Nasal steroids in snorers can decrease snoring frequency: a randomized placebo-controlled crossover trial

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1 J Sleep Res. (2015) 24, Snoring and nasal steroids Nasal steroids in snorers can decrease snoring frequency: a randomized placebo-controlled crossover trial IOANNIS KOUTSOURELAKIS, ANASTASIOS KELIRIS, ALIKI MINARITZOGLOU and SPYROS ZAKYNTHINOS Center of Sleep Disorders, A Department of Critical Care and Pulmonary Services, Evangelismos Hospital, Medical School of Athens University, Athens, Greece Keywords sleep-disordered breathing Correspondence Spyros Zakynthinos, MD, PhD, Center of Sleep Disorders, A Department of Critical Care and Pulmonary Services, Evangelismos Hospital, Medical School of Athens University, Ipsilandou Str, GR , Athens, Greece. Tel.: ; fax: ; szakynthinos@yahoo.com Accepted in revised form 7 September 2014; received 4 May 2014 DOI: /jsr SUMMARY Although it is anecdotally known that nasal obstruction is associated with snoring, it remains unknown whether the application of nasal steroids could decrease oral/oro-nasal breathing and increase nasal breathing, and subsequently decrease snoring indices. This study evaluated the effect of nasal budesonide on breathing route pattern and snoring. Twenty-four snorers were enrolled in a randomized, double-blind, crossover trial of 1-week treatment with nasal budesonide compared with 1-week intervention with nasal placebo. At the start and end of each treatment period, patients underwent nasal resistance measurement and overnight polysomnography with concomitant measurement of breathing route pattern and snoring. Twelve patients were randomly assigned to a 1-week treatment with nasal budesonide, followed by 2-week washout period and a 1-week intervention with the nasal placebo; and 12 patients were randomly assigned to a 1-week intervention with nasal placebo, followed by 2-week washout period and a 1-week treatment with nasal budesonide. Nasal budesonide was associated with a decrease in oral/ oro-nasal breathing epochs and concomitant increase in nasal breathing epochs, decrease of snoring frequency by [median (interquartile range)] 15.8% ( %), and an increase of rapid eye movement sleep; snoring intensity decreased only in patients with increased baseline nasal resistance by 10.6% ( %). The change in nasal breathing epochs was inversely related to the change in snoring frequency (R s = 0.503; P < 0.001). Nasal budesonide in snorers can increase nasal breathing epochs, modestly decrease snoring frequency and increase rapid eye movement sleep. INTRODUCTION Snoring is considered one of the cardinal symptoms of obstructive sleep apnea (OSA), and is estimated to affect 20 40% of the general population (American Academy of Sleep Medicine, 2005; Pevernagie et al., 2010). Although often regarded solely as a social nuisance, snoring has been increasingly recognized as a clinically significant respiratory sound because it may be associated per se with excessive daytime sleepiness, and an increased risk for acute myocardial infarction and stroke (Gottlieb et al., 2000; Kezirian and Chang, 2013; Koskenvuo et al., 1985; Palom aki, 1991). It is anecdotally known that patients snore more when their nose is blocked (Pevernagie et al., 2010). Despite this 160 relationship between nasal obstruction and snoring, the therapeutic effect of improving nasal airway patency on snoring indices remains a point of conjecture (Fitzpatrick et al., 2003a,b). Indeed, Braver and Block (1994), and Kiely et al. (2004) examined the effect of using a nasal vasoconstrictor or corticosteroid, respectively, and failed to show any improvement in the number of snores after their application. Furthermore, Hoffstein et al. (1991) documented that dilation of the anterior nares in patients without nasal pathology has a relatively weak effect on snoring, and thus nasal dilating appliances were not recommended for the treatment of snoring. Similarly, Craig et al. (2005) concluded that using a nasal corticosteroid results in minimal improvement of sleep. In contrast, intranasal corticosteroids have been shown to

2 Nasal steroids and snoring 161 reduce the apnea hypopnea index (AHI) and improve sleepiness in patients with OSA, implying that there might be an equivalent result for the use of nasal steroids on snoring indices (Kheirandish-Gozal and Gozal, 2008). The present authors have demonstrated a strong correlation between AHI and oral/oro-nasal breathing epochs in patients with OSA with normal nasal resistance (Koutsourelakis et al., 2006), and that the application of a combination of a nasal decongestant with corticosteroid can decrease oral/ oro-nasal breathing and increase nasal breathing epochs and modestly improve AHI (Koutsourelakis et al., 2013). However, the association between snoring indices and breathing route pattern before and after the application of nasal steroids has never been studied. Combining the aforementioned trials, it is plausible to hypothesize that snoring severity, in equivalence to OSA severity, might be associated with oral/ oro-nasal breathing epochs, and that the pharmacological prevention of nocturnal nasal obstruction in patients with normal nasal resistance at wakefulness (Kohler et al., 2006) or the improvement of nasal airway patency in patients with already increased nasal resistance might also decrease oral/ oro-nasal breathing epochs and concomitantly increase nasal breathing epochs and lead to decreased snoring indices. Therefore, the aim of this study was to examine the effect of nasal steroids on snoring indices in conjunction with the breathing route pattern. We hypothesized that the application of nasal steroids could have a beneficial effect on snoring indices if successful in increasing nasal breathing epochs. MATERIALS AND METHODS Study subjects Consecutive patients who referred from April 2012 to January 2013 to the Center of Sleep Disorders of Evangelismos General Hospital of Athens for suspected sleep-disordered breathing were recruited. The enrolment criteria were: (1) AHI less than 10 events h 1 ; (2) every night snoring; (3) no medication known to influence nasal resistance (e.g. antihistamines, vasoconstrictors, topical or systemic steroids); (4) no smoking for the last 6 months; (5) no upper or lower respiratory tract disease (e.g. upper respiratory tract infection, rhinitis, sinusitis, chronic obstructive pulmonary disease), including a history of nasal allergy; and (6) written informed consent from each patient. Exclusion criteria were considered: (1) duration of snoring less than 60 min during the sleep study; and (2) central apneas more than 5% of total apneas. The study was approved by the hospital ethics committee. Protocol A randomized, double-blind, placebo-controlled, crossover design was used. Using a table of random numbers, subjects were randomized into two groups. The patients of the first group initially underwent 1-week therapy with nasal budesonide (32 lg twice per day; Pulmicort nasal aqua â ; AstraZeneca, Lund, Sweden), then 2 weeks washout period, and thereafter 1-week therapy with an identically looking nasal placebo (normal saline; twice per day). The patients of the second group initially underwent 1-week therapy with nasal placebo followed by 2-week washout period, and thereafter by 1-week therapy with nasal budesonide. A 2- week washout period was employed because the time needed for the effect of nasal corticosteroids to vanish is about 1 week (Wilson et al., 1998). Nasal budesonide was used because it can attenuate nasal inflammation associated with snoring and OSA (Rubinstein, 1995). The patients underwent four assessments, at the start and end of each treatment period, which consisted of anterior rhinomanometry and polysomnography with concomitant measurement of snoring indices (snoring intensity, snoring frequency) and breathing route pattern. The ClinicalTrials.gov identifier is NCT Rhinomanometry For each subject, nasal resistance to airflow was measured at the night of the polysomnography during wakefulness without decongestion, first in the upright seated position and then in the supine position after lying down for 10 min by active anterior rhinomanometry (PDD-301/r; Piston, Budapest, Hungary), using a standard protocol (Clement and Gordts, 2005). Nasal resistance values <3.0 cmh 2 OL 1 s were considered within normal limits (McCaffrey and Kern, 1979). Polysomnographic method Full-night diagnostic polysomnography (EMBLA S7000; Medcare Flaga, Reikiavik, Iceland) was performed, as previously described (Koutsourelakis et al., 2006). Snoring sound measurement Snoring was measured using a calibrated microphone-sound meter system (Koutsourelakis et al., 2012). The two microphones were suspended at a distance of approximately 1 m above the surface of the patient s bed. This arrangement allowed a non-invasive measurement of snoring that simulated the distance between sleeping bed partners. Before every study the system was acoustically calibrated using a reference noise produced by a noise generator (86 db). The signal was sent at a sampling rate of 12 KHz through an analogue digital converter to a computer system for subsequent analysis. All digitized signals were recorded in the hard disk of a personal computer. A noise analyser was used for the intensity analysis of snoring sound (Boersma, 2001). After manually scoring the sleep stages, all awake time was excluded. Loud breathing measured at 1 m distance from the mouth is considered to register sound levels of up to 40 db; this value has been proposed as the threshold for the

3 162 I. Koutsourelakis et al. transition from loud breathing to snoring (Pevernagie et al., 2010), and also adopted in the present study. Indeed, spikes in sound intensity >40 db were always perceived as snores by the sleep technologist who was able to hear subjects breathing. The noise analyser automatically erases the noise of the background, producing a sampling period where there are sounds >40 db, generates a histogram of sound intensity and provides a summary of statistics, which includes the mean and maximum sound intensity over the sampling period expressed in db. Data analysis and definitions The code of the medication was maintained during randomization and was broken only after the completion of data analysis. Sleep stage was scored manually in 30-s epochs (American Academy of Sleep Medicine, 2007). Obstructive respiratory events were scored using standard criteria (American Academy of Sleep Medicine, 2007). Thus, apnea was defined as the absence of airflow for more than 10 s in the presence of continued respiratory efforts (American Academy of Sleep Medicine, 2007). Hypopnoea was defined either as 30% reduction in nasal pressure signal excursions from baseline associated with 4% desaturation from pre-event baseline or as the 50% reduction in nasal pressure signal excursions from baseline associated with 3% desaturation or arousal (American Academy of Sleep Medicine, 2007). The number of episodes of apneas and hypopnoeas per hour of sleep is referred to as the AHI, whereas the number of episodes of apnoeas, hypopnoeas and respiratory effort-related arousals per hour of sleep is referred to as the respiratory distress index (American Academy of Sleep Medicine, 2007). The route of breathing was evaluated by using the oral and nasal sensor signals to classify each 30-s epoch as nasal, oral or oro-nasal based on the predominant breathing route, and was expressed in % total sleep epochs, as previously described (Koutsourelakis et al., 2006). Cross-contamination between the oral and nasal channel was meticulously excluded by regular testing during polysomnographic calibration. Thus, we asked subjects to breathe normally and exclusively through the nose for 30 s, and subsequently through the mouth for another 30 s in both supine and lateral postures so that we could verify that each sensor was activated exclusively. We continuously checked sensors during the recording to avoid dislodgement. All measurements were analysed by a single investigator to ensure consistency, and all polysomnographies were scored by a single experienced sleep technologist and subsequently reviewed by the same investigator, who was blinded to the patient s group identity. Snoring was quantified by measuring snoring frequency/ index (defined as the number of snores per hour of sleep: snores h 1 ), and sound intensity (mean and maximum: db). Statistical analysis The minimum sample size was calculated on the basis of 80% power and a two-sided 0.05 significance level (G*Power software version ; Franz Faul, Kiel University, Kiel, Germany). Sample size capable of detecting a change of 60 snores h 1 for snoring frequency after pharmacological intervention was estimated using the standard deviations obtained from a previous study (Braver and Block, 1994). The critical sample size was estimated to be 21 patients. Values are presented as mean SD or median (interquartile range) after testing for normal distribution (Kolmogorov Smirnov test). Depending on the distribution of variables, either parametric (paired t-test) or non-parametric (Wilcoxon signed rank, Mann Whitney U, Spearman s rank) tests were used. Data were analysed according to the method of Jones and Kenward (1989). Comparison of data at the entry to each study period, i.e. at the start of the study and at the end of the washout period, was performed by using paired t-test. The treatment effect for each variable was estimated using the difference between the value at the end of treatment minus the value at the beginning of treatment. Treatment effect differences between nasal budesonide and nasal placebo were compared using Wilcoxon s signed rank test. Relationships between variables were determined by the Spearman s rank correlation coefficient (R s ). Comparison of data of patients with normal and increased nasal resistance was performed by using Mann Whitney U-test. A two-tailed P-value of < 0.05 was considered statistically significant. RESULTS In total, 24 patients were enrolled and completed the study uneventfully. The baseline demographics and patient characteristics are shown in Table 1. Twelve patients were randomly assigned to the first group, and 12 patients to the second group. The baseline demographics and characteristics of patients with normal (n = 18) and increased (n =6) baseline nasal resistance are depicted in Table S1 of the supporting information file. As can be seen, in patients with increased nasal resistance, mean and maximum snoring intensity and non-rapid eye movement (REM) sleep were increased, whereas REM sleep was decreased compared with patients with normal nasal resistance. Among patients with normal nasal resistance, nine were assigned to the first group and nine to the second group, whereas three patients with increased nasal resistance were assigned to the first group and three patients to the second group. Study entry and post-washout No carryover effect between study entry and post-washout assessment on the majority of measured parameters was observed. Indeed, there was no significant difference in mean and maximum snoring intensity, and breathing route pattern between these assessments. Only total and REM sleep time

4 Nasal steroids and snoring 163 Table 1 Anthropometric data, baseline sleep parameters and nasal resistance values Study participants, n 24 Age, years Male, n (%) 15 (63) Body mass index, kg m Mean snoring intensity, db Maximum snoring intensity, db Snoring frequency, snores h AHI, events h Respiratory distress index, events h Nasal resistance supine, cmh 2 OL 1 s Lowest oxygen saturation, % Total sleep time, min Sleep efficiency, % Non-REM, min Non-REM sleep time/total sleep time, % REM, min REM sleep time/total sleep time, % Sleep time in supine posture, % Epworth Sleepiness Scale, score AHI, apnoea hypopnoea index; REM, rapid eye movement. Data are presented as n, n (%) or mean SD. increased in the third assessment compared with the first assessment (P < 0.05). Data from all four assessments in both groups are included in Tables S2 and S3 of the supporting information file. breathing epochs and REM sleep time increased with nasal budesonide compared with nasal placebo. There was a median decrease of 15.8% ( %) of snoring frequency after 1-week therapy with nasal budesonide. The change of snoring frequency after 1-week therapy with nasal budesonide was inversely related to the change of nasal breathing epochs (R s = 0.503; P < 0.001; Fig. 1a). In contrast, the change of snoring frequency after 1-week therapy with nasal placebo did not correlate with the change of nasal breathing epochs (R s = 0.047; P = 0.15; Fig. 1b). Additionally, the change of nasal resistance after 1-week therapy with nasal budesonide did not correlate with the change of nasal breathing epochs (R s = 0.128; P = 0.12) or the change of snoring frequency (R s = 0.223; P = 0.21). Treatment effect differences in patients with normal and increased baseline nasal resistance are shown in Tables S4 and S5 of the supporting information file, respectively. In both groups, snoring frequency, oral breathing epochs and oronasal breathing epochs decreased, whereas nasal breathing epochs increased with nasal budesonide compared with nasal placebo. After nasal budesonide therapy, snoring frequency decreased by 14.4% ( %) in patients with normal and by 19.3% ( %) in patients with increased baseline nasal resistance. Snoring intensity decreased by 10.6% ( %) after nasal corticosteroid therapy in patients with increased baseline nasal resistance, whereas they did not change in patients with normal nasal resistance. Treatment effect differences Treatment effect differences are detailed in Table 2. Snoring frequency, oral breathing epochs, oro-nasal breathing epochs and non-rem sleep time decreased, whereas nasal DISCUSSION The main findings of this randomized, placebo-controlled, double-blind, crossover trial on the effect of 1-week therapy with nasal budesonide in snorers were that: (1) this treatment Table 2 Treatment effect differences Nasal budesonide Nasal placebo Nasal resistance supine, cmh 2 OL 1 s 0.3 ( 0.5 to 0.1) 0.1 ( 0.2 to 0.1) Respiratory distress index, events h ( 0.5 to 0.6) 0.1 ( 0.6 to 0.3) Mean snoring intensity, db 1.1 ( 2.1 to 0.6) 0.1 ( 0.4 to 0.6) Maximum snoring intensity, db 3.4 ( 5.2 to 1.9) 4.1 ( 6.1 to 2.8) Snoring frequency, snores h ( to 25.2) 5.8 ( 20.3 to 30.6)* Nasal breathing epochs, % total sleep epoch 8.1 (6.6 to 12.6) 1.5 ( 0.4 to 3.4)* Oral breathing epochs, % total sleep epoch 1.8 ( 2.7 to 0.7) 0.3 ( 0.6 to 0.2)* Oro-nasal breathing epochs, % total sleep epoch 6.7 ( 10.1 to 3.5) 0.6 ( 1.9 to 2.4)* Minimum oxygen saturation, % 0.4 ( 0.4 to 1.1) 0.2 ( 0.3 to 1.3) Total sleep time, min 8.2 ( 4.2 to 18.9) 4.2 ( 4.2 to 14.9) Non-REM sleep time, min 23.6 ( 43.2 to 10.9) 3.8 ( 12.5 to 11.9)* Non-REM sleep time/total sleep time, % 7.2 ( 13.1 to 3.2) 0.8 ( 3.9 to 3.6)* REM sleep time, min 37.6 (8.2 to 44.9) 7.6 (2.2 to 19.7)* REM sleep time/total sleep time, % 11.3 (2.4 to 13.5) 2.2 (0.2 to 6.1)* Sleep efficiency, % 1.4 (0.5 to 8.2) 2.1 (0.3 to 6.6) Sleep time in supine position, % 4.1 ( 0.2 to 7.1) 2.9 ( 0.7 to 4.6) REM, rapid eye movement. Data are presented as median (interquartile range). *P < 0.01 versus nasal budesonide (Wilcoxon signed rank test).

5 164 I. Koutsourelakis et al. (a) (b) Figure 1. Relationship between the change in nasal breathing epochs and the change in snoring frequency (a) after 1-week therapy with nasal budesonide (R S = 0.503; P < 0.001), and (b) after 1-week therapy with nasal placebo (R S = 0.047; P = 0.155). TSE, total sleep epochs. was associated with a decrease in oral and oro-nasal breathing epochs, and concomitant increase in nasal breathing epochs; (2) nasal budesonide therapy was associated with a median decrease in snoring frequency by 15.8%; (3) the change in nasal breathing epochs was inversely related to the change in snoring frequency; (4) snoring intensity decreased by 10.6% after nasal steroid therapy in patients with increased nasal resistance, whereas it did not change in patients with normal nasal resistance; and (5) this therapy increased REM sleep. The findings of the present study corroborate the pathophysiological association of snoring with the nose. To the best of our knowledge, it is the first study to examine in snorers the effect of nasal steroids on snoring indices in association with the breathing route pattern, and adds to the literature by demonstrating that 1-week therapy with nasal budesonide decreases snoring frequency, possibly by increasing nasal breathing epochs, as well as snoring intensity only in patients with increased nasal resistance at baseline, and increases REM sleep. The therapeutic use of nasal steroids for snoring has been supported by studies showing the presence of corticosteroid receptors in the upper airway (Friberg et al., 1998), as well as inflammation and swelling due to snoring-associated vibrations (Hultcrantz et al., 2010). However, the previous trials that have examined the potential beneficial effect of nasal steroids on sleep quality and snoring did not all assess snoring objectively (Craig et al., 2005; Kheirandish-Gozal and Gozal, 2008), and none has taken into account the breathing route pattern (Craig et al., 2005; Kheirandish- Gozal and Gozal, 2008; Kiely et al., 2004). Indeed, Craig et al. (2005) pooled the results from three double-blind, randomized crossover trials of the use of nasal steroids on sleep quality of patients with self-described poor quality of sleep, and found a decrease in sleep problems and sleepiness. This improvement appeared to correlate with improvement of nasal patency, but objective assessment of snoring or sleep apnoea indices were not included (Craig et al., 2005). Additionally, Kiely et al. (2004) examined 10 snorers with rhinitis and failed to show a benefit from fluticasone on snoring time spent above a certain db threshold. However, as the authors cited, the duration of time spent above the threshold was relatively short in most patients, which may reflect the fact that patients were not prescreened to include only those who snored loudly for most of the night (Kiely et al., 2004), which was the case in the current study. Finally, Kheirandish-Gozal and Gozal (2008) showed that intranasal budesonide improved significantly polysomnographic indices in children with mild OSA and adenoidal hypertrophy, but did not include objectively measured snoring parameters. Given that nasal resistance measured during wakefulness at the beginning of the night is lower than subsequent measurements during sleep by 26% (Kohler et al., 2006), it was assumed that nocturnal increased nasal resistance might play a role in the appearance of snoring in snorers with normal nasal resistance at wakefulness. This was the reason we recruited in the current study both snorers with normal and increased nasal resistance at baseline (Table 1). Interestingly, patients with increased nasal resistance at baseline presented a greater response to nasal budesonide in terms of mean and maximum snoring intensity and snoring frequency. This finding, however, must be cautiously interpreted because of the relatively small number of patients with increased nasal resistance (n = 6), though it is in line with the assumption that nasal obstruction results in a more negative intrapharyngeal pressure during inspiration that predisposes to greater oropharyngeal vibrations as the nose represents the primary route of breathing during sleep (Georgalas, 2011). It is noteworthy that the change in nasal breathing epochs was inversely related to the change in snoring frequency, implying that the more prominent nasal breathing becomes the less frequent snores occur. Several lines of evidence support the argument that the lack of nasal breathing induced by nasal obstruction facilitates the appearance of apnoeas. Indeed, Fitzpatrick et al. (2003a,b) documented a marked increase in OSA severity in mouth breathing as compared with nasal breathing, the normal pathway for ventilation during sleep. Furthermore, the proportion of oral and oronasal breathing epochs has been shown to be positively related to the severity of sleep-disordered breathing

6 Nasal steroids and snoring 165 (Koutsourelakis et al., 2006), and that the change in nasal breathing epochs is inversely related with the change in AHI after the surgical improvement of nasal patency (Koutsourelakis et al., 2008a,b). The results of the current study add weight to the same argument, implying that apnoeas and snoring have a parallel pathophysiological development (Pevernagie et al., 2010). Patients in the current study experienced a significant increase in REM sleep after 1 week therapy with nasal budesonide as compared with the nasal placebo. It is interesting that the increase of REM sleep has also been observed in patients with OSA with improved nasal patency even in the absence of any significant improvement of sleep apnoea severity (Heimer et al., 1983; Verse et al., 2002). Thus, it is plausible to hypothesize that the improvement in sleep architecture observed in the current study could be attributed to a reduction in nasal discomfort associated with the decrease of nasal resistance after nasal budesonide therapy (McLean et al., 2005). Some issues and possible weaknesses of the current study must be acknowledged and deserve consideration. Firstly, the instrumentation of nasal cannula/pressure transducer and oral thermistor to detect airflow presents some drawbacks that have been thoroughly discussed previously (Koutsourelakis et al., 2006). Secondly, although sensor dislodgement from the nose or mouth was meticulously checked by the technician on duty, it is possible that slight deviations in thermistor position may not have been completely avoided, and this may have then resulted in nasal airflow contamination of the oral signal. Thirdly, in the current study nasal resistance was not measured continuously, and thus it was not possible to directly, minute by minute, evaluate the association between nocturnal nasal resistance with the change in nasal breathing epochs and snoring indices. Fourthly, the increase in REM and total sleep time at the third assessment could be attributed to the so called first night effect (Scholle et al., 2003). Finally, due to the low number of patients with increased nasal resistance and the ensuing lack of adequate power, the conclusion drawn for this subgroup of patients should be cautiously interpreted. In terms of clinical relevance, the results of this study could provide a therapeutic alternative for clinicians who showed a rather limited efficacy of the short-term application of budesonide in snoring indices. Therefore, our data suggest that the acute effect of nasal corticosteroid on snoring could be regarded as a complementary treatment to other treatment modalities, especially for patients with increased nasal resistance. Moreover, the long-term use of nasal steroid has been shown to have an acceptable safety profile (Schafer et al., 2011). Indeed, based on the results of randomized, double-blind, controlled trials, prolonged use of nasal budesonide (64 lg day 1 ) for allergic rhinitis had an adverse-event profile similar to that of placebo, caused no clinically meaningful suppression of hypothalamic pituitary adrenal axis, and offered both nasal discomfort relief and improved sleep quality (Stanaland, 2004). Consequently, given the short-term results obtained in this study and the reasonably long time needed for intranasal glucocorticoid molecular mechanisms to take effect (Cosio et al., 2005), the long-term effect of nasal budesonide on snoring might be promising. 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