CURRENT THEFUI’EUTIC RESEARCH’ VOL. 59, NO. 4, APRIL 1998
EFFECTS OF CHONDROITIN CHARACTERISTICS:
SULFATE ON SNORING A PILOT STUDY
CHRISTINE LENCLUD,l PIERRE CHAPELLE,2 ALAIN VAN MUYLEM,’ PAUL LINKOWSKI: AND JEAN-CLAUDE YERNAULT’
‘Chest Department, Erasme Hospital, University of Brussels, Brussels, ‘Acoustic Laboratory, Polytechnic Faculty of Mons, Mans, and 3Department of Psychiatry, Emsme Hospital, University of Brussels, Brussels, Belgium
ABSTRACT The efficacy of bedtime nasal instillation of chondroitin sulfate solution was tested in a double-masked, crossover, placebo-controlled trial of seven nonapneic subjects who snored. Subjects were assessed for reduction in snoring using conventional polysomnographic studies. The analysis of snoring was performed using the recordings obtained by a multidirectional microphone placed above the subject’s head. Snoring was defined as an inspiratory, raspy, snort-like sound. The percentage of total sleep time (TST) spent snoring and the equal energy level related to sleep were calculated for each nocturnal sleep recording. Results of the sleep studies were similar with placebo and chondroitin sulf’ate. However, the mean percentage of TST spent snoring decreased from 46.6% with placebo to 31.3% with chondroitin sulfate, with important interindividual differences. Differences in the equivalent noise level related to TST decrease in the five subjects who were adequately recorded (74.1* 5.6 dR vs 70.0 f 4.9 dR) did not reach statistical significance. Results of this study suggest that chondroitin sulfate, a long-acting tissuecoating agent, has the potential to reduce snoring. Key words: chondroitin sulfate, snoring, polysomnographic study.
Snoring is a common phenomenon in the general population; between 3% and 31% of the adult population snore habitually.’ In people aged 60 to 65 years, the prevalence of snoring may reach 60% in men and 40% in women.2 The following therapeutic strategies have been used with variable success: weight loss; avoidance of sleep medications, alcohol, and smokingsy4; changes in body position; use of tongue-retaining devices and orthodontic inserts5~6; nasal dilators7,s; and nasal continuous positive airway pressure. ‘JO However, the surgical approaches-correction of nasal
Address correspondence Belgium.
to: Prof. J.-C. Yernault, Erasme Hospital, route de Lennik 808, B-1070 Brussels,
Received for publication on October 23, 1997. Printed in the USA. Reproduction
in whole or part is not permitted.
obstruction and uvulopalatopharyngoplasty-are often considered the definitive treatments for snoring.1’-14 Although serious complications are rare, this surgery is not free of side effects teg, excessive postnasal mucus, nasal regurgitation of fluids, hypernasal speech). Recently, Series and Marc” demonstrated the relative efficacy of protriptyline” (a nonsedating antidepressant) in the treatment of snoring. Although allergies, rhinitis, and chronic congestion of the nasal mucosa from other causes account for more than 25% of the cases of snoring,l’ and although treatment with nasal decongestants or corticosteroids is usually tried, no well-defined studies have confirmed the efficacy of such treatment. Hoffstein et all8 studied the efficacy of phosphocholinamin, a long-lasting tissuelubricating agent, compared with placebo. However, this trial was not double-masked, and sleep was not monitored polygraphically. To the best of our knowledge, no other study has assessed the efficacy of a topical nasal drug in the treatment of snoring (computer literature search, [email protected]
). Chondroitin sulfate* is a natural mucopolysaccharide; its absorbent properties allow the formation of a durable film on nasal and pharyngeal mucosa. Preliminary open-label studies have suggested that nasal instillation of chondroitin sulfate solution may reduce snoring. We hypothesized that reduction in turbulent flow achieved by coating the mucosa with a friction-reducing agent would result in reduced snoring. Chondroitin sulfate is nontoxic and has been shown to be effective in the treatment of dry keratoconjunctivitis.lg The aim of this study was to assess the effects of chondroitin sulfate on snoring characteristics by using a double-masked, crossover, placebocontrolled trial. SUBJECTS
Seven subjects who snored (3 men, 4 women; aged 41 to 57 years; body-mass index, 28.1 * 3.8 kg/m2 [mean * SD]) were included in the study. Each subject had a history of regular snoring confirmed by family or friends. To participate in the study, the apnea-plus-hypopnea index @I-II), defined as AH1 = (nAH x GO)/TST, where nAH is the total number of apnea and hypopnea episodes during the night and TST is the total sleep time in minutes,2’ had to be <10/h (1.3 * 1.7/h), and the subject had to be free of significant otolaryngologic abnormalities. None of the subjects had undergone previous treatment for snoring.
* Trademark: SNORRSTOP Gaboratoires Therabel S.A., Brussels, Belgium).
Snoring was recorded during conventional polysomnographic studies in the Erasme Hospital (University of Brussels, Brussels, Belgium) sleep laboratory. Subjects were assessed on two consecutive nights after an adaptation night in a double-masked, crossover, placebo-controlled manner. The random sequences of the crossover design were selected by drawing lots. Chondroitin sulfate (3 g/100 mL solution, 8 mg/instillation) or placebo contained in identical 60-mL nebulizer bottles to maintain double-masking of the study was administered at bedtime, one instillation into each nostril. The nostrils were pinched for 1 minute to promote contact with the nasal mucosa. Subjects were asked to avoid consuming alcohol for at least 12 hours before each recording session. The experimental protocol was approved by the Erasme Hospital ethics committee, and each subject signed an informed consent form before participation in the study. Recording Procedure An electret microphone (MKE 10, Sennheiser, Wedemark, Germany) was fixed by a wide adhesive band at the level of the suprasternal notch, 1 to 2 cm above the upper margin of the sternum. A multidirectional microphone (FV33, Sony, Tokyo, Japan) was placed 25 cm above the subject’s head. During the 2 treatment nights, the signals from tracheal and room microphones were recorded simultaneously (REVOX B77 MKll, Willi Studer AG, Zurich, Switzerland) under the same conditions (ie, position of microphones, level of amplification). The sleep laboratory was quiet but not soundproof. Data Collection and Statistical Analysis
Polysomnographic recordings were analyzed manually in 20-s epochs, and sleep stages and respiratory events were defined using standard criteria.21,22Tracheal signals sometimes created signal noise arising from the friction between the skin and the microphone or from saturation during heavy snores; therefore, the analysis was performed only on the recordings obtained by the room microphone. Snoring was defined as an inspiratory, raspy, snort-like sound.g The same observer, trained in the reading of polysomnographic records and unaware of the treatment received by the subject, monitored all magnetic bands and calculated the total time spent snoring each night. A sound level dosimeter (type 4426, Bruel and Kjaer, Nacrum, Denmark) measured the equivalent level of the noise (Leq) (ie, the level of a stable noise that has the same energy as the fluctuating noise) (Figure 1). The absolute level (in decibels [dBI) of a noise with an intensity I (W/m21is defined by L = 10 log I/I,, with I, = 1 pW/m2 (level of hearing at 1000 Hz). 236
Figure 1.. The equivalent level (Leq) is the level of a stable noise that has the same energy as the fluctuating noise, which primarily includes normal breath sounds (NBS) and snoring (SN).
The determination of the absolute sound level requires the calibration of each step of measurement with a sound level calibrator producing a known sound level. For signals such as snores, it is not necessary to perform this calibration if the question to be studied concerns the difference between two situations (eg, with and without treatment) under the same conditions of recording and reading. The difference between levels L, and L, can be written as follows: L, - I+ = 10 log Ii/I0 - 10 log I.JIc = 10 log Ii/I,. This difference is completely independent of the reference level I,,. If Leq decreased by 3 dB (ie, 10 dB in the absolute scale) with treatment, it means that the subject snored the same length of time but with a twofold (tenfold) lower intensity or that the subject snored with the same intensity but for a twofold (tenfold) shorter duration, or a combination of the two. Total time spent snoring and the Leq were related to TST. The characteristics of sleep and snoring obtained with placebo and chondroitin sulfate therapy were compared using Student’s paired t test and Wilcoxon’s test. Side effects reported spontaneously on waking were recorded. In addition, the investigator asked the subjects specific questions about possible systemic complaints (eg, excitation, abnormal dreams, drowsiness) and localized complaints (eg, nasal irritation, burning sensation, nosebleed, sneezing). RESULTS
No statistically significant differences were seen in TST or sleep characteristics between subjects receiving chondroitin sulfate and those receiving placebo (Table I). However, important inter-individual differences were noted in the time spent snoring (expressed as a percentage of TST) after 23’7
Table I. Sleep characteristics for placebo versus active treatment.* Placebo
402.6 i 50.6 3;;.9s ; i”i7 217 i 3:5
396.9 * 66.4 310.1 t 77.3 5;.; f ;;o
16.6 f 4.4 9.5 f 4.5
16:3 i 5:l a.2 i 2.8
Arousal index (no. SPTs/h)
NREM q non-rapid eye movement: REM q rapid eye movement; SPT ’ No between-treatment differences were statistically significant.
sleep period time.
chondroitin sulfate administration (Table II, Figure 2). The largest change was seen in a subject whose time spent snoring decreased from 61.6% to 8.0%; a decrease from 51.8% to 29.5% occurred in a second subject; three others had more moderate decreases (53.3% to 38.8%, 46.6% to 33.0%, 35.4% to 28.0%). No significant changes were observed in the remaining two subjects (54.0% to 55.8%, 23.0% to 26.0%). The mean percentage of TST spent snoring decreased from 46.5% with placebo to 31.3% with chondroitin sulfate therapy P < 0.05, using Wilcoxon’s and Student’s paired t tests). The Leq related to TST decreased with chondroitin sulfate therapy in the five subjects who were adequately recorded (71.8 to 70.0 dB, 68.2 to 62.5 dB, 76.0 to 72.4 dB, 78.0 to 72.4 dB, 66.0 to 64.5 dB) (Table III, Figure 3). The measurement of Leq could not be performed in two subjects because of technical problems. The difference between chondroitin sulfate therapy and placebo was not statistically significant. No side effects that were definitely treatment related were reported spontaneously by the subjects on waking. Nevertheless, the specific interview revealed systemic and local complaints. Of these, the complaints that were present before the subjects entered the study were not considered to be treatment related. They included 1 subject with asthenia after both
Table II. Time spent snoring, expressed as a percentage of total sleep time, after administration of chondroitin sulfate and placebo. Subject :
zr: 23:0 46.5 i 13.1
P < 0.05. 238
33:o E 31.3 *‘14.4*
Figure 2. Individual values of the percentage of total sleep time spent snoring obtained with placebo (P) and chondroitin sulfate (CS). P < 0.05.
nights, 1 with slight drowsiness after chondroitin sulfate was administered, and 1 with slight dizziness and subjective feelings of the inability to concentrate after placebo was administered. The other systemic complaints (thirst sensation both nights in 1 subject and slight headache after placebo administration in 1 subject) or local complaints (feeling of slight nasal dryness after placebo in 1 subject and a single sneeze after chondroitin sulfate in 1 subject) were not thought to be treatment related. Based on results of the interview, the number of complaints caused by chondroitin sulfate were similar to that caused by placebo; the difference was not statistically significant.
Table III. Equivalent noise level (Leq) (in decibels) related to total sleep time. Subject
1’ Z’ : ! Mean
2; :s! 66:o 74.1 i 5.6
* Results for 1 and 2 are not included because the recording was not adequate. 239
Figure 3. Individual values of the equivalent level (Leq) related to total sleep time measured with placebo (P) and chondroitin sulfate (CS). DISCUSSION
This pilot study showed that chondroitin sulfate therapy affected the percentage of TST spent snoring in 5 of 7 subjects as well as the Leq in the 5 subjects who were adequately recorded. On average, the equivalent noise level was 4.1 dB lower with treatment, a difference considered to be perceptible by the human ear. 23Because of the small number of subjects in the study, this decrease in sound level was not statistically significant. The efficacy of chondroitin sulfate may be a result of reducing the turbulent flow by coating the nasal and pharyngeal mucosa with a frictionreducing agent. Hoffstein et al” cited the same potential mechanism to explain the efficacy of the long-acting tissue-lubricating and coating agent, phosphocholinamin, in reducing snoring. In that study, the six subjects who received phosphocholinamin as nose drops had their maximum nocturnal decibel level reduced by 13 f 3% (mean * SD) and their snoring index (defined as the number of snores per hour of sleep) reduced by 25 * 12%. One of the problems inherent in evaluating the success rate of various treatments for snoring is the lack of objective documentation of snoring. Although it may be the only complaint that leads to a subject’s referral to a sleep laboratory, snoring is not systematically recorded during sleep studies. Even when snoring is recorded, no reliable methods are available for quantification. Until now, a series of clinical and acoustic methods have been used to assess the efficacy of medical and surgical treatments. The 240
studies of uvulopalatopharyngoplasty11-14 are based on interviewing subjects and their bed partners regarding suppression of snoring, improvement of snoring, or failure of the procedure. Fairbanks24 proposed that an observer (roommate or spouse) be instructed to carefully watch a typical l-hour period of sleep every night to assess snoring. Acoustic measurements of snoring have been reported since 1983, but currently no standard procedures exist regarding placement or number of microphones, calibration of the sound meter, the definition of snoring, or the choice of acoustic variables. In various studies, one or two microphones were placed in the room7,15,25or were taped to the [email protected]
or chest.g*26A snore event was defined as an inspiratory, raspy, snort-like sound (detected by a trained physician),g as a spike in sound intensity above 60 dB15,1sor above 45 dB,26 or as a noise exceeding the baseline by four units and lasting 0.5 s or the maximalsJs.2s and mean2s not_ longer. 27The snoring index, s,9,15,18,26,27 turnal noise level, snoring frequency,26 the total time spent snoring,26 and the percentage of TST above the 60-dB sound pressure level15 were used for the quantitative analysis of snoring. In the present study, the analysis was performed on the recordings obtained by the room microphone because of noise in the tracheal signals. We did not need calibration, because we focused on the change in sound level with treatment. The percentage of TST spent snoring and the equal energy level related to sleep were calculated for each nocturnal recording. The first variable is equivalent to the classical snoring index.8,g*‘5~18,26*27 Snoring was defined as in the study by Berry and Block,g because no consensus exists in establishing a sound level to define snoring, particularly pathologic snoring. The equal energy level is the acoustic index most often used in cases of fluctuating noises; it more closely reflects the perception of the human ear than the mean sound intensity. Treatment tolerance was considered to be excellent, in that no side effects were reported spontaneously by the subjects on waking. At the interview, some subjects complained of problems either experienced before their entry into the study or too minor and erratic to be considered treatment related. Moreover, the number of complaints revealed during the interview were no greater after administration of chondroitin sulfate than after administration of placebo. Although no definitive conclusions can be gathered from our study, the long-term tolerability of nasal instillation of chondroitin sulfate should be good. Actually, chondroitin sulfate is well tolerated when administered topically or orally to treat other pathologic conditions. A 6-month, double-masked study of this compound given as eyedrops in subjects suffering from dry eyes revealed no toxicity.28 In addition, a 3-month, double-masked study of oral chondroitin sulfate (2 g/d) in the treatment of osteoarthritis of the knees and hips revealed no more side effects in the chondroitin sulfate group than in the placebo group, even after an additional a-month follow-up period.2g 241
Results of this study indicate that chondroitin sulfate, a long-acting coating agent, has the potential to reduce snoring and was well tolerated. Larger studies will be required to confirm these results, to identify the responders, and to assess the long-term benefits and tolerability of the drug. Acknowledgments
We thank Therabel S.A., Brussels, for financial support and Professor J. P. Famaey of Therabel Research S.A., Brussels, Belgium, for his help in the preparation of this paper. References: 1. Parish JM, Shepard JW Jr. Cardiovascular effects of sleep disorders. Chest. 1990;97: 1220-1226. 2. Lugaresi E, Cirignotta F, Coccagna G, Piana C. Some epidemiological data on snoring and cardiocircukxtorydisturbances. Sleep. 1980;3:221-224. 3. Bloom JW, Kahenbom WT, Quan SF. Risk factors in a general population for snoring. Importance of cigarette smoking and obesity. Chest. 1988;93:678-683. 4. Rees J. Snoring. Tackle obesity, smoking, and alcohol consumption first. BMJ. 1991;302: 860-861. Editorial. 5. Cartwright RD, SameIson CF. The effects of a nonsurgical treatment for obstructive sleep apnea. The tongue-retaining device. JAMA. 1982;248:705-709. 6. SoII BA, George PT. Treatment of obstructive sleep apnea with a nocturnal airwaypatency appliance. NEJM. 1985;313:386-387. Letter. 7. Hiiijer U, Ejnell H, Hedner J, et al. The effects of nasal dilation on snoring and obstructive sleep apnea. Arch Otolaryngol Head Neck Surg. 1992;118:281-284. 8. Metes A, Cole P, Hoffstein V, MiIjeteig H. Nasal airway dilation and obstructed breathing in sleep. Laryugoscope. 1992;102:1053-1055. 9. Berry RB, Block AJ. Positive nasal airway pressure eliminates snoring as well as obstructive sleep apnea. Chest. 1984,85:X-20. 10. Krieger J. Long-term compliance with nasal continuous positive airway pressure (CPAP) in obstructive sleep apnea patients and nonapneic snorers. SZeep. 1992;15(6 Suppl):S42S46. 11. Simmons FB, Guilleminault C, Silvestri R. Snoring, and some obstructive sleep apnea, can be cured by oropharyngeal surgery. Arch OtolmyngoZ. 1983;109:503-507. 12. Meyer B, Chabolle F, Chouard CH. Resultats et complications a long terme de 1’uvulopaIatopharyngoplastie dans la ronchopathie sans syndrome d’apnb du sommeil. Ann Oto-laryng (Paris). 1988;105:291-297. 13. Ratsantonis GP, Friedman WI-I, Rosenblum BN, Walsh JR. The surgical treatment of snoring A patient’s perspective. Lmyngoscope. 1990;100:138-140. 242
C. LENCLUD ET AL.
14. Macnab T, Blokmanis A, Dickson RI. Long-term results of uvulopaiatopharyngoplasty for snoring. J Otolaryngol. 1992;21:350-354. 15. Series F, Marc I. Effects of protriptyline on snoring characteristics Chest. 1993;104:1418. 16. Borg S, Brodin K. Antidepressant drugs. In: Dukes MNG, ed. Mqyler’s Side-Effects of Drugs. 12th ed. Amsterdam: Elsevier; 1992:30-78. 17. Robin IG. Snoring. Proc R Sot Med. 1968;61:575-582. 18. Hoffstein V, Mateiko S, Haiko S, Taylor R. Reduction in snoring with phosphochoiinamin, a long-acting tissue-lubricating agent. Am J Otolaryngol. 1987;8:236-240. 19. Limberg MB, McCaa C, Kisshng GE, Kaufman HE. Topical application of hyaluronic acid and chondroitin sulfate in the treatment of dry eyes. Am J Ophthalmol. 1987;103:194197. 20. Poirrier R, Lacroix A. SommeiI et respiration. In Cluydts R, Kerkhofs M, eds. Slaap en slaapstoornissen. Sommeil et troubles du sommeil. Brussels: WB Press; 1994:101-150. 21. Rechtschaffen A, Kales A, eds. A Manual of Standardized Terminology, Techniques and Scoring Systems for Sleep Stages of Human Subjects. (Publication 204). Bethesda, Md: National Institutes of Health; 1968. 22. Martin RJ. Indication and standards for cardiopulmonary sleep studies. Sleep. 1985;8: 371-379. 23. Harris CM. Handbook of Acoustical Measurements and Noise Control. New York: McGraw Hill; 1991:1.181.25. 24. Fairbanks DNF. Predicting the effect ofnasal surgery on snoring: A simple test. Ear Nose Throat J. 1991;70:50-52. Letter. 25. Josephson SC, Rosen RC. Response-contingent awakening in the modification of chronic snoring. Sleep. 1983;6:121-129. 26. Hoffstein V, Mateika JH, Mateika S. Snoring and sleep architecture. Am Rev Respir Dis. 1991;143:92-96. 27. Bushel1 MK, Baldock PJ, Antic R, et al. Obligatory nasal breathing: Effects on snoring and sleep apnoea. Med JAust. 1991;155:83-85. 28. Deschamps F, Royer J, Montard H, Andermann C. Treatement des secheresses oculaires par un mucomimetique: La chondroltine sulfate A. Contactologia. 1981;3F131-137. 29. Mazieres B, Loyau G, Menkes CJ, et al. Le chondrortine sulfate dans le traitement de la gonarthrose et de la coxarthrose. R&ultata a 5 mois, d’une etude prospective, multicentrique, contr6lt%, en double aveugle, versus placebo. Rev Rhum Ma1 Osteoartic. 1992;59: 466-472.