Introduction

Botulinum toxin type A (BoNT-A) has been widely used to control several motor disorders due to local, long-lasting, and also reversible paralytic effects [1, 2]. In the beginning, when BoNT-A was used to control muscle hyperactivity, an analgesic effect preceding muscle paralysis was observed and attributed to its neuromuscular effect [3, 4]. Currently, different studies have shown a direct analgesic effect [5,6,7] independent from muscle relaxation; for this reason, the drug gained new indications in the pain-control field, including the orofacial and neck area [8,9,10].

Consequently, BoNT-A has been progressively introduced as a treatment option to control pain associated to many conditions [2] such as spasticity, temporomandibular disorders (TMD), movement disorders, and bruxism [4, 11]. Several studies [8, 12,13,14,15] also reported positive effects of BoNT-A injections for trigeminal neuralgia (TN) [16], which can already be considered as a level-A treatment according to the Therapeutics and Assessment Subcommittee of the American Academy of Neurology [17, 18]; in addition, a recent systematic review showed moderate evidence for BoNT-A therapeutic effects for myofascial pain which encourage clinicians to use it [19].

BoNT-A treatment is considered generally safe, since doses used for the mentioned conditions are distant from the lethal doses [20]. However, some minor (e.g., edema and infection due to the puncture at BoNT-A injection time) [21, 22] and mild adverse effects (e.g., not desired muscle paralysis, muscle weakness, and swallowing and chewing difficulties) have been reported [21, 23]. Experimental studies have also described severe side effects after BoNT-A injections such as changes in muscle fiber size and composition, replacement of contractile tissue for fat, and even loss of bone volume and density [22, 24]. In addition, bone changes were reported in patients receiving repeated injections of high doses of BoNT-A [25, 26].

Despite all existing evidence about BoNT-A use [19, 27], there are few studies summarizing its adverse effects on the orofacial area. Thus, based on these premises and considering the rapid increase in the use of the neurotoxin, the present manuscript aims to systematically review the findings from all studies assessing BoNT-A safety and the report of the possible adverse effects.

Materials and methods

The present systematic review methodology was approved and registered (protocol- CRD42017079250) in the International Prospective Register of Systematic Reviews (PROSPERO).

Search strategy

A systematic search was conducted to identify articles assessing the adverse effects produced by BoNT-A applications, as well as the efficacy of this treatment for myofascial pain in the orofacial and for trigeminal neuralgia. PubMed, EMBASE, Web of Science, and Scopus databases were explored using the Medical Subject Headings (MeSH) and related terms which were divided into two groups as follows: for masticatory myofascial pain (myofascial pain) OR (temporomandibular joint disorders) OR (TMD) AND (“botulinum toxin”) OR (botox) OR (dysport) OR (myobloc) OR (onabotulinumtoxina) AND (adverse effects) OR (safety) OR (tolerability). For trigeminal neuralgia (trigeminal neuralgia) OR (neuropathic pain) AND (“botulinum toxin”) OR (botox) OR (dysport) OR (myobloc) OR (onabotulinumtoxina) AND (adverse effects) OR (safety) OR (tolerability).

On phase 1, citations were first screened by titles and abstracts (TiAb screening) by two independent researchers (G.D.C and R.L.P). On phase 2, potential articles were then obtained in full text and carefully read to screen for those whose purposes were not in accordance with the aim of the present review. Any disagreement between the reviewers was solved by a third researcher (V.R.M.L).The eligibility of the studies was based on the following criteria:

  1. 1.

    Participants must be over 18 years old;

  2. 2.

    Clinical trials that investigated the effects of BoNT-A among participants with myofascial pain in masticatory muscles or TN were considered eligible for this systematic review independently if they present a control or a comparison group;

  3. 3.

    For masticatory myofascial pain, diagnostic criteria should be based on the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) or on the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD);

  4. 4.

    For TN, diagnostic criteria should be based on the “International Classification of Headache Disorders (ICHD), 3rd edition (beta version).”

    No publication time and language restrictions were applied.

Data collection and assessment of papers

Data for each study were extracted and analyzed according to a PICO-like structured reading, which comprises the population/problem (P), intervention (I), comparison group (C), and outcomes (O) of each study (Table 1). The following question was adopted to conduct data collection: “Are botulinum toxin injections (I) tolerable and safe for the treatment (O) of patients with masticatory myofascial pain and/or with trigeminal neuralgia (P), when compared to other treatments (C)?”

Table 1 Characteristics of the included studies based on PICO-like structured reading
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Quality assessment for the included randomized clinical trials was based on the “Cochrane Handbook of Systematic Reviews of Interventions” and for the included cohort studies, it was based on the Critical Appraisal Skills Programme (CASP).

Results

Literature search outflow

The search strategy provided 436 citations, of which 158 were overlaps. Thus, 278 citations were evaluated for eligibility (Fig. 1). Based on the reported criteria, 59 papers were read in full text and, after consensus, 16 citations were included in this systematic review (eight randomized controlled clinical studies (RCTs) and eight cohort studies) (Table 1).

Fig. 1
figure 1

Flowchart of the search strategy for the identification of articles

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Included studies

Among the 16 included studies, seven treated patients diagnosed with TMD (five RCTs and two Cohorts) and nine treated patients diagnosed with TN (three RCTs and six cohorts). Quality assessment for the RCTs by Cochrane Collaboration’s risk of bias tool and the quality assessment for the cohort studies by CASP are shown in Tables 2 and 3, respectively.

Table 2 Quality assessment of RCTs based on the Cochrane Handbook of Systematic Reviews of Interventions
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Table 3 CASP quality assessment of the reviewed cohort studies
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TMD studies

Regarding the seven TMD studies (Table 1), 246 patients (age range from 20 to 71 years) with masticatory myofascial pain were assessed. The total number of participants in each study varied from 10 [28] to 116 [29] with a prevalence of females. Follow-ups fluctuated from 28 days [30] to 6 months [31], and dosage of BoNT-A injection in the masseter and temporalis muscles ranged from 10 to 150 U. Only Abboud et al. [32] used 30 to 180 U of BoNT-A into one to six painful muscles (masseter, anterior temporalis, sternocleidomastoid, and posterior digastric muscles). In four studies [28, 30, 31, 33], the control group received 0.9% NaCl injections. One study [34] compared BoNT-A injection with fascial manipulation and only one study [29] reported no comparison group.

In all studies, the treatment was well tolerated, and BoNT-A injections improved pain and maximum mouth opening. The most common adverse effects were temporary regional weakness, tenderness over the injection sites, and minor discomfort during chewing [30, 32,33,34]. In addition, three studies reported asymmetric smile [28, 30, 32], and just one study [29] reported mild to severe adverse effects such as reduction in the size of the masticatory muscle (especially, masseter muscles), paraesthesia, eye drooping or muscle weakness, difficulty swallowing, speech changes, perioral swelling, and bruising. Regarding quality assessment, most of the RCTs were classified as “poor quality,” while only one study was classified as “good quality". Cohort studies varied in quality scores from 2 to 4 (Tables 2 and 3).

TN studies

As for TN (Table 1), 359 patients (age range from 28 to 85 years) were assessed with prevalence of females. The total number of participants in each study varied from 13 [35] to 100 [36]. Follow-ups fluctuated from 60 days [35] to 6 months [14, 37], and dosage of BoNT-A injection ranged from 15 U [38] to 200 U [39]. The site of the injection was intradermal, submucosal, and varied according to the patient trigger zone, except for one study in which BoNT-A injections were applied into the maxillary and mandibular nerves [37]. In three studies, the control group received 0.9% NaCl [40,41,42], four studies presented no comparison group [14, 35, 37, 38], one study compared different doses of BoNT-A [36], and another one compared the effect of BoNT-A among patients of different ages [39].

In all studies, BoNT-A injections significantly reduced pain intensity, pain attack frequency, and the number of acute medications. Two studies reported patients without side effects after treatment [35, 37]. BoNT-A was generally well tolerated, and no serious adverse effects were reported [38]. The most common adverse effects were a short-term facial weakness on the injection side [37], short-term facial asymmetry, transient edema, itching, and pain at the injection area [35, 36, 40, 41] (2014). One study reported transient paralysis of the buccal branch of the facial nerve (Bohluli et al., 2011), and one study reported transient whole-body discomfort, mild left eye ptosis, and slight oral deviation (Liu et al., 2018). Most studies showed a spontaneous resolution of adverse effects. Regarding the quality assessment, the RCTs were classified as “poor quality” to “fair quality,” and the cohort studies varied in quality scores from 1 to 9.5 (Tables 2 and 3).

Discussion

Results of the present systematic review showed that among the 16 included studies, only minor adverse effects are the most frequent after BoNT-A injections (edema, itching, and pain at the injection site). Mild adverse effects such as regional muscle weakness, short-term facial asymmetry, difficulty swallowing, speech changes, asymmetric smile, and slight oral deviation were found in less proportion, and only two studies reported severe side effects such as transient paraesthesia of the buccal branch of the facial nerve [14] and reduction in the size of the masticatory muscles [29]. Most studies reported a spontaneous resolution of minor and mild adverse effects and concluded that BoNT-A treatment is well tolerated. Notwithstanding, it is important to highlight that the majority of the selected studies did not aim to assess BoNT-A adverse effects, limiting data to self-reported adverse effects that should be carefully interpreted.

Botulinum toxin injection is an off-label therapy in dentistry. The lack of well-designed studies due to the absence of validated clinical protocols and the standardization of dosage and dilution between commercial brands contribute to increase the controversy around this treatment [43]. For these reasons, a diversity of treatment protocols was found in the included studies, with doses varying between 10 and 150 U for masticatory myofascial pain and 15 and 200 U for TN, a fact that certainly could influence the development of adverse effects. The neuromuscular effect of BoNT-A is dose- and muscle-size dependent [4], which means that bulkier muscles require higher doses to achieve a satisfactory therapeutic effect, a fact that turns even more difficult to establish protocols since there is a variety of muscles size. This pattern was also found in the included studies between the masseter and temporalis muscle, inasmuch as masseter muscles are bulkier than temporalis and require more units of BoNT-A to achieve an adequate clinical effect. Notwithstanding, none of the included studies assessed muscles size in order to propose a doses protocol.

Since BoNT-A is used in different doses, it is logical to hypothesize that higher doses and even repeated injections of this treatment could be determinant factors to develop adverse effects on muscular tissue. Muscle weakness, which is an undesired effect when BoNT-A is injected for analgesic reasons, was the most reported adverse effect. Even though this issue is spontaneously resolved in the first 3 months of treatment, none of the studies evaluated this variable objectively. In addition, muscle weakness can lead to a series of other effects such as the reduction of occlusal and bite force for a period of 12 to 18 weeks [26, 42, 44] and the decline in masticatory performance [45]. These findings can be explained by the duration of BoNT-A into muscles. The toxin reaches its maximum muscle effect between day 14 and 21 after injection, and it is sustained for about 90 days before it gradually diminishes [4]. This means that the effects of a single application of BoNT-A in muscle function seems to be transient. On the other hand, a reduction in the size of the masticatory muscles after two applications of BoNT-A was reported in Khawaja et al. [29] and Lee et al. [26], who also reported a significant decrease in masseter muscle thickness and cross-sectional areas after 6 months of BoNT-A treatment with high doses. For both studies, no data about muscle recovery was reported. Taken together, this data could confirm that higher doses or repeated applications of this treatment could lead to possible structural changes in muscle fibers. From a physiological point of view, the inhibition of the exocytose of acetylcholine toward motor endplate by BoNT-A causes a direct paralytic effect on muscles, a fact that could provoke atrophy and a reduction in muscle size. Experimental studies have demonstrated that muscle atrophy after BoNT-A injections is due to the decrease of fibers size [46], replacement of contractile tissue for fat [47], changes in muscle-fiber composition (i.e. from IIa to IIb fibers type) [46] and also by influencing the mRNA content of myosin of the treated muscles [48]. Unfortunately, due to the lack of clinical trials assessing repeated injections or higher doses of BoNT-A, the doubt if repeated injections could extend the mentioned adverse effects for a longer period of time remains.

It is well known that muscle size and muscular force, diminished by BoNT-A injections, are necessary factors to promote an appropriated muscle contraction and stimulate the apposition and resorption bone process [49]. Therefore, it would not be erroneous to cogitate that BoNT-A could have at least an indirect effect on bone tissue, due to the lack of stimulus coming from altered muscle function. None of the included studies reported or aimed to assess BoNT-A effects on bone tissue. Notwithstanding, experimental studies have reported less trabecular bone, high incidence of bony defects filled with active fibrocartilaginous tissue, higher bone porosity, bone loss in the alveolar region, trabecular bone loss in the condyle, and a decrease in bone volume after 1 to 3 months of BoNT-A injections [22, 24, 50].

Furthermore, some clinical studies that were not included in the present systematic review due to a lack of use of standardized diagnostic tools (RDC/TMD, DC/TMD, and ICHD beta version) have demonstrated a decrease in bone density of the mandibular condyle after multiple injections of BoNT-A [25] and a significant reduction in mandibular volume angle area after a second BoNT-A injection [26]. Based on these findings, it could be hypothesized that BoNT-A could have a direct toxicity effect on skeletal cells, or that the general inhibition of neurotransmitters release could affect another local signaling in the bone and cartilage [50]. However, it is also possible that these effects are merely consequences of modifying bone loading.

Clinically, BoNT-A therapeutic injections are usually given at intervals of 3 to 6 months, Severe side effects reported in this systematic review came mainly from studies performing one (experimental studies) or multiples (clinical studies) injection sessions of BoNT-A; based on that, it can be assume that patients treated with this drug could develop side effects in muscle and bone tissues. Therefore, it is important to analyze BoNT-A effectiveness for the conditions reported in this review. Even though BoNT-A reduced pain in almost all included studies, it was not superior when compared with placebo or other treatments, mainly due to the lack of standardized therapeutic protocols (doses and injection sessions) which are important for achieving an adequate effectiveness on any drug. It is important to consider the lack of evidence about BoNT-A effectiveness and the development of side effects before using this treatment.

To our knowledge, this may be the first systematic review dedicated to BoNT-A toxin adverse effects. The main purpose of any systematic review is to connect data from high-quality studies, synthesizing knowledge about a specific topic. The present review explored different databases to gather literature regarding BoNT-A adverse effects within an adequate search strategy and a strict criterion for the inclusion of papers. However, mainly due to the small sample size and an inadequate study design, the overall quality of the evidence was considered “poor,” owing to the risk of bias. Also, most of the studies included in this review did not assess objectively BoNT-A adverse effects, limiting to describe minor self-reported adverse effects (edema, itching, and pain at the injection site) that might be caused by the needle and/or clinician’s skills and not by the BoNT-A itself. As a final remark, we strongly recommend assessing the ratio between BoNT-A effectiveness and the possible development of adverse effects (mainly from multiple applications) before clinically using BoNT-A in the orofacial region.

Conclusion

Within the limitations of this review, it can be concluded that even though none of the included studies aimed to assess objectively BoNT-A adverse effects, this treatment in general was reported as well tolerated, since self-reported minor adverse effects with a spontaneous resolution were the most prevalent. Notwithstanding, it is recommended that future studies assess BoNT-A adverse effects mainly produced from multiple or high-dose applications, as well as the ratio between the effectiveness and the probability of developing adverse effects when this substance is the treatment choice.