1. Introduction
Obstructive sleep apnea (OSA) is an increasingly common disorder, affecting approximately 17% of adult women and 34% of men [
1]. The main pathophysiological feature of OSA is repetitive narrowing (hypopnea) or closure (apnea) of the upper airway (UA) during sleep, causing intermittent hypoxia, intrathoracic pressure swings, sympathetic surges, and sleep fragmentation [
2]. Due to these perturbations, OSA is linked to a range of harmful sequelae: excessive daytime sleepiness, fatigue, an impaired cognitive performance, a reduced quality of life, an increased risk of occupational and traffic accidents [
3], metabolic disturbances [
4], hypertension [
5], cardio- and cerebrovascular morbidity, and OSA-related mortality [
6].
Due to the high prevalence, as well as the individual and socioeconomic healthcare issues related to OSA, the effective management of this chronic disorder is imperative. The standard treatment for patients with moderate to severe OSA is continuous positive airway pressure (CPAP), applying pressurized air throughout the respiratory cycle to keep the upper airway patent [
7]. Although CPAP is highly efficacious in reducing the severity of OSA, the clinical effectiveness is often compromised by low patient acceptance and suboptimal adherence [
8].
Oral appliance therapy is increasingly prescribed as a non-invasive treatment option for patients with OSA. Oral appliances are indicated for use in patients with mild to moderate OSA who prefer oral appliance therapy to CPAP, who do not respond to CPAP, are not appropriate candidates for CPAP, or who fail treatment attempts with CPAP [
9].
2. Types of Oral Appliances
Oral appliances can be divided into three main categories, based on their mode of action. First, soft palate lifters aim to reduce vibrations from the soft palate by elevating both the soft palate and uvula. However, there is little evidence regarding their effectiveness [
10,
11]. Second, tongue retaining devices (TRD) use a suction pressure to hold the tongue in a forward position during sleep and thereby prevent the tongue from falling back into the pharyngeal airway [
12,
13]. The third category is the oral appliances advancing the mandible and the attached tongue during the night, known as mandibular advancement devices (MADs), mandibular advancement appliances (MAAs), mandibular repositioning appliances (MRAs), or mandibular advancement splints (MASs) [
12]. The MAD is the most common type of oral appliance therapy used for the treatment of OSA [
14]. The mechanism of action of the MAD is usually assumed to cause the enlargement of the cross-sectional upper airway dimensions by anterior displacement of the mandible and the attached tongue, resulting in improved upper airway patency [
15,
16,
17].
There is a huge variety of commercially available MADs, all with different design features [
18]. MADs can be custom-made or prefabricated thermoplastic devices. Custom-made appliances are fabricated from dental casts of the patient’s dentition and bite registration by the dentist. A lower cost alternative are the thermoplastic or “boil and bite” appliances, that can be fitted without the need for plaster casts or bite registrations. A randomized controlled trial comparing the efficacy of a custom-made appliance with a thermoplastic device provided primary evidence that a custom-made MAD is more efficacious in reducing the OSA severity than a prefabricated MAD [
19]. Therefore, custom-made appliances are recommended over prefabricated devices made out of thermoplastic materials [
19].
Furthermore, the concept of custom-made MADs has evolved from the “monobloc” type of device where upper and lower parts are rigidly connected, towards the current “duobloc” types. The rigid monobloc MADs restricts mandibular movements, which sometimes produces temporomandibular discomfort. The so-called titratable MADs allow for fine-tuning of the mandibular advancement as the upper and lower parts are separate but dynamically interconnected [
20,
21]. Several titratable MADs with different basic advancement mechanism are tested in the literature and are summarized in
Figure 1.
A randomized controlled trial demonstrated that a thermoplastic heat-molded titratable MAD was non-inferior in the short-term to a custom-made acrylic MAD. Therefore, such a thermoplastic titratable MAD can be used as a simple, cheap, and ready to use method to identify patients likely to benefit from long-term MAD therapy [
22].
According to the literature, the amount of protrusion constitutes a key factor in optimizing MAD efficacy, although more protrusion does not always yield better results [
23]. Therefore, the optimal mandibular protrusion for MAD therapy needs to be determined in the individual patient and thereafter adjusted in terms of tolerability versus efficacy [
24]. However, up until now, no proven standard is available on how to determine this optimal MAD protrusion. Most outcome studies on MAD therapy are using a so-called “subjective titration protocol,” relying on both the physical limits of the patient’s mandibular protrusion and the self-reported evolution of symptoms, such as snoring and/or daytime sleepiness [
25,
26,
27,
28]. However, such subjective improvement in symptoms may not provide the most accurate indicator for efficient titration of the MAD: it may result in a suboptimal treatment outcome, since the reduction of the subjective complaints may encourage a premature interruption of the titration [
29,
30]. So, at this stage, MAD titration remains a “trial and error” approach [
31]. In an approach analogous to a CPAP titration night, the mandible can be progressively advanced during sleep, each time respiratory events occur. A so-called “remotely controlled mandibular positioner” (RCMP) has been applied in overnight sleep studies to prospectively determine the optimal mandibular protrusion for MAD treatment in individual patients [
24,
31,
32,
33,
34]. Literature has shown a greater reduction in OSA severity after RCMP titration as compared to conventional titration methods [
32].
Additionally, there is a controversy in the literature regarding the possible role of vertical opening. Each MAD has a given material thickness due to its construction features causing the mandible to be positioned simultaneously in a more caudal direction, resulting in an increase in the inter-incisal distance or so-called vertical dimension [
35,
36,
37,
38,
39].
3. Side Effects
Mild and transient side effects are commonly reported in the initial period of MAD therapy. Short-term side effects include dry mouth, excessive salivation, tooth discomfort, muscle tenderness, temporomandibular joint pain, myofascial pain, and gum irritation [
40,
41]. These symptoms are mostly temporarily, generally resolving within days to weeks with regular use and appropriate adjustment of the device. However, sometimes these symptoms are more severe and continuous, resulting in cessation of the therapy. The major long-term adverse effects are occlusal changes with prolonged MAD use, but these changes have not been reported as being related to treatment withdrawal [
42,
43,
44,
45,
46,
47,
48]. Conversely, skeletal or postural changes were negligible.
5. Patient Selection
Although MAD therapy significantly reduces OSA severity in the majority of patients, around one-third of patients only showed negligible improvement in OSA severity [
57]. Therefore, patient selection and an individually tailored treatment plan is a key issue in MAD therapy and other non-CPAP treatment modalities. In the literature, it is described that MAD therapy is more likely to be successful in younger female patients [
65], with lower body mass index [
83], a smaller neck circumference [
61] and less severe sleep apnea [
26,
65,
84].
Ideally, however, patient selection for MAD therapy should be based on validated prospective elements.
Current predictive approaches for the different OSA therapies rely on the heterogeneity of the disorder and the variability in OSA pathophysiology between patients. Patients with mild upper airway collapsibility and low loop gain, referring to a more stable ventilatory control system, are more likely to benefit from MAD therapy [
85,
86].
Regarding anatomical phenotypes: cephalometric evaluations of morphological variables are inconsistent in predicting treatment success with MAD therapy [
87].
Drug-induced sleep endoscopy (DISE) is a procedure that enables a dynamic evaluation of the localization and pattern of upper airway collapse [
88]. This technique has shown its value in optimizing the selection of patients for surgical interventions of the upper airway [
89]. In addition, it has been suggested as a valuable prognostic indicator of successful MAD therapy in the individual patient [
90,
91]. It is known that MAD treatment response is specifically related to the site, degree, and pattern of upper airway collapse as assessed during DISE. Based on the results of a recent prospective trial, tongue base collapse is a beneficial DISE phenotype and both complete concentric collapse at the level of the palate and complete laterolateral collapse of the oropharynx are adverse DISE phenotypes towards MAD treatment outcome [
92].
Furthermore, during the DISE procedure, a so-called chin-lift maneuver can be performed, whereby the mandible is actively guided forward by grasping it and advancing it to a maximal protruded position. A possible criticism on the chin-lift maneuver is that it is a non-reproducible and, in most non-sedated patients, an unrealistic mandibular protrusion [
93]. The use of a simulation bite in the maximal comfortable protrusion during the DISE procedure is a reproducible method to mimic mandibular protrusion. To make the simulation bite, the patient is asked to protrude the mandible maximally followed by a slow retraction of the mandible until a position is reached that the patient describes as the maximal comfortable protrusive position. This position is then transferred to a registration fork covered. The use of this simulation bite during DISE is found to be effective in predicting the therapeutic outcome of MAD therapy [
93,
94].
Recently, a “remotely controlled mandibular positioner” (RCMP) was applied in overnight polysomnography (PSG) to prospectively determine the optimal mandibular protrusion for MAD treatment in individual patients and to prospectively predict MAD treatment outcome [
24,
32]. By progressively protruding the mandible during a single-night sleep study, the mechanical action of the jaw advancement on the airway of the patient is simulated. It is shown that such a mandibular titration study with RCMP tends to predict therapeutic outcomes with MAD with significant accuracy [
24]. However, this is a time-consuming and labor-intensive procedure, limiting routine clinical use. In order to avoid this, Kastoer et al. [
95] recently showed that the use of an RCMP during a 30-min DISE is feasible and that it allows for the determination of the target mandibular protrusion. Nowadays, a feedback-controlled mandibular positioner identifies respiratory events in real-time was developed for use during a home-based sleep study (the “home-RCMP”) [
96], protruding the mandible according to predetermined algorithms showing promising results.
6. Combination Therapy
In patients with limited mandibular protrusion, the addition of a tongue bulb may provide a better treatment effect, however, convenient appliance designs for this combination approach are needed [
64].
In a retrospective analysis on patients undergoing MAD therapy, it was described that one-third of patients under MAD therapy have a residual positional OSA, defined as having twice as many respiratory events in the supine sleeping position compared to the non-supine sleeping position [
97]. Patients with positional OSA can benefit from positional therapy, aimed at preventing sleep in the supine position. In Cartwright et al. [
98], the efficacy of combining a posture alarm, which gives an auditory beep when in the supine position, and a tongue retaining device (TRD) was described. Patients were assigned to either therapy with the posture alarm, the TRD, or combination therapy with the posture alarm and the TRD. The results of that study suggested that the combination of TRD and positional therapy is better than one of the treatment modalities alone [
98]. In a more recent study by Dieltjens et al. [
99], the efficacy of combination therapy of a chest-worn vibrational alarm with MAD therapy was evaluated. The results indicate that combination therapy of MAD and positional therapy leads to a higher therapeutic efficacy in patients with a residual positional OSA under MAD compared to one of the treatment modalities alone [
99]. These findings suggest that when patients are unsuccessfully treated with MAD treatment, the presence of the positional OSA should be checked and combination therapy could be suggested in eligible patients.
7. Conclusions
Oral appliance therapy is increasingly prescribed as a non-invasive treatment option for patients diagnosed with OSA. The recommended type of oral appliance is the custom-made, titratable mandibular advancement device allowing for gradual mandibular protrusion. Recent studies have shown comparable health outcomes with CPAP and MAD treatment, despite greater efficacy of CPAP in reducing OSA severity. This likely reflects greater nightly adherence to MAD compared to CPAP therapy. In unselected OSA patients, MAD therapy reduces OSA severity in the majority of these patients leaving about one-third with a negligible improvement. Therefore, the selection of appropriate candidates for MAD therapy is an ongoing item in order to increase the overall efficacy of the therapy. So far, several prediction tools have been proposed but currently, there is no validated method that can achieve a prospective up-front selection of the ideal candidate for MAD therapy in an accurate and reliable way.