1. exp Narcotics/ or exp Opiate Alkaloids/ or exp Fentanyl/ or exp meperidine/ or exp Morphine Derivatives/ or exp Methadone/

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1 Appendix 1A-Search strategy Appendix 1A-Search strategy Search Date: Database searched: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present+Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations November 25, 2014 Search strategy: 1. exp Narcotics/ or exp Opiate Alkaloids/ or exp Fentanyl/ or exp meperidine/ or exp Morphine Derivatives/ or exp Methadone/ 2. (narcoti* or opioid or opium or opiate or remifentanil or fentanyl or sufentanil or alfentanil or codeine or morphine or oxycodone or hydrocodone or hydromorphone or methadone or meperidine).mp or 2 4. exp Sleep Apnea Syndromes/ or sleep apnoea?.mp. or Sleep Apnea?.mp. or "OSAHS".mp. or Hypopnea Syndrome?.mp. or Sleep Hypopnea?.mp. or Hypopnoea Syndrome?.mp. or Sleep Hypopnoea?.mp. or "Hypersomnia with Periodic Respiration".mp. or Sleep Disordered Breathing.mp. or Central Apn?ea.mp. or central apnea?.mp. or Obstructive Apn?ea.mp. or obstructive apnea?.mp. or "OSA".mp. or Central Alveolar Hypoventilation.mp. or "Pickwickian Syndrome?".mp. or "Obesity? Hypoventilation Syndrome?".mp. or "upper airway resistance syndrome?".mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 5. (apnoea hypopnoea ind* or apnea hypopnea ind* or apnoea hypopnea ind* or apnea hypopnoea ind* or "AHI" or Apn?eic hypopn?eic episode* or apnea ind* or apnoea ind* or hypopnoea ind* or hypopnea ind* or respiratory disturbance* ind* or "RDI" or respiratory disorder* ind* or respiratory distress ind* or "RERA" or "RERAs" or "RERA ind*" or "RERAs ind*" or "respiratory effort related arousal*" or "respiratory event related arousal*").mp and 4 and 5 7. limit 6 to ((english or french) and last 30 years)

2 Appendix 1B-Search strategy Appendix 1B-Search strategy Search Date: Database searched: embase 1974-nov 25 Search strategy: 1. exp narcotic analgesic agent/ or opiate/ or opiate derivative/ 2. (narcoti* or opioid or opiate).mp. 3. exp Sleep disordered breathing/ or sleep apnoea?.mp. or Sleep Apnea?.mp. or OSAHS.mp. or Hypopnea Syndrome?.mp. or Sleep Hypopnea?.mp. or Hypopnoea Syndrome?.mp. or Sleep Hypopnoea?.mp. or "Hypersomnia with Periodic Respiration".mp. or Sleep Disordered Breathing.mp. or Central Apn?ea.mp. or central apnea?.mp. or Obstructive Apn?ea.mp. or obstructive apnea?.mp. or Central Alveolar Hypoventilation.mp. or "Pickwickian Syndrome?".mp. or "Obesity? Hypoventilation Syndrome?".mp. or "upper airway resistance syndrome?".mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 4. exp apnea hypopnea index/ or apnoea hypopnoea ind*.mp. or apnea hypopnea ind*.mp. or apnoea hypopnea ind*.mp. or apnea hypopnoea ind*.mp. or "AHI".mp. or Apn?eic hypopn?eic episode*.mp. or apnea ind*.mp. or apnoea ind*.mp. or hypopnoea ind*.mp. or hypopnea ind*.mp. or respiratory disturbance* ind*.mp. or "RDI".mp. or respiratory disorder* ind*.mp. or exp respiratory disturbance index/ or respiratory distress ind*.mp. or "RERA".mp. or "RERAs".mp. or "RERA ind*".mp. or "RERAs ind*".mp. or "respiratory effort related arousal*".mp. or "respiratory event related arousal*".mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 5. 1 or and 4 and 5 7. limit 6 to ((english or french) and last 30 years)

3 Appendix 1C-Search strategy Appendix 1C-Search strategy Search Date: Database searched: EBM Reviews - ACP Journal Club 1991 to November 2014, EBM Reviews - Cochrane Central Register of Controlled Trials October 2014, EBM Reviews - Cochrane Database of Systematic Reviews 2005 to October 2014, EBM Reviews - Database of Abstracts of Reviews of Effects 4th Quarter 2014 Search strategy: 1. (narcoti* or opioid or opium or opiate or remifentanil or fentanyl or sufentanil or alfentanil or codeine or morphine or oxycodone or hydrocodone or hydromorphone or methadone or meperidine).mp. 2. (sleep apnoea? or Sleep Apnea? or "OSAHS" or Hypopnea Syndrome? or Sleep Hypopnea? or Hypopnoea Syndrome? or Sleep Hypopnoea? or "Hypersomnia with Periodic Respiration" or Sleep Disordered Breathing or Central Apn?ea or central apnea? or Obstructive Apn?ea or obstructive apnea? or "OSA" or Central Alveolar Hypoventilation or "Pickwickian Syndrome?" or "Obesity? Hypoventilation Syndrome?" or "upper airway resistance syndrome?").mp. 3. (apnoea hypopnoea ind* or apnea hypopnea ind* or apnoea hypopnea ind* or apnea hypopnoea ind* or "AHI" or Apn?eic hypopn?eic episode* or apnea ind* or apnoea ind* or hypopnoea ind* or hypopnea ind* or respiratory disturbance* ind* or "RDI" or respiratory disorder* ind* or respiratory distress ind* or "RERA" or "RERAs" or "RERA ind*" or "RERAs ind*" or "respiratory effort related arousal*" or "respiratory event related arousal*").mp and 2 and 3 5. limit 4 to english language 6. limit 5 to last 30 years 7. from 4 keep 1-6

4 Appendix 2A and 2B The funnel plots below illustrate publication biais. Appendix 2A- Funnel plot for the data on the apnea hypopnea index (AHI)

5 Appendix 2B- Funnel plot for the data on the central apneas index (CAI)

6 Appendix 3A-Quality Assessment of Case-Control Studies Criteria Yes No 1. Was the research question or objective in this paper clearly stated and appropriate? 2. Was the study population clearly specified and defined? 3. Were controls selected or recruited from the same or similar population that gave rise to the cases (including the same timeframe)? 4. Were the definitions, inclusion and exclusion criteria, algorithms or processes used to identify or select cases and controls valid, reliable, and implemented consistently across all study participants? 5. Were the cases clearly defined and differentiated from controls? 6. Were the investigators able to confirm that the exposure/risk occurred prior to the development of the condition or event that defined a participant as a case? 7. Were the measures of exposure/risk clearly defined, valid, reliable, and implemented consistently (including the same time period) across all study participants? 8. Were key potential confounding variables measured and adjusted statistically in the analyses? If matching was used, did the investigators account for matching during study analysis? Other (CD, NR, NA)* Quality Rating (Good, Fair, or Poor) (see guidance) Rater #1 initials: Rater #2 initials: Additional Comments (If POOR, please state why): *CD, cannot determine; NA, not applicable; NR, not reported (24)

7 Appendix 3B-Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies Criteria Yes No 1. Was the research question or objective in this paper clearly stated? 2. Was the study population clearly specified and defined? 3. Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? 4. For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? 5. Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? 6. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 7. Was loss to follow-up after baseline 20% or less? 8. Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? Other (CD, NR, NA)* Quality Rating (Good, Fair, or Poor) (see guidance) Rater #1 initials: Rater #2 initials: Additional Comments (If POOR, please state why): *CD, cannot determine; NA, not applicable; NR, not reported (24)

8 Appendix 3C-Summary tool for case-control studies Appendix 3C-Summary tool for case-control studies First author, date Research question Study population Groups recruited from the same population Inclusion and exclusion criteria prespecified and applied uniformly Case and control definitions Exposure assessed prior to outcome measurement Exposure measures and assessment Statistical analysis Guilleminault 2010 Ramar 2012 Rose 2014 Rostami 2010 Troitino 2014 Walker 2007 Low Risk High Risk Unclear Risk

9 Appendix 3D-Summary tool for Observational Cohort/Cross-sectional studies Appendix 3D-Summary tool for Observational Cohort/Cross-sectional studies First Author, date of publication Research question Study population Groups recruited from the same population and uniform eligibility criteria Exposure assessed prior to outcome measurement Sufficient timeframe to see an effect Exposure measures and assessment Follow-up rate Statistical analyses Jungquist 2012 Low Risk High Risk Unclear Risk