Methadone Dose and Timing of Administration as Predictors of Sleep Apnea Syndrome During Methadone Maintenance Treatment: A Retrospective Cross-sectional Study

Document Type : Original Article


1 1. Sleep Exploration Centre, La Chartreuse Psychiatric Hospital, 21000 Dijon, France 2. Depression Unit, La Chartreuse Psychiatric Hospital, 21000 Dijon, France

2 1. Medical Mind Association, Yaoundé, Cameroon 2. Sleep Specialized Transversal Training, Psychiatry Internship Program, University of Burgundy, 21000 Dijon, France

3 1. Sleep Exploration Centre, La Chartreuse Psychiatric Hospital, 21000 Dijon, France 2. Addictology Unit, La Chartreuse Psychiatric Hospital, 21000 Dijon, France

4 Sleep Exploration Centre, La Chartreuse Psychiatric Hospital, 21000 Dijon, France

5 Pharmacy Unit, La Chartreuse Psychiatric Hospital, 21000 Dijon, France

6 Service D’épidémiologie Et D’hygiène Hospitalière, CHU Hôpital D’enfants, 14 Rue Paul 10 Gaffarel, 21079, Dijon, France



Background: This study aimed to assess the association of sleep apnea syndrome (SAS) with methadone dose and timing of 
administration in patients receiving methadone maintenance treatment (MMT) for opioid use disorder (OUD).
Methods: This retrospective cross-sectional study was conducted on adult patients receiving MMT who had a nocturnal 
respiratory polygraphy between November 2015 and December 2021. Data on methadone treatment and polygraph recording, 
including the apnea-hypopnea index (AHI) were collected.
Findings: A total of 40 patients, mostly male (72.5%), with a mean age of 35±6.7 years and a mean body mass index (BMI) of 
25.1±4.5 kg/m² were included. The daily dose of methadone was significantly associated with an AHI≥15 events/h as well as 
an AHI≥30 events/h, even after adjustment for age, gender, BMI, and benzodiazepine use. However, these associations were not 
preserved when the time of administration (day vs evening) was considered, while the evening administration was significantly 
associated with an AHI≥15 events/h. The best sensitivity and specificity for the prediction of AHI≥15 events/h and AHI≥30 
events/h were obtained with daily methadone doses of≥72.5 mg and 77.5 mg, respectively.
Conclusion: In this sample of MMT patients, methadone doses of 72.5 mg and 77.5 mg were the best cut-off values for predicting 
AHI≥15 and≥30 events/h, respectively, especially when taken in the evening. These results should draw clinicians’ attention to 
the importance of SAS screening, and further studies are needed, notably comparisons with buprenorphine. 


  1. Gupta R, Levine RL, Cepeda JA, Holtgrave DR. Transforming 
    management of opioid use disorder with universal treatment. 
    N Engl J Med. 2022;387(15):1341-4. doi: 10.1056/
    2. Taylor JL, Samet JH. Opioid use disorder. Ann Intern Med. 
    2022;175(1):ITC1-16. doi: 10.7326/aitc202201180 %m 
    3. Alexander GC, Stoller KB, Haffajee RL, Saloner B. An 
    epidemic in the midst of a pandemic: opioid use disorder and 
    COVID-19. Ann Intern Med. 2020;173(1):57-8. doi: 10.7326/
    4. Gallien Y, Martin A, Caserio-Schönemann C, Le Strat Y, 
    Thiam MM. Epidemiological study of opioid use disorder in 
    French emergency departments, 2010-2018 from OSCOUR 
    database. BMJ Open. 2020;10(10):e037425. doi: 10.1136/
    5. Wilkerson AK, McRae-Clark AL. A review of sleep disturbance 
    in adults prescribed medications for opioid use disorder: 
    potential treatment targets for a highly prevalent, chronic 
    problem. Sleep Med. 2021;84:142-53. doi: 10.1016/j.
    6. Hassamal S, Miotto K, Wang T, Saxon AJ. A narrative review: 
    the effects of opioids on sleep disordered breathing in chronic 
    pain patients and methadone maintained patients. Am J 
    Addict. 2016;25(6):452-65. doi: 10.1111/ajad.12424.
    7. Stein MD, Herman DS, Bishop S, Lassor JA, Weinstock M, 
    Anthony J, et al. Sleep disturbances among methadone 
    maintained patients. J Subst Abuse Treat. 2004;26(3):175-80. 
    doi: 10.1016/s0740-5472(03)00191-0.
    8. Peles E, Schreiber S, Adelson M. Variables associated with 
    perceived sleep disorders in methadone maintenance 
    treatment (MMT) patients. Drug Alcohol Depend. 
    2006;82(2):103-10. doi: 10.1016/j.drugalcdep.2005.08.011.
    9. Correa D, Farney RJ, Chung F, Prasad A, Lam D, Wong J. 
    Chronic opioid use and central sleep apnea: a review of the 
    prevalence, mechanisms, and perioperative considerations. 
    Anesth Analg. 2015;120(6):1273-85. doi: 10.1213/
    10. Vallecillo G, Pedro-Botet J, Fernandez S, Román I, Elosua R, 
    Camps A, et al. High cardiovascular risk in older patients with 
    opioid use disorder: differences with the general population. 
    Drug Alcohol Rev. 2022;41(5):1078-84. doi: 10.1111/
    11. Sweeney MM, Antoine DG, Nanda L, Géniaux H, Lofwall 
    MR, Bigelow GE, et al. Increases in body mass index and 
    cardiovascular risk factors during methadone maintenance treatment. J Opioid Manag. 2019;15(5):367-74. doi: 10.5055/
    12. Sharkey KM, Kurth ME, Anderson BJ, Corso RP, Millman 
    RP, Stein MD. Obstructive sleep apnea is more common 
    than central sleep apnea in methadone maintenance 
    patients with subjective sleep complaints. Drug 
    Alcohol Depend. 2010;108(1-2):77-83. doi: 10.1016/j.
    13. Webster LR, Choi Y, Desai H, Webster L, Grant BJ. Sleepdisordered breathing and chronic opioid therapy. Pain Med. 
    2008;9(4):425-32. doi: 10.1111/j.1526-4637.2007.00343.x.
    14. Peles E, Schreiber S, Adelson M. Documented poor sleep 
    among methadone-maintained patients is associated 
    with chronic pain and benzodiazepine abuse, but not 
    with methadone dose. Eur Neuropsychopharmacol. 
    2009;19(8):581-8. doi: 10.1016/j.euroneuro.2009.04.001.
    15. Xu L, Han F, Keenan BT, Kneeland-Szanto E, Yan H, Dong X, 
    et al. Validation of the Nox-T3 portable monitor for diagnosis 
    of obstructive sleep apnea in Chinese adults. J Clin Sleep 
    Med. 2017;13(5):675-83. doi: 10.5664/jcsm.6582.
    16. Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, 
    et al. Rules for scoring respiratory events in sleep: update of the 
    2007 AASM Manual for the Scoring of Sleep and Associated 
    Events. Deliberations of the Sleep Apnea Definitions Task 
    Force of the American Academy of Sleep Medicine. J Clin 
    Sleep Med. 2012;8(5):597-619. doi: 10.5664/jcsm.2172.
    17. Kapur VK, Auckley DH, Chowdhuri S, Kuhlmann DC, Mehra 
    R, Ramar K, et al. Clinical practice guideline for diagnostic 
    testing for adult obstructive sleep apnea: an American 
    Academy of Sleep Medicine clinical practice guideline. J Clin 
    Sleep Med. 2017;13(3):479-504. doi: 10.5664/jcsm.6506.
    18. Unal I. Defining an optimal cut-point value in ROC analysis: 
    an alternative approach. Comput Math Methods Med. 
    2017;2017:3762651. doi: 10.1155/2017/3762651.
    19. Walker JM, Farney RJ, Rhondeau SM, Boyle KM, Valentine K, 
    Cloward TV, et al. Chronic opioid use is a risk factor for the 
    development of central sleep apnea and ataxic breathing. J 
    Clin Sleep Med. 2007;3(5):455-61.
    20. Ripamonti C, Groff L, Brunelli C, Polastri D, Stavrakis A, 
    De Conno F. Switching from morphine to oral methadone 
    in treating cancer pain: what is the equianalgesic dose 
    ratio? J Clin Oncol. 1998;16(10):3216-21. doi: 10.1200/
    21. Ayonrinde OT, Bridge DT. The rediscovery of methadone for 
    cancer pain management. Med J Aust. 2000;173(10):536-40.
    22. Mercadante S, Casuccio A, Fulfaro F, Groff L, Boffi R, Villari 
    P, et al. Switching from morphine to methadone to improve 
    analgesia and tolerability in cancer patients: a prospective 
    study. J Clin Oncol. 2001;19(11):2898-904. doi: 10.1200/
    23. Wong E, Walker KA. A review of common methods to convert 
    morphine to methadone. J Community Hosp Intern Med 
    Perspect. 2012;2(4):19541. doi: 10.3402/jchimp.v2i4.19541.
    24. Ahmad A, Ahmad R, Meteb M, Ryan CM, Leung RS, 
    Montandon G, et al. The relationship between opioid use 
    and obstructive sleep apnea: a systematic review and metaanalysis. Sleep Med Rev. 2021;58:101441. doi: 10.1016/j.
    25. Chen K, Yaggi HK, Fiellin DA, DeRycke EC, Athar W, Haskell 
    S, et al. Associations between obstructive sleep apnea and 
    prescribed opioids among veterans. Pain. 2020;161(9):2035-
    40. doi: 10.1097/j.pain.0000000000001906.
    26. Roisman G, Rabec C, Escourrou P. Apnées et Hypopnées 
    Centrales du Sommeil [Internet]. EM-Consulte. Masson 
    E. Available from:
    Accessed December 11, 2022.
    27. Mikhaeil JS, Pepper CG, Hayward GC. Mechanisms of 
    opioid-induced respiratory depression in sleep apnoea: new 
    insights for anaesthesiology. J Physiol. 2020;598(18):3827-8. 
    doi: 10.1113/jp280214.
    28. Wang D, Yee BJ, Grunstein RR, Chung F. Chronic opioid use 
    and central sleep apnea, where are we now and where to go? 
    A state of the art review. Anesth Analg. 2021;132(5):1244-53. 
    doi: 10.1213/ane.0000000000005378.
    29. Freire C, Sennes LU, Polotsky VY. Opioids and obstructive 
    sleep apnea. J Clin Sleep Med. 2022;18(2):647-52. doi: 
    30. Salloum A, Rowley JA, Mateika JH, Chowdhuri S, Omran Q, 
    Badr MS. Increased propensity for central apnea in patients 
    with obstructive sleep apnea: effect of nasal continuous 
    positive airway pressure. Am J Respir Crit Care Med. 
    2010;181(2):189-93. doi: 10.1164/rccm.200810-1658OC.
    31. Yue HJ, Guilleminault C. Opioid medication and sleepdisordered breathing. Med Clin North Am. 2010;94(3):435-
    46. doi: 10.1016/j.mcna.2010.02.007.
    32. Davis AM, Inturrisi CE. d-Methadone blocks morphine 
    tolerance and N-methyl-D-aspartate-induced hyperalgesia. J 
    Pharmacol Exp Ther. 1999;289(2):1048-53.
    33. Cheatle MD, Webster LR. Opioid therapy and sleep disorders: 
    risks and mitigation strategies. Pain Med. 2015;16 Suppl 
    1:S22-6. doi: 10.1111/pme.12910.
    34. Inturrisi CE, Verebely K. The levels of methadone in the 
    plasma in methadone maintenance. Clin Pharmacol Ther. 
    1972;13(5 Pt 1):633-7. doi: 10.1002/cpt1972135part1633.
    35. Eap CB, Buclin T, Baumann P. Interindividual variability of 
    the clinical pharmacokinetics of methadone: implications for 
    the treatment of opioid dependence. Clin Pharmacokinet. 
    2002;41(14):1153-93. doi: 10.2165/00003088-200241140-
    36. Barbosa Neto JO, Garcia MA, Garcia JB. Revisiting 
    methadone: pharmacokinetics, pharmacodynamics 
    and clinical indication. Rev Dor. 2015;16(1):60-6. doi: 
    37. Adimi Naghan P, Setareh J, Malekmohammad M. The effect 
    of buprenorphine vs methadone on sleep breathing disorders. 
    Adv Respir Med. 2021;89(4):439-43. doi: 10.5603/ARM.
    38. Wang D, Lintzeris N, Leung S, Haber PS, Yee BJ, Grunstein RR. 
    Reversal of centr