FormalPara Key Points

Evidence clearly indicates that BoNT-A has positive effects in the treatment of M-TMD but it is not superior to standard treatments.

BoNT-A treatment for M-TMDs could cause adverse effects on muscle and bony tissue of major importance that must be considered.

This umbrella review presents the highest level of evidence regarding BoNT-A treatment for M-TMDs, since it included only SRs with low risk of bias/high quality.

1 Introduction

Botulinum toxin (BoNT) is a very potent biological toxin produced by several species of the Clostridia bacteria family, such as Clostridium botulinum [1, 2]. Intake of BoNT type A (BoNT-A) and other BoNT serotypes causes botulism, a condition that leads to flaccid paralysis of skeletal muscles and dysautonomia in humans. This effect is caused by interference with neurotransmitter release (acetylcholine) at presynaptic terminals [3, 4]. Because of the muscle paralysis, BoNT-A has become a common medical treatment used for autonomic disorders, spasticity, and hyperkinetic movement disorders, as well as in aesthetics for cosmetic purposes [5]. Recently, there has been a growing interest in its pain-reducing properties. Initially, the analgesic effect in neuromuscular disorders and musculoskeletal pain was attributed to the muscle relaxant effect, until the anti-hyperalgesic effect in non-muscular pain models was unequivocally demonstrated in human and animal models [6, 7].

In this regards experimental studies have proposed and demonstrated several antinociceptive mechanisms through local injections of BoNT-A that may reduce peripheral and central sensitization [8]. Some of the proposed analgesic effects of BoNT-A are: (1) suppression of the peripheral and central release of transport neurotransmitters (such as glutamate, calcitonin gene related peptide (CGRP), and substance P (SP)) to sensory regions of the trigeminal ganglia; (2) regulation of the pain modulation system by influencing the gamma-aminobutyric acid (GABA) and opioid-ergic systems; (3) reduction of microglia activation; and (4) modulation of ion channels [transient receptor potential vanilloid 1 (TRPV1), calcium (C+), and sodium (Na+)] [6, 9,10,11,12]. Notwithstanding, there is no evidence of the role and importance of these mechanisms. Thus, due to its analgesic properties, BoNT-A is used as a treatment approach for chronic pain conditions such as chronic migraine (on-label), but also other pain conditions such as neuropathic, back, pelvic, and myogenous temporomandibular disorder (TMD) pain (M-TMD) (off-label) [13,14,15,16].

M-TMD is the most common (45%) diagnosis among the TMD diagnoses and is characterized by regional pain and increased tenderness in the masticatory muscles, diminished masticatory performance, and restricted jaw movements [17]. Although several treatment approaches have been shown to be successful in the management of M-TMD [17,18,19,20,21], persistence of pain in the masticatory muscles is common [22]. Results from well conducted randomized placebo-controlled clinical trials (RCTs) on the effects of BoNT-A on persistent M-TMD differ, but those showing positive effects of BoNT-A indicate improvements in pain levels, somatosensory alterations, muscle tenderness, jaw mobility, and psychological well-being [23,24,25,26,27,28,29]. More recently, a large number of animal and clinical studies have shown that injections of BoNT-A into the masticatory muscles could produce several adverse events, such as muscle atrophy, alterations of the muscle’s histological composition, replacement of contractile tissue with fatty tissue [30,31,32], muscle weakness [33], reduction in maximum bite force, decrease in masticatory performance [34], and reduction in mandibular bone volume and other bony structural changes mainly in the mandible’s head and alveolar region [35, 36]. Taken together, the lack of consistent evidence regarding the benefits of BoNT-A for persistent M-TMD and its high probability of causing adverse events makes the clinical decision process challenging.

Since use of BoNT-A for M-TMDs is of great interest, many systematic reviews (SRs) have been performed over the last 15 years aiming to summarize the available literature, and to reach pertinent conclusions for the use of BoNT-A for treatment of patients with M-TMD. However, due to the inconclusive data, and to shortcomings in data curation and presentation of some SRs, no treatment protocols have yet been published and no definite conclusions have been drawn regarding the efficacy and safety (adverse events) of BoNT-A in the management of M-TMD. Formulating such conclusions are necessary since the use of BoNT-A as a primary treatment approach for M-TMD is increasing worldwide. Therefore, the aim of the present umbrella review was to systematically assess the findings and quality of SRs evaluating BoNT-A regarding its treatment effects on pain intensity, mandibular range of motion, and adverse events in patients with M-TMDs.

2 Material and Methods

2.1 Protocol

This umbrella review (UR) followed the protocol that was registered a priori in PROSPERO (the International Prospective Register of Systematic Reviews, registration number CRD42023468160). The UR was conducted according to the methodology published by Aromataris et al. [37], which includes the methodological development, conduct, and reporting of an UR.

2.2 Selection Criteria

The following inclusion criteria were adopted based on the PICOTS approach:

P = Population, I = Intervention, C = Comparator, O = Outcome, T = Time, S = Study

The population (P) was adult patients with mastication myalgia (M-TMD).

The intervention (I) was intramuscular injections of BoNT-A, regardless of doses and the number of injections administered.

The comparators (C) were no treatment, placebo, or other non-invasive, minimally invasive, or invasive therapeutic interventions.

The primary outcome (O) was reduction of pain intensity using a Visual Analogue Scale (VAS), Numerical Rating Scale (NRS), or other measurable pain scale. The secondary outcomes were changes in mandibular range of motion and adverse effects. Every measurable jaw-movement limitation was considered, with a focus on Maximum Mouth Opening (MMO). When available, adverse events (AEs) were collected.

The follow-up time (T) was either short term, i.e., ≤ 3 months, intermediate term, i.e., 3–5 months, or long term ≥ 6 months.

The study design (S) included only SRs that reported the outcomes of interest.

The following exclusion criteria were used: (1) studies presented in other languages than English, Spanish, Portuguese, Greek, and Scandinavian languages; (2) editorials, letters, legal cases, interviews, case-series, duplicates, observational studies, cross-sectional studies, case-control studies, non-randomized and randomized clinical trials, cohort studies, narrative review articles, and in vitro and animal studies; (3) SRs not investigating BoNT-A treatment for M-TMD.

2.3 Search Strategy

In partnership with the librarians Narcisa Hannerz (NH) and Sabrina Gillsund (SG) at the Karolinska Institutet University Library, a literature search strategy was developed to find SRs that discuss BoNT-A treatment for patients with mastication myalgia. The search was conducted electronically on 6 December 2023 and included SRs in English, Spanish, Portuguese, Greek, and Scandinavian languages without any restrictions on publication date. The search utilized eight databases including as MEDLINE, EMBASE, CINAHL, Cochrane Central Registry of Controlled Trials (CENTRAL), Web of Science, Epistemonikos, ClinicalTrials.gov, and ICTRP from the time each database was established.

In MEDLINE (Ovid), in partnership with NH and SG, the search strategy was formulated. SG reviewed the search strategies prior to NH executing the search. Each search concept involved identifying Medical Subject Headings (MeSH terms) and free text terms. The search was partly translated into other databases using the Polyglot Search Translator [38]. To eliminate duplicates, the method outlined by Bramer et al. was utilized [39]. Detailed search strategies for all databases can be found in the Online Supplementary Material (OSM) 2.

The Rayyan tool aided in screening titles and abstracts [40]. Two authors (HJ and AL) independently and blindly evaluated the titles and abstracts. All articles included by at least one of the authors were eligible for full-text assessment. Subsequently, all potentially eligible studies were obtained, and full-text articles were assessed by the same authors (HJ and AL) for meeting the inclusion criteria. Any discrepancies were resolved through discussion involving the third author (NC).

2.4 Data Extraction

For this review, a data extraction form was created and tested on two randomly chosen studies by authors MCS and ME to ensure uniformity in extraction. The form was adjusted based on a pilot test. Any discrepancies in data extraction were settled through discussion with a third author acting as an adjudicator (GDC). Extracted information encompassed study and participant details such as authors, type of SR, year of publication, objectives, diagnostic criteria, patient age, treatment groups, number and date range of database searching, date range, number and type of studies included in each review, instruments to appraise primary studies and their quality, methods of synthesis/analysis to synthesize evidence, and outcome measures.

2.5 Assessment of Risk of Bias and Methodological Quality of Included Systematic Reviews

Authors MCh and RP assessed the risk of bias independently using the critical appraisal checklist developed by the UR methodology working group [41]. Any discrepancies were resolved through discussion with a third author acting as an adjudicator (NC). Each of the questions posed in the checklist could be scored as being ‘met,’ ‘not met,’ ‘unclear,’ or ‘not applicable.’ The decision to include only high-quality SRs was made based on a pre-determined proportion of all criteria. The following seven questions were chosen as required to be met to get a score of high quality and low risk of bias: “Were the inclusion criteria appropriate for the review question?”, “Was the search strategy appropriate?”, “Were the sources and resources used to search for studies adequate?”, “Were the criteria for appraising studies appropriate?”, “Was critical appraisal conducted by two or more reviewers independently?”, “Was the likelihood of publication bias assessed?” and “Were recommendations for policy and/or practice supported by the reported data?” The question: “Is the review question clearly and explicitly stated?” was chosen to either be met or be unclear to get a score of high quality and low risk of bias, whereas the following two questions were chosen to not affect the methodological quality/risk of bias: “Were the methods used to combine studies appropriate?” and “Were the specific directives for new research appropriate?”

2.6 Curation and Processing of Data

Authors GDC and NC were responsible for reviewing and summarizing the evidence and data, a process that was then validated by the author EA. Subsequently, this information was organized into a table featuring a visual stop-light indicator. In this indicator, green signifies a beneficial (effective) intervention, orange represents no difference in the comparison, and red indicates that the intervention is either detrimental or less effective than the comparator. When it comes to adverse events, green indicates no adverse events, orange mild, and red indicates moderate or major/severe adverse events (Table 3).

3 Results

3.1 Literature Search Outcome

The electronic search yielded 6,514 articles from all databases. After removal of 3,205 duplicates, a total of 3,309 article titles and abstracts were screened for suitability. After reading titles and abstracts, 3,171 of the 3,309 articles were excluded because they did not meet the inclusion criteria. Thus, 138 were sought for retrieval, and three could not be retrieved. No further SRs were found from other sources, such as reference-lists, theses, etc. Finally, after reading the 135 full-text SRs, 34 met the inclusion criteria and were then evaluated regarding methodological quality/risk of bias, and data extracted. After this final assessment, 18 SRs reached the preset quality criteria and were included [18, 19, 36, 42,43,44,45,46,47,48,49,50,51,52,53,54,55,56]. Figure 1 shows the PRISMA flow diagram with the process of evaluating the SRs for inclusion.

Fig. 1
figure 1

The PRISMA flow-chart of the database search strategy

Full size image

3.2 Study Characteristics and Assessment of Risk of Bias/Methodological Quality

The initial search resulted in 34 SRs. The risk of bias/quality assessment is presented in OSM 3. Seven studies [57,58,59,60,61,62,63] were found to have some concerns (orange) and nine studies [64,65,66,67,68,69,70,71,72] a high risk of bias/low quality (red) and were excluded from the UR due to their methodological concerns. The study characteristics from the 18 SRs [18, 19, 36, 42,43,44,45,46,47,48,49,50,51,52,53,54,55,56] that were finally included are presented in detail in Table 1. These SRs were published between 2011 and 2023, and displayed a low risk of bias/high quality (green).

Table 1 The extracted study characteristics of the eighteen included systematic reviews
Full size table

3.3 Summary of Findings

The majority (15 out of 18) of the included SRs investigated the pain-reducing effect of BoNT-A [18, 19, 42,43,44,45,46,47,48, 50,51,52,53, 55, 56], whereas eight investigated the effect of BoNT-A on mandibular movements [18, 19, 43,44,45,46, 52, 53]. Seven of the included SRs reported adverse events induced by treatment with BoNT-A [36, 44,45,46, 51, 52, 54]. A quantitative presentation of these outcomes is shown in Table 2. Table 3 summarizes the evidence from the quantitative research synthesis regarding the effects and adverse events after treatment with BoNT-A. Additionally, the number of times that the original RCTs were cited in each SR are presented in Table 4. Below is a brief description of each of these three outcomes reported in the included SRs.

Table 2 (a) Quantitative findings regarding the effect of BoNT-A treatment on muscle pain intensity, (b) Quantitative findings regarding the effect of BoNT-A treatment on mandibular movements, (c) Quantitative findings regarding the effect of BoNT-A treatment on adverse events
Full size table
Table 3 (a) Summary of the evidence from quantitative research synthesis regarding the effect of BoNT-A treatment on muscle pain intensity, (b) Summary of the evidence from quantitative research synthesis regarding the effect of BoNT-A on mandibular movements, (c) Summary of the evidence from quantitative research synthesis regarding the effect of BoNT-A on adverse events
Full size table
Table 4 Original randomized controlled studies from the systematic reviews included in this umbrella review
Full size table

3.3.1 Effect of BoNT-A Treatment on Pain Intensity

The effect of BoNT-A on pain intensity was reported in 15 SRs [18, 19, 42,43,44,45,46,47,48, 50,51,52,53, 55, 56], summarized in Tables 2a and 3a. In nine SRs the results pointed to an effect favoring treatment with BoNT-A compared to placebo (isotonic saline) [19, 44,45,46,47,48, 52, 53, 55]. Two SRs did not find any difference in pain reduction between BoNT-A and placebo (isotonic saline) [51, 56]. There were no significant differences between BoNT-A and standard treatments for M-TMD (occlusal splints, jaw exercises, etc.) [18, 19, 42, 44, 52, 53]. When compared with dry needling, three articles showed a significantly greater pain-reducing effect favoring dry needling compared to BoNT-A [43, 46, 48], and one showed similar results [50].

3.3.2 Effect of BoNT-A on Mandibular Movements

The effect of BoNT-A on mandibular movements was reported in eight of the included SRs [18, 19, 43,44,45,46, 52, 53] and summarized in Tables 2b and 3b. While two of the included SRs indicated that there is a favorable effect on mandibular movements for treatment with BONT-A compared to baseline (before-after) or to placebo (isotonic saline) [45, 46], four SRs did not show any significant improvements after treatment with BoNT-A compared to placebo [18, 19, 52, 53] or standard treatments [44, 52, 53]. One SR [43] concluded that dry needling therapy increased the range of motion more than wet needling with BoNT-A or other agents.

3.3.3 Reported Adverse Events Associated with Treatment with BoNT-A

With regard to possible adverse events associated with the use of BoNT-A in the masticatory muscles, seven SRs reported such outcomes [36, 44,45,46, 51, 52, 54]. The majority of these found impairment related to the reduction of masseter size with subsequent muscle weakness, leading to discomfort during chewing [44, 45]. Major adverse events reported were mostly related to injection technique and included paresthesia, eye drooping or muscle weakness, speech changes, perioral swelling, bruising, and an asymmetric smile [45]. A single study reported increased pain after injection with BoNT-A [44]. Bony changes were evaluated in two SRs, which found significant decreases in cortical thickness and volume after BoNT-A [36, 54]. Three SRs did not report any major adverse events compared to placebo or other therapies [46, 51, 52], as shown in Tables 2c and 3c.

3.3.4 Synthesis of Evidence for a Favorable Effect of BoNT-A

In summary, seven out of the 11 included SRs reporting data on the pain-reducing effect of BoNT-A versus placebo point to a favorable effect of BoNT-A [19, 44,45,46,47,48, 55]. Further, two of the 11 included SRs that reported data on the pain-reducing effect of BoNT-A versus placebo could only show a favorable effect of BoNT-A in less than half of the RCTs included in these SRs [52, 53]. However, the other two SRs did not show any favorable effect of BoNT-A when compared to placebo [51, 56]. When treatment with BoNT-A was compared to other treatments of TMD, none of the included SRs showed a favorable effect of BoNT-A. However, six of the included SRs showed similar effects between BoNT-A and other treatments of TMD [18, 19, 42, 44, 50, 53] (Table 3a).

With regard to mandibular movements, one of the included SRs showed a favorable effect with increased mandibular movements after treatment with BoNT-A when compared to baseline or placebo [45], while another SR only showed a favorable effect with increased mandibular movements after treatment with BoNT-A when compared to placebo in half of the RCTs included in this SR [46] (Table 3b).

4 Discussion

Presently, there is no unanimous agreement on the use of BoNT-A for treatment of M-TMDs. The main results of this UR show that BoNT-A is more effective than placebo in reducing pain intensity levels in M-TMD, but not more effective than standard therapies. In addition, treatment with BoNT-A does not seem to result in any significant improvement in jaw mobility compared to placebo or standard treatments of M-TMD. Moreover, this UR indicates that BoNT-A may not be entirely risk free for treatment of M-TMD due to its potential side effects like muscle atrophy and weakness, injection-related complications, and even alterations in the jaw-bone structure.

The pain-relieving effects by local BoNT-A injection are unequivocal, with numerous animal studies show-casing its ability to reduce pain through various mechanisms [6]. Recent research suggests that BoNT-A not only acts locally on sensory nerve endings, but is also transported to the nerve cell bodies in the trigeminal and dorsal root ganglia and to the caudal trigeminal nucleus and spinal nerve terminals within the central nervous system, where it influences the pain modulation system [9, 10]. This dual action on peripheral and central sensitization makes BoNT-A a candidate for treatment of M-TMDs. The consistent effectiveness of BoNT-A over placebos in most SRs included in this study supports this notion. This is further reinforced by a recent RCT on persistent M-TMD patients, showing that BoNT-A outperformed placebo in diminishing pain and improving somatosensory alterations by increasing the pressure pain threshold and improving conditioned pain modulation [29]. However, the crucial question remains about whether this superiority over placebo holds when compared to standard treatments. Our findings suggest that BoNT-A is as effective as standard treatments for M-TMDs. One of the major problems when comparing BoNT-A with other treatments, also discussed in a previous article from our group [45], is that there is not a validated protocol for BoNT-A, and RCTs used different doses and injection protocols, injecting the substance in different muscles, which are factors that certainly influenced the results. Another difficulty is that even though we only included SRs of low risk of bias/high quality, most RCTs included in these SRs present methodological drawbacks, which influences their conclusions. In addition, the SRs are based on a limited number of RCTs and, even if, to the authors’ knowledge, there are no studies concerning the cost-effectiveness of BoNT treatment, the yearly treatment cost is high, which is why we question if it can be cost-effective. Thus, in line with a recently published clinical practical guideline, we recommend that healthcare providers reassess the use of BoNT-A as a treatment for M-TMDs and limit its application only to specific cases with persistent M-TMD where standard treatments are not sufficient to relieve pain [73].

Regarding the secondary outcomes, our results show that there are no beneficial effects of BoNT-A on mandibular movements, when compared to either placebo or standard treatments [18, 19, 43, 52, 53]. Only two SRs showed a positive effect of BoNT-A [45, 46], but only in half of the included RCTs in one of the reviews [46]. Although mandibular movements often are reduced in patients with M-TMD [17] as a consequence to the pain, BoNT-A does not seem to improve the range of mandibular movements, in accordance with a previous network-meta analysis showing that neither dry needling or wet needling with BoNT has a positive effect on mandibular movements [18]. One can only speculate as to why the effect on mandibular movements did not follow the pain-reducing effects shown in these SRs. Several studies show that the sensitivity of evaluating mandibular functioning is low since there is a large variability in mandibular movements among different individuals, between different ages, and also between genders [74,75,76,77]. Other studies have shown that mandibular movements correlate with body height and facial morphology, and that these variations among individuals themselves affect any possible assessment on a group level [78,79,80]. Further, reduction in mandibular movement is often associated with temporomandibular joint problems, like internal derangements and inflammatory conditions. Since these often co-exist with M-TMD, it could be difficult to assess any possible treatment effect on mandibular movements when just treating M-TMD. Finally, recent studies have shown that patients with M-TMD also suffer from kinesiophobia, i.e., an irrational and restrictive fear of movement. Thus, since they have heightened anxiety and apprehension about re-encountering painful episodes, they actively avoid situations that could trigger such painful episodes, in this case opening the mouth wide [81]. Thus, when treatment—like BoNT-A or any other treatment—reduces pain, the patients will be less anxious and more confident about opening their mouth wide. However, that does not per se mean that BoNT-A itself improved the mandibular movements; it could just be a result of decreased levels of kinesiophobia making the patients more confident and therefore feeling less anxious about opening their mouth wider [82]. Taken together, to assess treatment efficacy on mandibular movements could be misleading, resulting in inconclusive results in this patient group suffering from M-TMDs.

Although this UR indicates that BoNT-A in most cases only displays minor or mild adverse events, treatment with BoNT-A cannot be considered a safe and risk-free treatment approach for M-TMDs. Though most studies reported a spontaneous resolution of mild or minor adverse events, one has to consider that most of them did not investigate adverse events of BoNT-A treatment, but included that as a secondary variable from patient self-reports [45]. However, recent studies indicate that potential moderate and severe adverse events such as muscle atrophy [83,84,85,86,87,88], muscle weakness with significantly reduced occlusal and bite forces, as well as masticatory performance [34, 89], injection-related complications [45], and even alterations in the jaw-bone structure [36, 54] are evident after BoNT-A injection. Previous animal studies and some human studies indicate that this could be a result of incomplete re-innervation of the injected area [88], fatty infiltration [31], fibrosis [90], and increased genetic expression of bone resorption markers (Rankl/18S) [35]. Even atrophy due to necrosis of muscle fibers has been reported in mice [91] and humans [92]. However, it is important to highlight that a single injection of a low dose of BoNT-A resulted in an improvement in pain intensity but was not shown to cause adverse events such as muscular and bone changes [28].

To summarize the adverse events associated with treatment with BoNT-A on muscle thickness, muscle activity, masticatory performance, reduction in mandibular bone density and cortical thickness in relation to the moderate pain-reducing effect in patients with M-TMD, we recommend dentists and other medical care providers carefully evaluate the beneficial aspects of BoNT-A and the possible or potential side effects of BoNT-A for treatment of pain or even when used for aesthetic purposes [89]. Further, we also recommend that dentists and other medical care providers use a single injection of a low dose of BoNT-A for treatment of pain or for aesthetic purposes in masticatory muscles. This is based on the fact that a single injection of low-dose BoNT-A has been shown to be equally effective as repeated injections or higher doses [28, 55].

Notwithstanding, even though the long-lasting effects of BoNT-A in M-TMD were reported in only one study [93], it is recommended that future RCTs assess the durability of the positive effects and adverse events of BoNT-A injections and the effects of long-term repeated injections in patients with M-TMD. Also, another aspect to investigate in future RCTs is the effect of BoNT-A on centrally mediated muscle pain. To our knowledge, one study has indicated that treatment with BoNT-A could have a positive effect on centrally mediated pain, but that the effect was significantly better for localized M-TMD when compared to centrally mediated muscle pain [94].

4.1 Study Strengths and Limitations

The main strength of this UR is that it systematically reviews existing SRs. A SR itself offers a comprehensive evaluation of available information on a particular subject. However, an UR can provide insightful conclusions through thorough analysis by integrating prior SRs and/or meta-analyses. Further, URs like this one can expedite the assessment of extensive evidence and facilitate comparison with findings from previous SRs. In contrast to SRs on the use of BoNT-A where the results from different SRs vary and are inconclusive, this UR adds an additional step by synthesizing the existing high-quality reviews establishing an overall coherence [95]. It can serve as a valuable resource for immediate clinical decision making and the development of future guidelines concerning the utilization of BoNT-A in dental practice for M-TMD patients. Additionally, it streamlines the process for decision makers by presenting a consolidated view rather than requiring review of multiple individual SRs.

In the same way that this UR systematically reviews existing outcomes from SRs, it is highly dependent on the quality as well as the data from the SRs that are included for the conclusions. Another strength of this UR is therefore the strict inclusion criteria regarding high methodological quality, and that the criteria were set a priori to the start of the quality assessment. However, this can be seen as a limitation since several SRs were excluded due to methodological considerations (16 out of 34 possibly eligible SRs). Another limitation could be the fact that the included RCTs also display methodological drawbacks, etc.

4.2 Conclusion

The synthesis in this UR provides the highest level of evidence currently available. Taken together, there are indications of effectiveness of BoNT-A for treatment of M-TMDs, supported by moderate evidence. However, considering the risk of causing serious adverse events, treatment with BoNT-A is recommended to be the last treatment alternative.