Efficacy of botulinum toxin type a in the targeted treatment of sleep bruxism: a double-blind, randomised, placebo-controlled, cross-over study

Introduction

Bruxism is a repetitive masticatory muscle activity characterised by clenching or grinding of the teeth and/or bracing or repetitive thrusting of the mandible, occurring while awake, asleep (sleep bruxism, SB) or both.1–3 Bruxism can cause morbidity in the form of abnormal tooth wear, grinding noises and jaw or more widespread craniocervical discomfort and pain.1 4 Bruxism common, however, prevalence has been difficult to establish, at least in part due to the variable nature of the condition within affected individuals and the inherent difficulty in defining ‘abnormal’ function from normal physiological function.5 6 In the largest epidemiological study to date, prevalence in the general population was 5.5%–7.4% depending on criterion used.6 The aetiology and pathophysiology of bruxism is not fully understood but it is likely to be multifactorial, with contributing factors varying among affected individuals. Both peripheral and central neurological contributions have been reported in otherwise well individuals, including alterations in dopaminergic pathways, sleep arousal and psychological factors.4 7–9 Bruxism can also occur in association with particular neurological disorders (eg, craniocervical dystonia, Huntington’s disease, cerebellar disease,1 2 graft-versus-host disease10) and secondary to centrally acting medications (eg, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, barbiturates, phenethylamines and some opiates.11

Despite the prevalence and morbidity associated with bruxism, effective treatment options are lacking. Current treatment modalities include dental occlusal splints,12–14psychobehavioural therapies12 14 and systemic pharmacological therapies (eg, benzodiazepines and dopaminergic therapies),12 all of which have demonstrated limited efficacy. More recently, targeted botulinum toxin A (BTX-A) has emerged as a potential therapy, with most but not all studies demonstrating benefit, including three small placebo-controlled trials.2 15–18 Despite its subsequent off-label use for this indication in several regions, current evidence does not adequately guide the use of BTX-A for the treatment of SB, in particular, the most effective and safe dose and pattern of BTX-A injection has not been evaluated. Evidence, to date, has been particularly limited by small sample sizes, significant variability in doses, injection paradigms and outcome measures between studies.

As such, the primary aim of this double-blind, randomised, placebo-controlled, cross-over study was to evaluate the efficacy and safety of targeted injections of BTX-A in participants with bruxism. We further investigated the optimal treatment strategy and doses, duration of benefit, and factors associated with benefit following BTX-A injection.

Methods

Results

Thirty-five participants were recruited to take part in the study, however, 13 were excluded after commencement due to inability to complete the study or dataset collection (figure 1). Of the remaining 22 participants, 14 were female and 8 male. Participants ranged from 22 to 68 years old (mean 42.1 years). Six participants were randomised to group A, seven to group B and nine to group C (table 1). Coexistent headache disorders were common at the time of enrolment, with 18/22 participants having coexistent headache; 14 participants having episodic tension-type headache, four episodic migraine without aura and five episodic migraine with aura (7 participants had more than one headache type). The majority (18/22) of the participants included for analysis had trialled occlusive splints for symptom control.

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Mean baseline BI for all participants was 8.29 (SD=2.88) (table 1) and there was no evidence of differences in baseline BI between the three treatment groups (F (2, 21)=1.59, p=0.25).

Active versus placebo intervention

A two-way repeated measures ANOVA demonstrated a significantly different BI during the treatment phase, compared with the placebo phase (F (1, 21)=8.09, p=0.01). Further post hoc analysis showed that during the treatment phase, BI was significantly lower at 4 weeks postinjection when compared with placebo (mean difference=−1.66, p=0.003), but this difference was not sustained at 12 weeks (p=0.58) (table 2, figure 2).

Table 2

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Bruxism Index across time points

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Figure 2

Change in Bruxism Index from baseline following botulinum toxin injection.

Analysis across intervention groups

Secondary analysis demonstrated that Group C experienced the largest reduction in BI at 4 weeks post injection of BTX compared with placebo (see figure 3). Participants in this group experienced a mean reduction of 2.15 in BI (p=0.009). Groups A and B did not demonstrate a significant difference by the same measure (group A: p=0.287; group B: p=0.073), nor did we find evidence of difference among the treatment groups (F(2, 21)=2.11, p=0.15), and there were no differences in BI between active and placebo at the 12-week mark for any group.

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Figure 3

Mean bruxism index by injection group.

Comparison of intervention groups

Secondary analysis (ANCOVA) demonstrated that group C experienced the largest reduction in BI at 4 weeks postinjection of BTX compared with placebo (figure 3). Participants in this group experienced a mean reduction of 2.15 in BI (p=0.009). The decrease observed in groups A and B was relatively smaller and did not reach the level of statistical evidence (group A: p=0 .287; group B: p=0.073). Further, we did not find evidence of difference in the BI change among the treatment groups (F(2, 21)=2.11, p=0.15), and there were no differences in BI between the active treatment groups and placebo at the 12-week mark for any group.

Further analysis demonstrated that participants who had a higher BI at baseline experienced a greater effect of BTX-A compared with placebo after 4 weeks compared with participants with a lower baseline BI (F(1, 21)=7.76, p=0.012); (figure 4).

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Figure 4

Baseline Bruxism Index and change in Bruxism Index at 4 weeks compared with placebo.

There were no significant differences in the results of any subjective scales between the active and placebo phases at weeks four and 12 following injection, regardless of the dose of BTX-A injected (table 3).

Table 3

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Mean subjective rating across time points

Discussion

This study provides class II evidence for the efficacy and safety of targeted BTX-A injection in the treatment of SB, as measured objectively by sEMG. Comparison of different BTX-A doses and intramuscular injection paradigms demonstrates that bilateral masseter only (30U), masseter (30U)/temporalis (15U) and masseter (30U)/temporalis (15U)/medial pterygoid(15U) treatment regimens are comparable in terms of safety, and while our study was not powered to fully uncover between-group differences, there was a greater magnitude of effect among participants randomised to the injection paradigm with higher total dose and number muscles injected (ie, group C). The treatment was safe, with bruising over the masseter in one participant and only 5 out of the 35 participants experiencing mild short-lived focal weakness following injection with BTX-A.

While there was a reduction in BI following BTX-A injection at week 4, this did not persist at week 12, regardless of the dose of BTX-A or muscles injected. This wearing off of BTX-A effect is consistent with the biological effects of BTX-A, with gradual recovery of motor function usually 3–4 months after injection.27

In our cohort, the duration of effect of BTX-A was not significantly different despite an overall doubling of the dose and expansion of muscles injected between group A (60U total) and C (120U total). Between-group differences may have been uncovered with a larger sample size and longer follow-up period after repeated injections. The magnitude and duration of muscle weakness induced following BTX-A increases with repeated injection,28 and thus the degree and duration of effect of BTX-A on SB may increase with subsequent injections even with stable dosing. It is possible, however, that the beneficial effect of BTX-A on SB is not dose-dependent. By inducing a degree of masticatory muscle weakness, subsequent behavioural changes on affected individuals, exhibited by reduced clenching and grinding, may be independent of the degree of muscle weakness. Indeed, in measuring BI we are not measuring the strength of masticatory muscles, but rather the frequency and pattern of masticatory muscle activation.

We explored baseline participant characteristics associated with an objective response to BTX-A injections. The greater the baseline BI, the greater the objective change in BI following BTX-A injection at week 4, regardless of the dose injected (figure 3). This is an important and novel finding, and supports the use of objective measurements of bruxism severity in predicting benefit from BTX-A injection. Further still, participants with a higher baseline BI did not otherwise differ from the remainder of the group clinically or in baseline subjective measurements. In the absence of overnight EMG and BI determination, these more severely affected individuals would remain undifferentiated in clinical practice.

In considering how these findings compare with the effects of alternative treatments for SB, the most widely used and studied treatment for SB is oral splint devices. Objective benefit of splints on SB as measured by sEMG is limited to the immediate short-term (ie, the first nights of continuous use) but do not persist at weeks 2 onwards.13 29 It is widely understood that these devices will reduce dental destruction due to bruxism but not change the overall bruxing activity for sustained periods, and therefore, not reduce pain or headache associated with bruxism. Our study population reflects this; the majority (82.8%) of participants included in our analysis had previously or currently used dental splints.

We demonstrated a discrepancy between bruxism severity (measured by BI) and bruxism frequency (measured by questionnaires), with no subjective improvement reported at 4 and 12 weeks after injection. This is consistent with a prior study that demonstrated no significant change in the quantifiable portion of the Montreal Bruxism Questionnaire following BTX-A injection when compared with placebo, despite benefit measured by polysomnographic measures of bruxism and other subjective scales (a Clinical Global Impression and VAS of pain and bruxism overall).16 An explanation can be found in the nature of the bruxism symptom questionnaire, which asks the participant to indicate how often in the last month they think they bruxed at night, how often their sleeping partner thinks they bruxed at night and how often they woke with jaw stiffness, graded from zero (never) to five (every day). Specifically, although this clearly captures frequency of symptoms, the severity or morbidity of these symptoms is not reflected. Clinical evaluation and any future research evaluating BTX-A in the treatment of SB should therefore consider this observation when selecting appropriate outcome measures.

Similarly, we did not observe evidence for change in pain outcomes as measured by the SFM pain questionnaire (including sensory and affective subscores) or the VAS for pain. This was an unexpected finding and at odds with participants’ overall experience at the end of the study, with 24 (77%) requesting ongoing injection due to a perceived improvement in pain. Overall, changes to pain levels following BTX-A in SB have been conflictingly reported using SFM and VAS in other studies. For example, two studies using the VAS demonstrated change in jaw pain at week 4,16 30 while a separate study failed to find changes at this time point, instead finding a change at 6 months postinjection.17 Day-time sleepiness and headache-related disability following injection, as measured by the ESS and HIT score respectively, were not influenced by BTX-A injection at any dose evaluated in our study, replicating the observations of a prior placebo-controlled study.16 Taken overall, our findings suggest that current subjective outcome measures are less sensitive than objective measures for the purpose of evaluating treatment effect in SB. It is also possible that a longer period of bruxism treatment with BTX-A (for example with repeated injection) is required for bruxism-associated myofascial pain to improve with treatment; for example when Botox injections are used for prevention of chronic migraine, peak effect occurs after at least a second set of injections31 32 The best subjective outcome measures of SB and those most sensitive to change following intervention have not been established and need ongoing consideration in publications in the field.

The majority of participants had coexistent headache disorder, with 82% suffering either tension-type headache or migraine, and 32% having multiple types of headache. This exceeds the background estimated prevalence of these disorders.33 There are several potential contributors for this: there is an increased incidence of tension-type headache and migraine among those with SB.34 Referral bias is also possible, with those with concurrent headaches having greater disability and be more likely referred to a neurology centre for treatment. Importantly, however, the relatively high prevalence of headache disorders in our cohort may have reduced the sensitivity of our subjective outcome measures in detecting changes to bruxism frequency or severity, and thus contribute to the disparity between our objective and subjective measures of bruxism or bruxism related pain after active treatment.

Our study has several limitations. The small sample size may limit generalisability of these results, particularly in comparing individual treatment groups. On the other hand, this trial was sufficiently powered to unequivocally demonstrate efficacy of BTX-A for the treatment of bruxism. Concurrent EEG channel recordings would have confirmed that the recorded sEMG activity was truly occurring during sleep, however, the practicalities of such a system were beyond the scope of participants’ use at home. We feel that this has not significantly impacted study findings, as wakeful EMG activity can be distinguished from involuntary activity in sleep, and would be expected to occur equally at all time points in all participants. Due to randomisation and a cross-over design, we expect this potential noise to affect both intervention and placebo, and therefore, does not represent a bias. Finally, the techniques used in this study are accessible for more widespread use (as opposed to EEG monitoring), making these findings more applicable for clinical practice.

In conclusion, targeted BTX-A injection is safe and effective in the treatment for bruxism, as measured objectively by the BI. Those with more severe bruxism may derive a greater benefit from BTX-A injection and the use of overnight EMG recordings may assist in predicting a response following BTX-A. While a greater benefit may be achieved by administering BTX-A into a greater number of muscles (and therefore, at higher total doses), larger studies which include objective evaluation following repeated BTX-A injections are required to establish the optimal dosing of BTX-A in the treatment of SB.