus, which emphasized conservative management as first-line and pharmacological interventions as adjunctive strategies (7, 64-66).

Further subgroup analyses restricted to studies enrolling exclusively patients with arthralgia or myalgia provided additional insights into the differential therapeutic response across TMD phenotypes.

In arthralgia-only studies, pain reduction was significant and more consistent (SMD = –0.38) compared with the overall pooled estimate, accompanied by markedly reduced heterogeneity. This suggests that when patient populations are clinically homogeneous and joint-related mechanisms predominate, pharmacological and minimally invasive interventions yield a more stable and predictable therapeutic response. These findings are in agreement with previous evidence indicating a stronger and more reproducible benefit of pharmacological therapies in TMD-A (17, 67). Conservative and intra-articular pharmacological approaches achieved significant pain reduction, while surgical or combined procedures offered negligible benefit, reinforcing that invasive strategies provide little additional value beyond conservative or minimally invasive management (68).

In contrast, myalgia-only studies revealed more variable and heterogeneous pain outcomes (SMD = –0.83; 95% CI: –1.67 to 0.02; I² = 87.9), mirroring the high heterogeneity observed in the global analysis. The limited number of available trials and methodological variability, particularly regarding diagnostic criteria, follow-up duration, and intervention type, likely contributed to this inconsistency. Unlike arthralgia, where nociceptive mechanisms are predominantly peripheral, myalgia may involve central sensitization and psychosocial factors, which can attenuate pharmacological responsiveness and explain the wide dispersion of results (69, 70).

Regarding mandibular function, the overall MIO improvement was not significant in arthralgia studies, though a marked increase was observed in studies including less than 80% female participants, suggesting potential sex-related modulation of therapeutic response. Conversely, myalgia-only studies demonstrated a significant increase in MIO, although based on only four highly heterogeneous trials. This may indicate that functional recovery is more perceptible in muscular conditions, even when pain relief is inconsistent (10, 47, 49).

Taken together, these findings highlight that the underlying pathology, arthralgia or myalgia, strongly influences treatment response. Pharmacological and minimally invasive therapies are more consistently effective in arthralgia, whereas the variability seen in myalgia underscores the need for individualized and multimodal approaches. This supports the importance of accurate diagnostic stratification and standardized criteria to improve comparability across studies (10, 17).

Current evidence supports the use of pharmacological interventions, particularly corticosteroids, as effective adjuncts to conservative therapy in managing TMD-related myalgia and arthralgia (67). However, pharmacological treatment should not replace assisted self-management and conservative approaches, which remain the cornerstone of care (10, 71, 72). Surgical procedures should be reserved for rare, refractory cases with clearly defined indications (10, 73).

Implications for research

Future randomized controlled trials should: adopt standardized diagnostic criteria (DC/TMD) and outcome measures (VAS for pain, MIO in mm); include larger, more representative populations, including older adults and under-represented regions; compare different pharmacological agents head-to-head to identify optimal regimens; incorporate longer follow-up to evaluate sustained efficacy and safety; integrate patient-centered outcomes such as quality of life and functional impact.

Clinical implications for practice and quality of the evidence

The present evidence supports the use of pharmacological therapy as an effective adjunct to conservative management for temporomandibular disorders, particularly in cases of arthralgia, where the pooled analysis showed a significant and consistent reduction in pain (SMD = –0.38; 95% CI: –0.57 to –0.18) and moderate improvement in mandibular function, with lower heterogeneity. In contrast, studies limited to myalgia demonstrated highly variable results and wide confidence intervals, yielding no statistically significant reduction in pain, although a functional improvement in maximum interincisal opening was observed. Overall, pharmacological interventions—including corticosteroids and platelet-rich factors—showed moderate to high benefit when combined with conservative therapy, whereas surgical or combined invasive approaches provided limited additional value. The quality of the evidence ranges from low to moderate, mainly due to small sample sizes, methodological heterogeneity, and limited blinding across trials. Consequently, pharmacological treatment should be individualized, short-term, and reserved as an adjunct to evidence-based conservative management, which remains the cornerstone of care in both myalgia and arthralgia.

Conclusion

The meta-analysis demonstrates that pharmacological interventions, when used as adjuncts to conservative management, produce a moderate overall benefit in pain reduction and functional improvement in temporomandibular disorders. Evidence is stronger and more consistent for arthralgia, indicating a predictable therapeutic response and lower heterogeneity, whereas myalgia shows greater variability and limited pain reduction, likely reflecting multifactorial and centrally mediated mechanisms. Intra-articular and minimally invasive pharmacological strategies yield the most reproducible outcomes, while surgical interventions provide little additional benefit. The overall certainty of the evidence is low to moderate due to heterogeneity, small sample sizes, and methodological limitations. Further standardized, high-quality randomized controlled trials are required to confirm these findings and to refine phenotype-specific therapeutic recommendations. Factors such as age and geographical context had an impact on therapeutic outcomes, thus highlighting the importance of the clinical and sociocultural context in treatment response.