Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is a highly prevalent form of sleep disordered breathing and the milder spectrum of disease may affect up to 20% of the population. There remains uncertainty as to the most appropriate initial therapy in this group of patients, especially as CPAP therapy tolerance and adherence is poor. We reviewed the current evidence for non-CPAP therapies in mild to moderate OSAHS as defined by an apnoea hypopnoea index (AHI) of 5 to 30 events per hour. Mandibular advancement devices appear to offer a non-inferior option to CPAP therapy in mild to moderate OSAHS. These devices are better tolerated than CPAP in many patients. Traditional tennis-ball techniques (TBT) and newer sleep position trainers (SPT), which use a vibration feedback stimulus, aimed at preventing supine sleeping are very effective at treating positional obstructive sleep apnoea (POSA). However poor long term adherence and diagnostic difficulties due to night to-night variability in POSA severity present challenges to their widespread use. No drug therapy can be recommended for the treatment of mild-moderate OSAHS. Nasal steroids and decongestants appear to be helpful additional short-term therapies in patients with nasal symptoms. Very low calorie diets and lifestyle modifications aimed at weight loss are effective at treating OSAHS in motivated and closely supported patients.

• Obstructive sleep apnoea
• Obstructive sleep apnoea-hypopnoea syndrome
• Mandibular advancement device
• Positional obstructive sleep apnoea

Davidson JW, Pepperell JCT (2018) Non-CPAP Treatments for Mild to Moderate Obstructive Sleep Apnoea-Hypopnoea Syndrome. J Sleep Med Disord 5(3): 1096.

AHI: Apnoea-Hypopnoea Index; APOC: Amsterdam Positional Obstructive Sleep Apnoea Classification; CPAP: Continuous Positive Airway Pressure; ESS: Epworth Sleepiness Scale; MAD: Mandibular Advancement Device; ODI: Oxygen Desaturation Index; OSA: Obstructive Sleep Apnoea; OSAHS: Obstructive Sleep Apnoea-Hypopnoea Syndrome; POSA: Positional Obstructive Sleep Apnoea; SPT: Sleep Position Trainer; TBT: Tennis Ball Technique; VLCD: Very Low Calorie Diet; WSP: Worst Sleep Position

Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is a highly prevalent form of sleep disordered breathing characterised by repetitive arousal from sleep due to partial or complete obstruction of the upper airway. This results in arterial oxygen desaturation and activation of the sympathetic nervous system. It is estimated to affect 2-4% of the middleaged population and the milder spectrum of disease may affect up to 20% of the population [1]. Continuous positive airway pressure (CPAP) treatment is an effective treatment for OSAHS by splinting open the pharynx during sleep. However as many as 25% of patients will refuse to use CPAP or discontinue it within the first two weeks [2] and non-adherence rates, when defined as less than 4 hours usage a night, vary from 29 – 83 % [3]. There is a weak correlation between OSAHS severity and CPAP adherence [4]. Symptom severity, particularly excessive daytime sleepiness characterised by an Epworth Sleepiness Score (ESS) greater than 10, shows a stronger correlation with long-term adherence [5]. This suggests large numbers of patients exist with milder disease who are less likely to adhere to CPAP treatment long term either due to the inconvenience of CPAP therapy or lack of perceived symptom benefit. In this review article we focus on the alternative treatments to CPAP therapy with emphasis on the evidence in mild to moderate disease as defined by apnoea hypopnoea index (AHI) or oxygen desaturation index (ODI) of between 5 and 30 (Figure).

Figure 1: A conceptualised comparison of the treatment performance across various domains for CPAP, positional therapy devices, mandibular advancement devices (MAD) and drug therapy in the treatment of mild to moderate OSAHS.

Mandibular Advancement Devices

Mandibular advancement devices (MAD) take the form of plastic or composite moulded mouth pieces which advance the mandible and soft tissue structures resulting in the enlargement of the cross-sectional area of the upper airway. MAD treatment commonly used for patients with mild to moderate OSAHS [6]. When directly compared to CPAP treatment the improvements in AHI are not significantly different and evidence supports its use in this mild-moderate disease group [7-10]. Generally fewer side effects are reported with MAD versus CPAP therapy and the devices are well tolerated, in one trial 70% of patients expressed a preference for MAD over CPAP [11].

In a randomised controlled trial of crossover design comparing MAD to CPAP treatment Randerath et al.[8] recruited 20 symptomatic patients with an AHI of 5 – 30 to 6 weekswith each intervention. Patients had an average AHI of 15.5 events per hour (SD +/- 7.7) and following treatment with MAD AHI fell to 10.5/h (+/- 7.5, [p <0.05]) and on CPAP 3.5/h (+/- 2.9 [p < 0.01]). In a similar trial defining mild to moderate disease as an AHI range of 10 – 49 events per hour; MAD decreased AHI from 22.2/h (+/- 9.6) to 8.0/h (+/- 10.9 [p < 0.001]) [9]. Subjective excessive daytime sleepiness was also significantly reduced by MAD use (Epworth Sleepiness Scale, ESS 13.4 +/- 4.6 at baseline to 9.0 +/ - 5.1 [p < 0.001]). Gotsopoulos et al. [12] showed MAD treatment resulted in similar small improvements in the ESS. However in a larger trial of 96 patients with AHI < 30 using either a MAD or a placebo device no significant benefits in objective (OSLER test) or subjective (ESS/Karolinska) daytime sleepiness were seen despite a significant reduction in AHI [13] and in comparison to CPAP, MAD appear to be less effective at reducing excessive daytime sleepiness [14] (Table).

Table: Summary of clinical trials investigating mandibular advancement devices (MAD) included in this review article.

Reference	Inclusion Criteria	Trial Design	MAD Device	Primary Outcome	Selected Secondary outcomes	Adherence	Side effects and tolerability
Aarab et al.  2011 (7)	AHI 5 - 45 from  one night diagnostic polysomnography, ESS ≥10 or ≥2  AASMTF symptoms	64 patients RCT – MAD vs  nCPAP vs placebo (acrylic  mouthguard  covering hard  palate)	Custom made titratable device  (Amsterdams  Tandtechnisch  Laboratorium  (ATL), Amsterdam, The Netherlands)	Change in baseline  AHI (ΔAHI) MAD:16.3(±10.3)* nCPAP:  19.5(±8.7)** Placebo: 5.2(±10.5)	SF36 Questionnaire: NS differences vs placebo Respiratory  arousal index: MAD* and nCPAP* groups  showed significantly larger reductions than the  placebo	MAD: 90.6%  (SD, 13.3) of the  nights nCPAP: 82.9%  (SD, 7.2)  Placebo: 93.9%  (SD, 15.7)  No significant  group differences	MAD: sensitive  teeth (n = 9);  tenderness in  the masseter  muscle region  (13); discomfort  in wearing (10);  hypersalivation  (9); dry mouth  (4); feeling of a  changed occlusion (9) and difficulty in swallowing with the MAD  in situ (3).
Randerath et  al. 2002 (8)	AHI 5 – 30 on  two diagnostic  polysomnography recordings  and symptoms  of OSAHS	20 patients Randomised  crossover trial: 6 weeks CPAP  vs MAD	Custom made device Intra-oral sleep apnoea device, ISAD (IST Hinz, Herne, Germany)	Mean AHI Baseline: 17.5(±7.7) MAD 1 night: AHI 10.5(±7.5)* MAD 6 weeks: AHI 13.8(±11.1)(NS vs baseline) CPAP 6 weeks: AHI 3.2(±2.9)	Snoring frequency Baseline: 54.5(±25.9) epochs per hour MAD 6 weeks: 36.4(±17.7)* MAD complete response (AHI<10) n= 6 (30%)	CPAP vs MAD nights per week: NS CPAP vs MAD hours per night: NS	Ease of Use (1-6 scale) MAD: 1.8(±1.1) CPAP: 3.1(±1.5) (p<0.05 favouring MAD)
Tan et al.  2002 (9)	AHI <50 from  one night diagnostic polysomnography	24 patients Randomised  crossover design 2 months nCPAP vs MAD	10 patients, custom made vacuum formed single piece appliance ‘modified sports mouth guard’ 14 patients custom made two-part semirigid Silensor (Erkodent GmBh Tuttlingen, Germany)	Mean AHI Baseline: 22.2(±9.6) MAD: 8.0(±10.9)** CPAP: 3.1(±2.8)**	Sleepiness, ESS Baseline: 13.4(±4.6) MAD: 9.0(±5.1)** CPAP: 8.1(±4.1)** MAD Complete Response: (Adherence for 2 months and AHI <10) n=16 (70%)	Did not tolerate MAS n=1 (4%) Did not tolerate CPAP n=2 (8%)	Switched MAD mid trial due to reports of inadequate nocturnal respiration/unable to tolerate the device 17/21 (81%) expressed preference of MAD over nCPAP
Ferguson et  al. 1996 (10)	AHI 15 - 50  on single night  diagnostic polysomnography,  2 weeks wash  in home sleep  monitoring	27 Patients Randomised  crossover design 4 months  nCPAP vs MAD	Ready-made, self-moulded; Snore-Guard (Hays & Meade Inc; Albuquerque, NM)	Mean AHI Baseline: 19.7(±13.8) MAD: 9.7(±7.3)* CPAP: 3.5(±1.6)* CPAP vs MAD (p<0.05)	Snoring frequency Baseline 100% vs MAD 24%* Excessive Day time sleepiness / fatigue Baseline 84% vs MAD 48%*	n=6 (24%) unable to wear MAD even after adjustmen	Sore teeth jaw, excessive salivation with MAD Very satisfied with treatment: MAD 56% vs CPAP 19% (p<0.005)
Gagnadoux  et al. 2009  (11)	AHI 10 – 60 and ≥2 OSAHS  symptoms Baseline: AHI  34(±13)	59 patients Randomised  crossover design 8 weeks  MAD vs CPAP	Custom-made, titratable, AMCTM (Artech Medical, Pantin, France)	Median AHI CPAP: 2 (1-8) vs MAD: 6 (3-14) (p=0.001) Complete Response (AHI<10): MAD n=39 (70%) vs CPAP n=46 (82%)	Snoring Index CPAP: 16 (2-52) vs MAD: 55 (10- 149) (p<0.001) Sleepiness, ESS/ OLSER ESS for CPAP and MAD groups** and OSLER sleep latency*	Self-reported, hours per night CPAP: 6.0 (4.0– 7.0) MAD: 7.0 (6.0– 8.0) (p<0.001) Nights on treatment, % CPAP: 90 (40–99) MAD: 98 (90– 100) (p<0.001)	Mean side-effects score CPAP 3.2(±3.4) vs MAD 3.2(±3.1) (p = 0.8) n=42 (71%) preferred MAD, n=5 (9%) preferred CPAP
Gotsopoulos et al. 2002 (12)	Polysomnography showing RDI >10; ≥2 symptoms from fragmented sleep, snoring, witnessed apnoeas and daytime sleepiness	73 patients Randomised crossover design 4 weeks MAD vs placebo devic	Custom made acrylic titratable device	Respiratory Disturbance Index Placebo: 25(±2) MAD: 12(±2)**	Snoring frequency, events per hour Placebo: 366(±21) MAD: 207(±20)**	Self-reported hours per night MAS and placebo: 6.7(±0.1) Nights on treatment, % MAS: 97%(±1) Placebo: 96%(±1)	Significantly more SE with MAD than placebo; jaw discomfort**, tooth tenderness** and excessive salivation*.
Marklund et al. 2015 (13)	Snorers and Mild to moderate OSA (AHI9 or reported on questionnaire	91 patients A randomized, single-blinded, parallel study of the efficacy of MAD vs placebo device. 4-month intervention	Custom made elastomer device, titratable (SR Ivocap Elastomer; Ivoclar Vivaden)	Sleepiness ESS/KSS for MAD vs placebo NS	AHI Placebo: 16.7(±10.0) MAD: 6.7(±4.9)**	Nights used treatment for whole night, % Placebo: 76% MAD: 86%	Significantly more SE with MAD than placebo: jaw pain*, tooth pain*, hypersalivation* and bite changes** Totally or sufficiently fulfilled expectations of treatment; Placebo: 11%; MAD: 73%**
Lam et al. 2007 (14)	AHI >5-40 AND ESS >9 if AHI in 5-20 range One night diagnostic polysomnography	101 patients RCT of Sleep hygiene vs CPAP vs MAD 10 weeks (all overweight patients were also referred for weight loss programme)	Custom made non-adjustable oral appliance made of dental acrylic	Mean AHI MAD: 20.9(±1.7) to 10.6(±1.7)** CPAP: 23.8(±1.9) to 2.8(±1.1)**	Sleepiness, ESS MAD: 12(±1) to 9(±1)**	Self-reported use, MAD: 5.2(±0.3) nights per week and 6.4(±0.2) hours per night	MAD: excessive salivation (n=19, 56%), tempo romandibular joint discomfort (n=13, 38%), dryness of the throat (n=11, 33%) and tooth discomfort (n=11, 33%).
Johal et al. 2017 (15)	AHI 5-30	35 patients Randomised crossover design 3 months custom adjustable MAD (MADc) vs ready-made (MADr), 2 weeks washout	MADc: Medical Dental Sleep Appliance (R.J. and V.K. Bird, Middle Park, Victoria, Australia) MADr: Snoreshield (S4S, Sheffield, UK)	Mean AHI Baseline: 13.4 (11.6– 24.2) MADc: 4 (1–9.9)** (p<0.001 vs MADr) MADr: 9.6 (4.8– 17.8)*	Sleepiness, ESS Baseline: 9 (5- 11.5) MADc: 5 (3-8)* MADr: 7 (4.5 – 11.5)*	Nights worn per week MADc 7 (5–7) vs MADr 3 (0–6.5) (p=0.004) Hours per night MADc 5 (3–7) vs MADr 3 (0–6)	Patient preference: MADc 21 (84%) vs MADr 1 (4%) (p< 0.001)
Vanderveken et al. 2008 (16)	One night diagnostic polysomnography showing snoring and/or AHI <40 Patients with AHI 20-40 had refused or failed CPAP first	38 patients Randomised crossover design 4 months MADc vs MADr, 1 month wash out	MADc: custom made (Ivocap Elastomer, Ivoclar, Vivadent AG; Schaan, Liechtenstein) MADr: moulable thermoplastic (SomnoGuard Plus, Tomed Dr. Toussaint GmbH, Germany)	Partial or complete treatment response (AHI <5 or 50% reduction from baseline) MADc: 21/35 (60%). MADr: 11/35 (31%) (p=0.02)	Snoring, VAS a reduction in snoring of a least 3 points on VAS MADc: 28 (80%) MADr: 18 (51%) (p=0.01)	Self-reported adherence MADc: 6.4 nights/wk; 6.3 hours/night MADr: 4.5 nights/wk and 4.6 hours/night	19/23 subjects (82%) preferred MADc No serious side effects reported
Quinnell et al. 2014 (17)	AHI 5-30 ESS ≥9 Newly diagnosed or existing patients intolerant of CPAP	81 patients Randomised crossover design of custom made (MADc) vs semi-bespoke (MADs) vs readymade (MADr) device vs no treatment 2 weeks acclimatisation and 4 weeks therapy	MADr: ‘boil and bite’ device (SleepPro 1; Meditas, Winchester, UK); MADs: semibespoke device produced from a patient-moulded dental impression kit (SleepPro 2; Meditas); MADc: custom made MAD (Maxillofacial Laboratory, Department of Oral and Maxillofacial Surgery, Cambridge, UK)	Mean AHI Control: 14.6(±10.5) MADr: 10.8(±9.5)** MADs: 9.7(±8.9)** MADc: 9.4(±8.4)**	Sleepiness, ESS  Control:  10.1(±4.3) MADr:  8.5(±4.0)** MADs:  8.0(±4.1)** MADc: 7.7  (±3.8)**	% Nights device  never removed MADr 31%,  MADs 52%,  MADc 44%	Most common  SE mouth problems/ discomfort  (n=83, 92%) and  excess salivation  (n=48, 53%) with  MADs performing best 41% preferred  MADc, 30% preferred  MADs and 14%  opted for no  treatment
Gagnadoux 2017 (18) 9	Patients using MAD Mild to Moderate OSA OR Severe OSA and previous failure on CPAP therapy	158 patients Prospective non-randomised trial of 6 months custom made MAD (MADc) vs ready-made MAD (MADr)	MADr: titratable, thermoplastic MAD (BluePro®; BlueSom, France MADc: 63 pts AMO® device (SomnoMed, France) and 9 pts Somnodent® device (SomnoMed, France)	Mean AHI: MADr Baseline: 23.2(±1.6) 6 months 7.9(±1.1)** MADc Baseline: 32.2(±2.4) 6 months: 13.2(±1.5)** MADr vs MADc at 6 months NS differences	Sleepiness, ESS MADr Baseline:  9.9(±0.6) 6 months:  7.2(±0.6)** MADc  Baseline:  9.4(±0.6)  6 months:  6.5(±0.5)**	Mean use per  night, hrs MADr: 6.4(±0.2)  vs  MADc:7.1(±0.1)  (p<0.05) Compliant users  (>4hrs a night)  MADr 95.5% vs  MADc 100%	SE of jaw pain, muscle stiffness, dry mouth, hypersalivation NS difference between groups, tooth pain and occlusal changes higher in MADr (p<0.05)
Barnes 2004 (19)	AHI 5 – 30	104 patients Randomised crossover design, 3 months CPAP vs MAD vs placebo tablet. 2 week washout.	Medical Dental Sleep Appliance, R. J. and V. K. Bird, Australia	Mean AHI: Baseline: 21.3(±1.3) MAD: 14.0(±1.1) (p<0.001 vs baseline and placebo) CPAP: 9.2(±0.4)** (p<0.001 vs MAD) MAD: Complete response (AHI<10) 49.1%	Sleepiness, ESS Baseline:  10.7(±0.4) MAD: 9.2(±0.4)** CPAP 9.2(±0.4)**	Nights per week,  Hours per Night MAD: 5.3(±0.3)  nights/wk,  5.5(±0.3) hrs CPAP: (4.2±0.3)  nights/wk,  3.6(±0.3) hrs	MAD preferred treatment in 30% of subjects and 36% partners CPAP 44% and 40% respectively
Abbreviations: AHI: Apnoea-Hypopnoea Index; AASMTF: American Academy Of Sleep Medicine Task Force; ESS: Epworth Sleepiness Scale; KSS,  Karolinska Sleepiness Scale; MadC: Custom-Made Mandibular Advancement Device; Madr: Ready-Made Mandibular Advancement Device; Mads:  Semi-Bespoke Mandibular Advancement Device; (N) CPAP: (Nasal) Continuous Positive Airway Pressure; RCT: Randomised Controlled Trial; RDI,  Respiratory Disturbance Index; SE: Side-Effect Data are presented as mean (±SD) or median (interquartile range), unless otherwise stated.  NS – non-significant; *P<0.05 vs relevant placebo or baseline measure; **p<0.001 placebo or baseline measure

Comfort and tolerability varies with each device. Generally devices can be divided based upon whether they are custommade and fitted by trained dentists or are ready-made from mouldable thermoplastic. Two trials comparing non-adjustable custom- and ready-made devices in patients with mild obstructive sleep apnoea showed significantly better complete response with the custom-made designs (custom-made 64% vs ready-made 24%[15] and 60 vs 31% [16]). Complete response was based upon the AHI falling to < 5 events per hour on a single night polysomnogram after wearing the device for 3 and 4 months respectively. The TOMADO trial [17] examined three non-adjustable devices; a custom-made, a ready-made and an intermediate ‘semi-bespoke’ device. All these devices successfully reduced AHI and ESS compared to no treatment. No significant difference in the devices performance was detected although the ready-made device was the least preferred. Generally readymade thermoplastic devices seem to be associated with more side effects, particularly tooth pain and lower self-reported compliance [18]. Some devices can be titrated over time to allow gradual movement towards maximal tolerable mandibular advancement, the position most likely to achieve greatest reduction in airway collapsibility. This may be an important factor in minimising patient discomfort and hopefully improving adherence [19]. MAD treatment’s advantage over CPAP may lie in its improved compliance. Objectively measured compliance, via a microsensor attached to an adjustable custom-made device, demonstrated 83% of patients were still regular users (>4 hours a night and used on >70% of nights) at 1 year follow-up with a 9.8% discontinuation rate [20] which compares favourably with CPAP discontinuation rates of 20 to 50% [5, 21]. 

A primary concern of MAD treatment is the change induced in the temporomandibular joints, masticatory muscles and bite position due to the sustained jaw protrusion. A 3 year followup study showed no radiographic changes in the TMJ although patients reported noting significant changes in their oro-facial function and bite occlusion [22]. Several studies report patients successfully using devices for 10 years or more although they suggest the efficacy of the devices may wane over this period, conceivably due to deterioration in the severity of the OSA or bite position changes that may result in a lesser degree of mandibular advancement [23, 24].

MAD effectiveness at reducing cardiovascular morbidity and mortality is not established unlike for CPAP. This may be because it is primarily seen as a treatment for only milder disease and in this group of patients, even for CPAP therapy, the cardiovascular benefits of treatment are less well defined. Several studies report on MAD having beneficial effects on cardiac autonomic function [19, 25-27]. Mandibular advancement devices appear to be effective at reducing mean and diastolic blood pressure with 3 to 6 months use, but the long term cardiovascular benefits or utility in patients with resistant hypertension remains to be proven. Three months therapy with CPAP appears sufficient to see reversal in endothelial dysfunction [28] however the improved long-term adherence with MAD therapy may balance the relative smaller benefit seen in cardiovascular and endothelial dysfunction.

Mandibular advancement devices can be considered as an alternative option to CPAP therapy in treatment of OSAHS and they are non-inferior in terms of AHI reduction, although symptomatic improvement appears more variable. Even with custom-made devices excessive daytime sleepiness persisted in 33 to 45% of patients [15, 16]. The heterogeneity of devices limits generalisation but custom-made titratable devices seem to be preferable for patients although the length of production time and costs of these devices need to be considered in any analysis.

Positional Modification Devices

It is estimated that 56 to 75% of OSAHS patients may benefit from use of a positional modification device [29] however when considering this figure it is important to clarify how positional obstructive sleep apnoea (POSA) is defined. Crucial to the success of these therapies is the identification of patients whose apnoeas are present almost exclusively in a single worst sleep position (WSP), in 75% of people this is supine[30]. Several factors can confound the identification of a suitable study population. Many sleep services may only routinely screen patients with overnight oximetry (type IV monitors) and lack the ability to identify POSA in every patient. Additionally how representative a single night polysomnography recording is in identifying POSA is questionable given poor night-to-night repeatability [31]. Its presence in an individual may vary on a nightly basis, only in men with a ratio of supine AHI to non-supine AHI of 4:1 and with a non-supine AHI of less than 10 events per hour were two nights of recording consistent in identifying a supine-predominant OSA phenotype. There is variation in how the study populations with POSA are defined, many studies classify POSA as present if the supine AHI to non-supine AHI is greater than 2[32] or 1.5 [33] whilst others use the Amsterdam Positional Obstructive Sleep Apnoea Classification (APOC) [30].

Therapies are aimed at minimising sleep time in the worst sleep position. The ‘tennis-ball-technique’ or variations of it use a physical object that is worn or attached to clothing. This should then prevent sleep in the supine position or makes it uncomfortable enough to arouse the patient into moving position. A newer generation of devices have been developed often termed Sleep Position Trainers (SPTs) which involve wearing a small device usually strapped to the neck or chest. This can detect when the patient adopts a supine position and produces a vibratory stimulus intended to arouse the patient and prompt them to adopt a more suitable sleep position.

The tennis-ball-technique (TBT) has been shown to be effective at reducing the AHI in POSA patients, home-made devices seem to be equally as effective as commercially made ones [32].Generally initial adherence with therapy appears to be good with only 26% discontinuing use at 3 months[34]but longer term use is poor[35, 36]. After an average of 13 months followup de Vries et al.[32] found 65% of patients had stopped using their device. Surprisingly even in the subgroup shown to have more supine apnoeas, which would theoretically have gained most benefit from the therapy, 89% had stopped. The reason for the poor long-term tolerability may lie in the lack of perceived therapeutic benefit or that the discomfort and repetitive arousals due to the device itself may be perceived as worse than the symptoms of OSAHS. There does seem to be a cohort of patients for whom TBT type devices can be beneficial and produce similar reductions in AHI to CPAP therapy [37] but the challenge lies in identifying these patients, a near normal AHI in non-supine sleep positions seems to be the best predictor of response.

Multiple cohort studies [38-40] and randomised controlled trials [41-43] have demonstrated the effectiveness of SPT devices in reducing the AHI in mild to moderate POSA. Eijsvogel et al. compared a chest worn SPT (Night Balance, Delft, Netherlands) to a TBT device and demonstrated a greater proportion of patients AHI fell below 5 events per hour when using the SPT (68% vs 43%). Adherence was also better than the TBT, although this only over a 4 week period. Theoretically the SPT are designed to be more comfortable and tolerable to wear whilst sleeping which may account for improved adherence versus a TBT device. Comparisons to a MAD suggest compliance rates are similar over the first 3 months of use [44]. The use of some devices, particularly one positioned on the back of the neck, seems to increase number of awakenings and decrease sleep efficiency [43] which may account for why longer term adherence rates for SPT type devices seem to be poor. 49.4% had discontinued use at 6 months [45]. It is not clear if patients simply learn to ignore the vibration of these devices and no longer feel they gain benefit. Alternatively one may hope that these devices live up to their billing as ‘sleep trainers’ and that with prolonged use the patient naturally learns to adopt a non-supine position during sleep negating the need to wear the device, this is unproven.

One interesting concept is the combination of therapies and Dieltjens et al. used a SPT device in patients with residual POSA already treated with MAD. The combination of treatment was effective in reducing the mean AHI by 76% from baseline [46].

Overcoming the challenges of identifying POSA robustly and better understanding of why patients discontinue the therapy is required to see these devices being used more frequently as firstline therapies in the OSA referral pathway.

Drug Therapies

There are several proposed mechanisms by which drug therapies may act to treat OSAHS. Ten of the twenty-five studies in a 2013 Cochrane review demonstrated a significant reduction in AHI across a range of drug groups. Most drug studies include patients with a wide spectrum of disease severity so it is difficult to identify therapies that might be specifically effective in mild moderate disease.

Increasing the arousal threshold with the use of hypnotics potentially leads to less sleep fragmentation and could improve daytime sleepiness. Eszoplicone [47-49], zolpidem [50], zopiclone [51], temazepam [52], sodium oxybate [53, 54] and ramelteon, a nonsedating chronohypnotic which is selective for melatonin receptors [55], have all been investigated. Of these studies three specifically selected patients with mild to moderate disease but defined this as an AHI range from 10 to 40 events per hour [49, 53, 54], one defined mild to moderate range by AHI of greater than 5 and less than 20 events per hour [56] and one selected an elderly population with a mean respiratory disturbance index of 8.8 events per hour [52]. Sodium oxybate at a dose of 4.5grams significantly reduced the AHI versus the placebo group after 2 weeks use (change in AHI treatment group −8.2 ± 10.0 vs. placebo −0.8 ± 13.3; [p=0.03]) [53] and showed no change at the higher dose of 9.0grams [54]. The other positive trial demonstrated eszopiclone given as a single dose of 3mg reduced that night’s recorded AHI (AHI at baseline 25 +/- 6 vs eszopiclone 14 +/-4 events per hour) without prolonging the respiratory events or worsening hypoxaemia. The other studies did not demonstrate a reduction in AHI. Few studies examined objective or subjective symptomatic improvement and none showed benefit [49, 51]. Hypnotic medication does not appear to worsen AHI or hypoxaemia so these medications have a role in treating co-existing insomnia but they have not been shown to be effective therapies for OSAHS.

Increasing sympathetic stimulation to the pharyngeal dilator muscles could be a desirable target particularly for those patients with a highly collapsible upper airway and a reduced neuromuscular compensatory mechanism [57, 58]. Tricyclic antidepressants (TCAs) desipramine [59] and protriptyline [60-64] have been investigated. Desipramine investigated in a moderate to severe cohort (AHI >15) improves pharyngeal collapsibility [59, 65]and reduced AHI. This effect was particularly seen in those with minimal pharyngeal muscle compensation at baseline but the arousal threshold was lowered worsening OSA in some patients. Protriptyline trials had inconsistent results with two showing improvement in subjective daytime sleepiness [60, 63] but these included patients with very severe disease (mean AHI 87.3[63]). The anticholinergic side-effects of dry mouth, urinary retention and visual disturbance would likely impact on the tolerability of TCAs use long term [65].

The hypoglossal nerve is stimulated by serotonin leading to serotonin receptor agonists and reuptake inhibitors being investigated [66, 67]. Those trialledin mild to moderate disease include paroxetine [68] (mean baseline AHI 25.4 events per hour) and mirtazapine (AHI 24[69] and 24.1 [70]). Paroxetine showed a reduction in AHI but no improvement in sleepiness, results with mirtazapine were conflicting. The effects on weight gain and driving performance were concerning.

Drug therapies targeting increasing ventilatory drive in OSAHS almost exclusively have been studied in populations with moderate to severe disease (mean AHI >50) so the utility of aminophylline [71], acetazolamide [64, 72] and zonisamide, a carbnonic anhydrase inhibitor [73] in a mild disease population is unknown. Only theophylline has been investigated in mild disease, showing a statistically significant but likely clinically insignificant reduction in AHI (placebo 9.2 +/- 7.7 vs. theophylline 6.7 +/- 6.1 /hour) [74].

The contribution of nasal resistance and its role in the pathophysiology of OSA has led to its investigation as a conceivable treatment target [75, 76]. Patients with chronic allergic rhinitis and OSA using nasal steroids showed decreases in nasal resistance and improvements in AHI [77, 78]. Trials using nasal decongestants combined with nasal dilator devices showed decreases in NR with conflicting results on AHI but neither showed improvement in subjective daytime sleepiness [79, 80]. A small RCT of twelve OSA patients reporting co-existing symptoms of chronic nasal congestion, used xylometazoline as a nasal decongestant. It demonstrated during maximal nasal decongestion there was a reduction in the AHI, suggestive of a pathophysiological link. The decongestant effect was not sufficient to sustain an improvement in AHI throughout the night nor an improvement in symptoms of sleepiness [81]. The combination of nasal decongestant and steroid spray, tramazoline, and dexamethasone, successfully reduced the AHI in an OSA population with normal nasal resistance at baseline [82]. The long term benefit of such medication is uncertain but as a short term additional therapy in patients with OSA reporting nasal congestion and allergic rhinitis symptoms these medications have a role. Similarly, modafinil appears to be a useful additional therapy for residual sleepiness in mild to moderate OSA patients [83, 84], improving ESS and simulated driving performance in patients who are treatment naïve or during CPAP withdrawal periods. Its use as a sole treatment for OSA cannot be recommended.

The pathophysiology of OSA in an individual patient is likely multifactorial and dynamic. Medication specifically targeted at a single mechanism is therefore unlikely to demonstrate significant benefit. The approach of using a combination of medications may be promising [66]. Conceivably those patients with milder disease may have fewer pathophysiological mechanisms contributing to their OSA and they may be more amenable to a drug therapy, however generally they are a population that is understudied in therapeutic trials. Single night measurements and small sample sizes compounds the difficulty in drawing conclusions about the efficacy of drug therapies in mild to moderate OSAHS.

Weight Loss and Exercise

Lifestyle interventions of weight loss diets and exercise programmes certainly have a role in the management of OSAHS as obesity is perhaps the most important risk factor for the development of OSAHS.A very low calorie diet (VLCD) alongside a lifestyle counselling intervention can be effective for overweight (BMI 28 – 40 kg/m2 ) mildly severe OSAHS patients in reducing mean AHI by 40% and has shown to significantly reduce OSA symptoms [85].Similar studies using VLCD and motivational coaching whose participants had an mean AHI in the moderate severity range (AHI 29 [86], 24.6[87] and 23[88]) show similar improvements in disease severity and symptoms. These changes appear to be sustainable over a 4 year follow-up period [89, 90]. Significant weight loss to improve symptoms can take time and is difficult to maintain, lifestyle interventions are most suitable for motivated patients.

Bariatric surgery certainly has a role in the context of the morbidly obese patient with mild to moderate OSA [91]. Given the risks of surgery it would seem extreme to advocate it simply for OSAHS symptoms in these cases, but rather in the global context of the individual patients co-morbid metabolic disease.

OSAHS has a multifactorial and dynamic pathophysiology. As a result it seems unlikely a single targeted therapeutic intervention will achieve a similar level of response to CPAP therapy. However better understanding and identification of OSAHS phenotypes will help take us some way towards an individualised approach to OSAHS treatments. A combination of non-CPAP interventions may be required to achieve complete response. Particularly with mild to moderate disease there is likely to be increasing difficulty with adherence where a patient’s capacity to tolerate the inconvenience of therapy may be diminished when perceived benefit is smaller. There certainly remains much uncertainty as how best to treat the milder end of the OSAHS disease spectrum as it blurs with ‘normality’.

JP has been awarded an NIHR grant to study nasal decongestants in mild to moderate sleep apnoea.

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