Oral Appliances 221 reducing the number of obstructive breathing events and arousals, and improving arterial oxygen saturation, particularly in the mild-to-moderate OSA range. The overall success rate is dependent on the definition used, with almost 70% of patients achieving a greater than 50% reduction in the apnea–hypopnea index (AHI) (19), and up to 50% achieving an AHI < 5/hour (12,13,21). Given that the aim of treatment is to resolve OSA, it is important that the more stringent definition of treatment out- come be used. With regards to oxygen saturation parameters, studies have identified improvements in the minimum oxygen saturation, but rarely to normal levels. This is not surprising as, unlike CPAP, oral appliances do no inflate the lungs. With regards to sleep architecture and arousals, the data are less consistent, with only some studies reporting an increase in rapid eye movement sleep and reductions in the arousal index (12,13,21). Less is known regarding the efficacy of TRD. Modest reductions in AHI (22), and improvements in minimum oxygen saturation and oxygen desaturation index (23) have been reported. Limited data suggest that supine-dependent OSA and absence of obesity are associated with a more favorable outcome (22). Hypersomnolence Whilst there has been a consistent observation across studies that subjective day- time sleepiness improves with oral appliances, randomized controlled trials using inactive control devices suggest that at least part of this improvement could be a placebo effect (12,13), similar to that identified with sham CPAP and oral tablet pla- cebo (24,25). With regards to objective sleepiness there are indications of a small improvement, although more work is required in this area. In one study, the mean sleep latency on the multiple sleep latency test after four weeks of MAS treatment was significantly improved compared with an inactive control oral device, but the mean increase was relatively small (1.2 minutes) (13). Two studies compared oral appliances to CPAP over 8 to 12 weeks, using the maintenance of wakefulness test, and found no significant difference (26,27). Neuropsychological The few studies that have examined neurocognitive outcomes suggest an improve- ment with oral appliances. Comparisons have been made to inactive oral device, CPAP, and tablet placebo. An enhancement in psychomotor speed has been reported after one month of active treatment (28). The two studies comparing oral appliance to CPAP are somewhat conflicting, with one indicating no difference between treat- ments across a range of domains (27), and the other suggesting differential effects (26). The latter study found that oral appliance improved tension-anxiety, divided attention, and executive functioning, but CPAP was superior in improving psycho- motor speed and other aspects of mood state (26). Notably, this study included a placebo arm (tablet) and found a significant placebo effect for many of the neuro- cognitive measures. Cardiovascular Given the strong association between OSA and cardiovascular morbidity and mor- tality, it is important to know whether oral appliance treatment has a similar beneficial cardiovascular effect compared with CPAP. To date, the only cardiovascular out- come to be assessed is blood pressure, and two randomized placebo-controlled 222 Cistulli and Darendeliler studies, using intention-to-treat analyses, have reported a modest reduction in 24-hour blood pressure (2–4 mmHg) with oral appliance treatment over period of one month (29) and three months (26). One study compared an oral appliance to CPAP, and found a small reduction in nocturnal diastolic blood pressure with oral appliance only (26). More recently, an uncontrolled study involving 161 subjects reported reductions in office blood pressure, with the change being significantly correlated to baseline blood pressure (30). These early studies suggest a beneficial effect of oral appliances, and additional work is required to further examine blood pressure and other cardiovascular outcomes. Quality-of-Life Quality-of-life is an important health outcome, and has been demonstrated to improve with CPAP treatment. The effect of oral appliance therapy remains unclear from the existing limited literature. A study published in 2004 found that three months of oral appliance treatment improved the quality-of-life as measured by the Functional Outcomes of Sleep Questionnaire mean score and Short Form 36 (SF-36) overall health score compared to placebo tablet, with a similar effect to CPAP (26). In contrast, Engleman et al. (27) reported that CPAP was superior to oral appliance treatment in improving well-being more than three months, as assessed by the SF-36 scores for health transition and mental component (27). A long-term study evaluated quality-of-life in a randomized one-year follow-up of oral appliance treat- ment or uvulopalatopharyngoplasty (UPPP), and found that vitality, contentment, and sleep scores improved significantly in both groups, but the surgical group dem- onstrated significantly greater contentment than the oral appliance group (31). Placebo-controlled studies are needed to examine the long-term impact of oral appliance treatment on quality-of-life. Snoring Oral appliances, unlike CPAP, have an important role in the management of habitual snoring, regardless of the presence of OSA. The majority of patients report improve- ment, largely based on partner reports (32). From an objective point of view, snoring frequency and intensity have been shown to reduce substantially (40–60% for snoring frequency and 3 decibels for mean intensity) compared to an inactive oral control device (12,13). Comparison with Other Treatments There are seven published randomized controlled trials comparing oral appliances to CPAP, and these have been the subject of published systematic reviews (33,34). It is important to note that there is significant variability amongst these studies in terms of the type of oral appliance used, the measurement techniques used for assessing treatment response (e.g., home monitoring versus in-laboratory monitoring), inclusion criteria (including severity of OSA), definitions of severity and treatment response, treatment interval, and drop-out rates, making it difficult to draw firm clinical recommendations. What is clear, is that CPAP is superior at reducing the AHI and improving oxygen saturation, but not arousal index, sleep architecture, or objective sleepiness (33,34). However, patient preference in most of the studies was in favor of oral appliance treatment. In terms of symptomatic outcomes, particularly daytime sleepiness (subjective and objective) but also neuropsychological measures, Oral Appliances 223 no substantial differences have been identified between CPAP and oral appliance treatments (33,34). When one considers the recent studies showing a similar reduction in blood pressure with oral appliance as that seen with CPAP, it raises the important possibility that the health effects of both treatments are of similar magnitude, as a result of the superior efficacy of CPAP being offset by its inferior adherence relative to oral appliances. This is an area that merits considerable attention, as it has major implications for clinical practice. To date, there has only been one randomized study comparing oral appliance therapy to a surgical procedure (UPPP) in patients with mild-to-moderate OSA, over a four-year period (31). They found that both short- (one-year) and long-term (four-year) outcomes were better with oral appliance treatment (31). Adherence It is clear from the CPAP literature that treatment adherence in OSA patients is often not optimal. In the case of CPAP, this is partly attributable to the obtrusive nature of the treatment. Little work has been carried out to evaluate adherence to oral appliance treatment. A key problem is that there is currently no routinely available procedure for measuring objective use, which may differ considerably from partner or self-reported usage. A number of studies suggest that patients use their oral appliance on most nights and for the majority of the sleeping period, at least in the short-term (12,13,35). The only report in the literature in which objective adherence was measured used a novel intraoral monitoring device: patients used the appliance on an average of 6.8 hours per night (ranging between 5.6 and 7.5 hours) (36), which is similar to the findings of studies that used subjective measures. In the intermediate term (one year) the median use is approximately 77% of nights (19). Long-term adherence, up to five years, also seems to be acceptable amongst selected patients (37). Reasons for stopping treatment include the development of side effects, appliance wear and tear, and attenuation of the efficacy of treatment over time (37). It is likely that adherence is influenced by many factors, including appliance attributes, patient characteristics, and the quality of dental treatment and follow-up procedures. Studies are required to define the relative importance of these and other factors, so that appropriate clinical recommendations aimed at optimizing adherence can be developed. In the only comparison of MAS and TRD treatment adherence to date, Barthlen et al. (38) reported that adherence was superior with MAS (100% vs. 62%). PREDICTION OF TREATMENT OUTCOME Despite active research, a key unresolved issue limiting the role of oral appliances for the treatment of OSA is the inability to reliably predict treatment response. A number of studies have examined the influence of polysomnographic and anthro- pomorphic factors on oral appliance treatment outcome. In general, it is considered that a good response is more likely in mild-to-moderate OSA, although benefit in severe OSA has been reported (12,13). Cephalometric variables such as a shorter soft palate, longer maxilla, decreased distance between mandibular plane and hyoid bone, alone or in combination with other anthropomorphic and polysomnographic variables, are thought to provide some predictive power (12,39). Clinical features reported to be associated with a better outcome include younger age, lower body mass index, supine-dependent OSA (40), smaller oropharynx, smaller overjet, shorter soft palate, and smaller neck circumference (41). Whilst there is a suggestion 224 Cistulli and Darendeliler that there is a “dose-dependent” response to mandibular advancement, namely that greater advancement is associated with greater reductions in sleep-disordered breathing (15), this has not been a consistent finding across studies. Importantly, worsening of OSA with oral appliance has been noted, and hence mandibular advancement per se will not always be of benefit. Physiological studies indicate that retroglossal, rather than velopharyngeal, collapse during sleep is highly predictive of success (42). Upper airway imaging during wakefulness may aid in predicting treatment response. One study using MRI examined the airway response to the Müller maneuver, with and without man- dibular advancement, and found that the persistence of collapse during mandibular advancement was predictive of treatment failure (7). Our own ongoing work with MRI indicates that while baseline airway and soft tissue anatomical characteristics do not differ between responders and nonresponders, the changes consequent to mandibular advancement do differ such that increases in airway volume are rea- sonably predictive of a favorable outcome (43). Whilst such studies are helpful in understanding fundamental mechanisms, the clinical utility of such approaches is limited and further work is required to develop simpler techniques for predicting outcome. A relatively novel approach to the problem has been the development of single-night titration procedures using hydraulic or electronic means of incremen- tally advancing the mandible during sleep to determine treatment responsiveness and the required dose of advancement. Two studies have demonstrated that such an approach is feasible, and that treatment outcome can be predicted with a reasonable degree of accuracy (44,45). Further work to translate these findings into clinical practice is warranted. ADVERSE EFFECTS All oral appliances, regardless of design, have potential short- and long-term side effects. Most MAS are modified or similar to orthopedic appliances used routinely in the treatment of mandibular deficiencies for growth modification. Dental and bony changes associated with the use of orthopedic appliances in growing patients are well-documented, and are a desirable effect of treatment (46,47). However, MAS are largely prescribed to adult OSA patients for use during sleep only, and dental and skeletal changes would be considered undesirable. The main action of MAS is to increase the airway space by providing a stable anterior position of the mandible and advancement of the tongue, soft palate, and related tissues. This action of the MAS mediates posteriorly directed pressure on the upper dentition and anteriorly directed pressure on the lower dentition and causes immediate bite and jaw posture changes. Since there are no adaptive growth and/or major remodeling changes in adults, postural jaw modification may trigger dental and temporomandibular joint (TMJ) discomfort. Most patients experience acute side effects during the initial phase of treat- ment. Excessive salivation (38–50%) and transient dental discomfort (33%), particu- larly of the upper and lower front teeth, for a brief time after awakening, are commonly reported with initial use and may prevent early acceptance of an oral appliance (19). TMJ discomfort (12.5–33%), dryness of the mouth (28–46%), gum irritation (20%), headaches and bruxism (12.5%) are other side effects that have been reported (12,19,48). Although these acute side effects are common, for most patients these are minor and transient, subsiding with continued use of the oral appliance. Oral Appliances 225 Potential long-term adverse effects can be broken and/or loosened teeth, dislodgement of existing dental restorations, tooth mobility, periodontal complica- tions, muscle spasms, and otalgia (49–53). These complications can often be avoided by simple recognition and appropriate early response to initial complaints. To monitor for these potential problems, it is suggested that patients with oral appli- ances should make periodic visits to the treating dental clinician. There are now published studies assessing long-term adverse effects out of seven years of use. Occlusal changes are predominantly characterized by a reduction in overjet and overbite, that is, backward movement of the upper front teeth, forward movement of the lower front teeth, and mandible and an increase in lower facial height (Fig. 5) (51–54). Even though the degree of overjet reduction is generally small, ranging from 0.4 mm to 3 mm (51), these changes can be clinically important. However, these changes uncommonly warrant cessation of treatment, and have to be weighed against the benefit provided by the oral appliance and the desirability of alternative treatments. Previous studies have suggested that changes occur within the first two years of MAS use, after which they appear to stabilize (55). However, such studies have had methodological problems. More recently, a seven-year follow-up study reported progressive changes over time and also found that the magnitude of reduction in overjet was correlated with the magnitude of the initial overbite (56,57). Even though the influence of oral appliance design on side effects is not yet well-studied, the use of soft elastomeric devices, even if less durable, appears to provide some relative protection from large reductions in overjet (58). Predictably, the prevalence of side effects increases with more frequent use of the device (58). Whilst the literature suggests that the changes in the occlusion are largely temporary and revert after cessation of MAS use, permanent dental side effects requiring orthodontic treatment have been reported in a minority of cases (48). Hence it is important that patients are fully informed about these potential risks before commencing treatment. Whilst not yet investigated, it may be possible to avoid such side effects with the use of prosthetic and/or auxiliary implants as anchorage units on the upper and lower jaws. These types of anchorage units are currently successfully used to avoid unwanted effects of orthodontic forces. FIGURE 5 Close-up cephalometric radiographs of a 44-year-old female patient before, after 1.5 years, and after four years of mandibular advancement splint use, showing considerable reduction in overjet and overbite during that time. 226 Cistulli and Darendeliler CLINICAL PRACTICE ISSUES Indications and Contraindications According to the updated AASM practice parameters published in 2006, oral appli- ances are indicated in patients with mild-to-moderate OSA who prefer this form of treatment over CPAP, or who do not respond to or are unable to tolerate CPAP (20). The AASM also recommends that patients with severe OSA be considered for CPAP in preference to oral appliances whenever possible, given its greater efficacy. A major clinical limitation of oral appliance therapy, stemming from the need for titration during an acclimatization period, is in circumstances where there is an imperative to commence treatment quickly. This includes situations involving severe symptomatic OSA (e.g., concern about driving risk), with or without coexis- tent medical comorbidities such as ischaemic heart disease. Not all patients are suitable candidates for the use of oral appliances. This treatment modality has no known role in treating central sleep apnea or hypoven- tilation states. Some case reports have shown OSA being worsened by oral appli- ance therapy (59,60), and this together with the known potential for a placebo reponse (12,13), highlights the need for objective assessment of treatment response. Caution is warranted in patients with TMJ problems, and it may be advisable to seek expert dental/specialist assessment prior to initiation of treat- ment. Insufficient number of teeth to permit adequate retention of the appliance may preclude treatment. It is commonly accepted that 10 teeth on each dental arch would represent the minimum number required (61). Less teeth will increase the partition of the pressure on each tooth and will cause more dental side effects. Similarly, the presence of periodontal disease may promote excessive tooth move- ment with an oral appliance. These cases may benefit from using TRD, although there is no strong evidence for this approach. In partial denture patients, the den- ture may become loose after the use of splints due to dental movements. All these factors tend to limit the scope of this form of therapy, and one European study has suggested that up to one-third of patients are excluded on the basis of such factors (62). Clinical Evaluation and Management An interdisciplinary, medical, and dental approach to diagnosis and management would appear to be conducive to good patient care. It is generally recommended that initial medical assessment and diagnosis precede the prescription and initiation of oral appliance therapy (20). Once the medical decision to proceed with oral appli- ance therapy has been made, it is recommended that the dental component be carried out by appropriately qualified and experienced dental practitioners (20). During the initial dental consultation the oral health status is assessed for suitability and informed consent is obtained. A lateral cephalometric X-ray may be advisable to evaluate airway continuity and dimensions as well as for baseline documentation of the position and angulation of the teeth. A regular alginate impression with buccal and palatal soft tissue features is required. The precision of the impression depends on the design of the splint. A construction bite in an initial 75% protrusive mandibu- lar position using regular pink wax is advised, as this amount of initial activation will represent a clinically reliable start point for the acclimatization phase (12). Existence of crowns and bridges, periodontally compromised teeth, as well as inadequate under-cuts need to be identified; these areas may need reduced retention, reduced in and out shear pressure, and may require modification of the Oral Appliances 227 regular appliance design. Extra clasps may be needed to increase retention in some cases. Following the insertion of the splint, patients may encounter problems fitting the splint and irritations to soft or hard tissues. These need to be corrected as soon as possible. It is common for patients to have uncomfortable sleep during the first few nights, but they usually reach an appropriate length of sleep after about a week. At the completion of titration, the patient should be re-evaluated from a medical per- spective to ascertain the clinical response and to make decisions regarding the appropriate ness of long-term use. Appliance Selection This is area requiring considerable research. Considering that there is wide variability in the reported efficacy across different studies, there is a strong suggestion that oral appliance design, in addition to dental expertise and titration procedures, has an important influence on treatment outcome. The appropriate design of the appliance needs to take into consideration the occlusal and dental health, hard and soft tissues, the number of anchorage teeth, and the need for sagittal adjustment and/or reactivation, and this will vary on a case-by-case basis. Duobloc designs are generally preferable because of greater comfort and the ability to titrate, allowing attainment of the most comfortable and efficient position of the mandible and greater degree of lower jaw movements. MAS that permit lateral jaw movement or opening and closing whilst maintaining advancement may confer advantages in terms of reduction of the risk of complica- tions and better patient acceptance. However, monobloc devices, whilst more rigid and bulky, are sometimes used to resolve issues related to anchorage needs, dental conditions, and the occlusal relationship. Another important consideration is the vertical dimension of the oral appliance. Minimum vertical opening depends on the amount of overbite. Initial opening may be required before advancement of the mandible is possible, particular in cases with deep overbite (Fig. 6). However, if overbite is absent there may be no necessity to increase the vertical dimension. There are conflicting data on the effect of the degree of bite opening induced by oral appliances on treatment outcome, although most patients appear to prefer minimal interocclusal opening (21). In mouth breathing patients, splint design must have an anterior opening to permit comfortable breathing. In the case of edentulous patients wearing partial dentures, splint design should adapt to dental structures without dentures. In cases of insuffi- cient teeth and concerns about retention there may be role for TRD. FIGURE 6 Schematic diagram showing the influence of the depth of bite on the distance (d) of verti- cal opening required in order to permit advancement of the mandi- ble. The deeper the bite, that is, the greater the overlap between upper and lower incisors in occlu- sion (as per this example), the greater the amount of vertical opening required. 228 Cistulli and Darendeliler Titration Protocol A period of acclimatization, over a period of weeks or months, is generally needed to initiate treatment. During this period incremental advancement of the mandible is performed according to clinical response and comfort, followed by medical reas- sessment to determine clinical response. This is currently a major limitation of the therapy, particularly in patients where rapid initiation of treatment is warranted. Furthermore, there is considerable interindividual variability in the degree of pro- trusion and time frame required to achieve a positive clinical outcome. The degree of protrusion required generally ranges between 50% and 90% of the maximum protrusion (12,35,63). The correlation between the amount of advancement and therapeutic effect is not strong. Hence, there is no basis for providing a fixed amount of advancement (e.g., 75% of maximal protrusion) to all patients, as has been pro- posed by some authors (64,65). The amount of advancement may be also limited by the degree of tolerance of the patient. Essentially no research has been undertaken to define the optimal procedures for this acclimatization period. It is unclear whether the advent of single-night titration procedures will enable a reduction in the dura- tion of acclimatization required to attain an optimal result (66). Follow-up Procedures Once successful acclimatization is complete, and efficacy is verified, it is generally recommended that patients undergo dental review every six months for the first year, and yearly beyond that (20). This is to monitor clinical efficacy, adherence, oral health and occlusion, and device deterioration. Medical follow-up is required to assess the clinical response to treatment, usually with polysomnography or a porta- ble monitoring device. Subsequent medical review is required to assess adherence and ongoing efficacy of the treatment. This may require periodic review with poly- somnography if there is concern about attenuation of efficacy. CONCLUSIONS Despite the encouraging progress witnessed over the last decade, a number of key unresolved issues represent barriers to the widespread use of oral appliances in the treatment of snoring and OSA. In particular, the inability to predict treatment out- come creates uneasiness at the prospect of an unsatisfactory outcome, involving a not insubstantial investment of time and money on the part of the patient. Hence further research aimed at identifying clinical factors that predict success and failure are critical. Another important issue is the need for an acclimatization phase before maximal efficacy is achieved. Research comparing different acclimatization proto- cols, including the potential clinical use of single-night titration protocols, may herald the development of a more efficient process. Such an approach would hope- fully assist with the individualization of treatment “dosage,” that is the degree of mandibular advancement required to control OSA in the individual patient. There is an ongoing need for long-term follow-up studies, with an emphasis on both efficacy and adherence. The development of objective adherence monitors, as is available for CPAP therapy, would be an important advance. Given the likely important, but largely unstudied, influence of appliance design on treatment out- come and side effects, the field requires comparative studies to help guide clinical recommendations regarding choice of appliance. To date, there has been little or no consideration for the potential of combining therapies in order to achieve an adeqaute clinical outcome (67). 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