search
Back to results

Morphine in Moderate Obstructive Sleep Apnoea (MIMOSA)

Primary Purpose

Obstructive Sleep Apnoea

Status
Terminated
Phase
Phase 3
Locations
United Kingdom
Study Type
Interventional
Intervention
Morphine sulphate
Sponsored by
Papworth Hospital NHS Foundation Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Obstructive Sleep Apnoea focused on measuring Obstructive Sleep Apnoea, Morphine sulphate, Sleep Disordered Breathing, Central Sleep Apnoea, Hypoxaemia, Hypercapnia, Cheyne-Stokes Respiration, Analgesia, Respiration, Apnoea-Hypopnea Index, Oxygen Desaturation Index, Oximetry, Respiratory Polygraphy, Polysomnography

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age ≥ 18 years
  2. Patients with diagnosis of moderate or severeOSA at screening, diagnosed by nocturnal oximetry, rPSG or PSG (defined as AHI or ODI of 15-50 events/hour) established on Continuous Positive Airway Pressure (CPAP)
  3. Patients established on CPAP with confirmed moderate OSA (AHI 15-29 events/hr) 6 nights after withdrawal of CPAP (confirmed at baseline rPSG)
  4. Patients diagnosed with moderate OSA by rPSG or PSG, naïve to CPAP treatment

Exclusion Criteria:

  • Inability to give informed consent or comply with the protocol
  • Current, clinically significant acute respiratory tract infection (at screening and at study visit)
  • Chronic respiratory disease (other than OSA), symptomatic ischemic heart disease
  • Pregnancy or suspected pregnancy/breast feeding
  • Current or recent (within last week of entering the trial and for the duration fo the trial) use of gabapentin, pregabalin, melatonin, mirtazapine, benzodiazepines, barbiturates, sodium oxybate, ramelteon, Z-drugs and opiates/opioids
  • Monoamine oxidase inhibitors (MAOIs), linezolid taken within two weeks of participation in the trial
  • A known allergy to the investigational medicinal product (IMP) or non investigational medicinal product(s) (NIMP)(s)
  • Patients with an inadequate command of English and such that an interpreter would be required overnight
  • Change in weight of greater than 5% since the baseline rPSG
  • Vital signs recordings (oxygen saturations, blood pressure, pulse rate) that in the clinician's opinion deem the patient unsafe to participate in the trial
  • Clinician deems the patient unsafe to participate in the trial (e.g. severely sleepy patients who cannot withdraw from CPAP)
  • CPAP intolerant/poor responder
  • History of drug abuse (oral and intravenous) including: alcohol, substituted amphetamines, barbiturates, benzodiazepines, cocaine, methaqualone, cannabis and opioids
  • A drop of oxygen saturations below 85% continuously for longer than five minutes during the baseline rPSG
  • Professional driver

Sites / Locations

  • Papworth Hospital NHS Foundation Trust

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Morphine sulphate

Arm Description

Participants will be given a first dose of morphine sulphate (intravenously) before bedtime and a second dose four hours later. In both instances 4 mg of intravenous ondansetron will be administered after the morphine sulphate dose to prevent sickness

Outcomes

Primary Outcome Measures

Change in Apnoea-Hypopnea Index (AHI)
Change in the mean number of apnoeas and hypopneas.

Secondary Outcome Measures

Change in arterial oxygen desaturations
Number of arterial oxygen desaturations of greater than or equal to 4% per hour (Oxygen Desaturation Index) measured by pulse oximetry during the rPSG
Change in the percentage of time spent with nocturnal saturations
Percentage of time spent with nocturnal saturations of less than or equal to 90% measured by pulse oximetry during the rPSG

Full Information

First Posted
June 13, 2016
Last Updated
November 28, 2018
Sponsor
Papworth Hospital NHS Foundation Trust
search

1. Study Identification

Unique Protocol Identification Number
NCT03127800
Brief Title
Morphine in Moderate Obstructive Sleep Apnoea
Acronym
MIMOSA
Official Title
The Effect of Acute Intravenous Morphine Administration on Sleep Disordered Breathing (SDB) in Patients With Moderate Obstructive Sleep Apnoea (OSA): A Paired Design Trial
Study Type
Interventional

2. Study Status

Record Verification Date
November 2018
Overall Recruitment Status
Terminated
Why Stopped
Difficulties with recruitment
Study Start Date
May 20, 2016 (Actual)
Primary Completion Date
November 4, 2017 (Actual)
Study Completion Date
June 6, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Papworth Hospital NHS Foundation Trust

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The aim of this study is to investigate the effects of morphine (a drug commonly used for the treatment of moderate to severe pain, particularly following surgery) on the number of pauses in breathing in patients with moderate obstructive sleep apnoea (OSA). Morphine has been shown to reduce upper airway muscle tone and can also cause shallow breathing, which can affect breathing function in patients with sleep apnoea. However, to date these effects have not been proven in clinical trials. Although, caution is advised when prescribing morphine to patients with sleep apnoea, there is currently no strong evidence that morphine makes sleep apnoea worse. Only one randomised controlled trial (considered the gold standard in medical research) has shown no worsening of symptoms for patients with sleep apnoea. The effect of morphine on patients with sleep apnoea will be assessed in a safe, controlled, hospital environment. Information from the study will help inform doctors about the safety of giving morphine to patients with sleep apnoea in urgent situations, for example after surgery. The results of this study will enable clinicians to make better decisions when prescribing this drug to patients with OSA in the future.
Detailed Description
Sleep Disordered Breathing (SDB) is a term used to cover a range of breathing events encountered during sleep and includes Obstructive Sleep Apnoea (OSA). OSA is the most common form of SDB and is caused by partial or complete upper airway occlusion during sleep leading to repetitive arousals to restore the airway patency. These frequent, obstructive events can be associated with symptoms of unrefreshing sleep and adverse health outcomes. The incidence of OSA is increasing due to rising levels of obesity, which has been identified as the strongest risk factor for developing OSA. It is estimated that at present 80% of sufferers are undiagnosed. It must therefore be assumed that some of these patients are referred for surgery. Morphine, opiates and opioids remain the treatment of choice for moderate and severe pain relief. Inevitably, a large number of patients will be presenting for surgery and receiving postoperative opioid analgesia. Opioids may reduce respiratory rate and tidal volume, decrease chemoresponsiveness to hypercapnia/hypoxia as well as decrease upper airway muscle tone. These effects might further impair respiratory function in patients with SDB. There is limited data showing increased extubation complications, increased incidence of paradoxical breathing patterns and pronounced oxygen desaturations in patients with SDB receiving opioid-based analgesia, but only one randomised controlled trial examining the effect of an opioid in subjects with SDB. Therefore, the current evidence base regarding the management of patients with OSA and their peri-operative risk is sparse. As such the current recommendation from the American Society of Anaesthesiologists to limit the use of opioids in such patients, is based on expert opinion only. Indeed the effect of opioid analgesia on patients with SDB remains poorly understood, making informed decisions when prescribing such substances to patients with SDB a challenge. This prospective, paired design trial will investigate the effect of intravenous morphine sulphate on respiration during sleep in patients with moderate OSA.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obstructive Sleep Apnoea
Keywords
Obstructive Sleep Apnoea, Morphine sulphate, Sleep Disordered Breathing, Central Sleep Apnoea, Hypoxaemia, Hypercapnia, Cheyne-Stokes Respiration, Analgesia, Respiration, Apnoea-Hypopnea Index, Oxygen Desaturation Index, Oximetry, Respiratory Polygraphy, Polysomnography

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Morphine sulphate
Arm Type
Experimental
Arm Description
Participants will be given a first dose of morphine sulphate (intravenously) before bedtime and a second dose four hours later. In both instances 4 mg of intravenous ondansetron will be administered after the morphine sulphate dose to prevent sickness
Intervention Type
Drug
Intervention Name(s)
Morphine sulphate
Other Intervention Name(s)
Morphine sulphate 10mg/ml
Intervention Description
5mg of intravenous morphine sulphate diluted to 5ml with normal saline (0.9% sodium chloride) will be administered 30 minutes before participant's bed time. The same dose will be administered four hours later. In both instances 4 mg of intravenous ondansetron will be administered after the morphine sulphate dose to prevent sickness.
Primary Outcome Measure Information:
Title
Change in Apnoea-Hypopnea Index (AHI)
Description
Change in the mean number of apnoeas and hypopneas.
Time Frame
Change in AHI from baseline Respiratory Polygraphy (rPSG) through to completion of study at overnight visit, within 4 months of baseline
Secondary Outcome Measure Information:
Title
Change in arterial oxygen desaturations
Description
Number of arterial oxygen desaturations of greater than or equal to 4% per hour (Oxygen Desaturation Index) measured by pulse oximetry during the rPSG
Time Frame
Change in arterial oxygen desaturations from baseline Respiratory Polygraphy (rPSG) through to completion of study at overnight visit, within 4 months of baseline
Title
Change in the percentage of time spent with nocturnal saturations
Description
Percentage of time spent with nocturnal saturations of less than or equal to 90% measured by pulse oximetry during the rPSG
Time Frame
Change in percentage of time spent with nocturnal saturations from baseline Respiratory Polygraphy (rPSG) through to completion of study at overnight visit, within 4 months of baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 18 years Patients with diagnosis of moderate or severeOSA at screening, diagnosed by nocturnal oximetry, rPSG or PSG (defined as AHI or ODI of 15-50 events/hour) established on Continuous Positive Airway Pressure (CPAP) Patients established on CPAP with confirmed moderate OSA (AHI 15-29 events/hr) 6 nights after withdrawal of CPAP (confirmed at baseline rPSG) Patients diagnosed with moderate OSA by rPSG or PSG, naïve to CPAP treatment Exclusion Criteria: Inability to give informed consent or comply with the protocol Current, clinically significant acute respiratory tract infection (at screening and at study visit) Chronic respiratory disease (other than OSA), symptomatic ischemic heart disease Pregnancy or suspected pregnancy/breast feeding Current or recent (within last week of entering the trial and for the duration fo the trial) use of gabapentin, pregabalin, melatonin, mirtazapine, benzodiazepines, barbiturates, sodium oxybate, ramelteon, Z-drugs and opiates/opioids Monoamine oxidase inhibitors (MAOIs), linezolid taken within two weeks of participation in the trial A known allergy to the investigational medicinal product (IMP) or non investigational medicinal product(s) (NIMP)(s) Patients with an inadequate command of English and such that an interpreter would be required overnight Change in weight of greater than 5% since the baseline rPSG Vital signs recordings (oxygen saturations, blood pressure, pulse rate) that in the clinician's opinion deem the patient unsafe to participate in the trial Clinician deems the patient unsafe to participate in the trial (e.g. severely sleepy patients who cannot withdraw from CPAP) CPAP intolerant/poor responder History of drug abuse (oral and intravenous) including: alcohol, substituted amphetamines, barbiturates, benzodiazepines, cocaine, methaqualone, cannabis and opioids A drop of oxygen saturations below 85% continuously for longer than five minutes during the baseline rPSG Professional driver
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ian Smith, MBBS
Organizational Affiliation
Papworth Hospital NHS Foundation Trust
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Martina Mason, MBBS
Organizational Affiliation
Papworth Hospital NHS Foundation Trust
Official's Role
Principal Investigator
Facility Information:
Facility Name
Papworth Hospital NHS Foundation Trust
City
Papworth Everard
State/Province
Cambridgeshire
ZIP/Postal Code
CB23 3RE
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
There is no plan to make individual participant data available
Citations:
PubMed Identifier
14742377
Citation
Beloeil H, Delage N, Negre I, Mazoit JX, Benhamou D. The median effective dose of nefopam and morphine administered intravenously for postoperative pain after minor surgery: a prospective randomized double-blinded isobolographic study of their analgesic action. Anesth Analg. 2004 Feb;98(2):395-400. doi: 10.1213/01.ANE.0000093780.67532.95.
Results Reference
background
PubMed Identifier
19104169
Citation
Bernards CM, Knowlton SL, Schmidt DF, DePaso WJ, Lee MK, McDonald SB, Bains OS. Respiratory and sleep effects of remifentanil in volunteers with moderate obstructive sleep apnea. Anesthesiology. 2009 Jan;110(1):41-9. doi: 10.1097/ALN.0b013e318190b501.
Results Reference
background
PubMed Identifier
9854662
Citation
Boldt J, Thaler E, Lehmann A, Papsdorf M, Isgro F. Pain management in cardiac surgery patients: comparison between standard therapy and patient-controlled analgesia regimen. J Cardiothorac Vasc Anesth. 1998 Dec;12(6):654-8. doi: 10.1016/s1053-0770(98)90237-3.
Results Reference
background
PubMed Identifier
15087614
Citation
Brown KA, Laferriere A, Moss IR. Recurrent hypoxemia in young children with obstructive sleep apnea is associated with reduced opioid requirement for analgesia. Anesthesiology. 2004 Apr;100(4):806-10; discussion 5A. doi: 10.1097/00000542-200404000-00009.
Results Reference
background
PubMed Identifier
4014768
Citation
Catley DM, Thornton C, Jordan C, Lehane JR, Royston D, Jones JG. Pronounced, episodic oxygen desaturation in the postoperative period: its association with ventilatory pattern and analgesic regimen. Anesthesiology. 1985 Jul;63(1):20-8. doi: 10.1097/00000542-198507000-00004.
Results Reference
background
PubMed Identifier
17557450
Citation
Dimsdale JE, Norman D, DeJardin D, Wallace MS. The effect of opioids on sleep architecture. J Clin Sleep Med. 2007 Feb 15;3(1):33-6.
Results Reference
background
PubMed Identifier
11254524
Citation
Duran J, Esnaola S, Rubio R, Iztueta A. Obstructive sleep apnea-hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yr. Am J Respir Crit Care Med. 2001 Mar;163(3 Pt 1):685-9. doi: 10.1164/ajrccm.163.3.2005065.
Results Reference
background
PubMed Identifier
2530406
Citation
Esclamado RM, Glenn MG, McCulloch TM, Cummings CW. Perioperative complications and risk factors in the surgical treatment of obstructive sleep apnea syndrome. Laryngoscope. 1989 Nov;99(11):1125-9. doi: 10.1288/00005537-198911000-00004.
Results Reference
background
PubMed Identifier
16645462
Citation
Gross JB, Bachenberg KL, Benumof JL, Caplan RA, Connis RT, Cote CJ, Nickinovich DG, Prachand V, Ward DS, Weaver EM, Ydens L, Yu S; American Society of Anesthesiologists Task Force on Perioperative Management. Practice guidelines for the perioperative management of patients with obstructive sleep apnea: a report by the American Society of Anesthesiologists Task Force on Perioperative Management of patients with obstructive sleep apnea. Anesthesiology. 2006 May;104(5):1081-93; quiz 1117-8. doi: 10.1097/00000542-200605000-00026. No abstract available.
Results Reference
background
PubMed Identifier
21836134
Citation
Kohler M, Stoewhas AC, Ayers L, Senn O, Bloch KE, Russi EW, Stradling JR. Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med. 2011 Nov 15;184(10):1192-9. doi: 10.1164/rccm.201106-0964OC.
Results Reference
background
Citation
Koo, CY. Respiratory effects of opioids in perioperative medicine. The Open Anesthesiology Journal (Suppl 1-M6):23-4. 2011.
Results Reference
background
PubMed Identifier
16171294
Citation
Kushida CA, Littner MR, Morgenthaler T, Alessi CA, Bailey D, Coleman J Jr, Friedman L, Hirshkowitz M, Kapen S, Kramer M, Lee-Chiong T, Loube DL, Owens J, Pancer JP, Wise M. Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep. 2005 Apr;28(4):499-521. doi: 10.1093/sleep/28.4.499.
Results Reference
background
PubMed Identifier
18683000
Citation
Mogri M, Desai H, Webster L, Grant BJ, Mador MJ. Hypoxemia in patients on chronic opiate therapy with and without sleep apnea. Sleep Breath. 2009 Mar;13(1):49-57. doi: 10.1007/s11325-008-0208-4. Epub 2008 Aug 6.
Results Reference
background
Citation
Scottish Intercollegiate Guidelines Network. Management of Obstructive Sleep Apnoea/Hypopnoea Syndrome in Adults. A national clinical guideline. (Guideline Number 73). 2003.
Results Reference
background
PubMed Identifier
9249130
Citation
Ostermeier AM, Roizen MF, Hautkappe M, Klock PA, Klafta JM. Three sudden postoperative respiratory arrests associated with epidural opioids in patients with sleep apnea. Anesth Analg. 1997 Aug;85(2):452-60. doi: 10.1097/00000539-199708000-00037. No abstract available.
Results Reference
background
PubMed Identifier
16477954
Citation
Shaw IR, Lavigne G, Mayer P, Choiniere M. Acute intravenous administration of morphine perturbs sleep architecture in healthy pain-free young adults: a preliminary study. Sleep. 2005 Jun;28(6):677-82. doi: 10.1093/sleep/28.6.677. Erratum In: Sleep. 2006 Feb 1;29(2):136. Dosage error in published abstract; MEDLINE/PubMed abstract corrected.
Results Reference
background
Citation
American Pain Society. Principles of analgesic use in the treatment of acute pain and cancer pain. 1999.
Results Reference
background
PubMed Identifier
12753355
Citation
Stradling J, Smith D, Radulovacki M, Carley D. Effect of ondansetron on moderate obstructive sleep apnoea, a single night, placebo-controlled trial. J Sleep Res. 2003 Jun;12(2):169-70. doi: 10.1046/j.1365-2869.2003.00342.x. No abstract available.
Results Reference
background
PubMed Identifier
16162728
Citation
Wang D, Teichtahl H, Drummer O, Goodman C, Cherry G, Cunnington D, Kronborg I. Central sleep apnea in stable methadone maintenance treatment patients. Chest. 2005 Sep;128(3):1348-56. doi: 10.1378/chest.128.3.1348.
Results Reference
background
PubMed Identifier
18489633
Citation
Webster LR, Choi Y, Desai H, Webster L, Grant BJ. Sleep-disordered breathing and chronic opioid therapy. Pain Med. 2008 May-Jun;9(4):425-32. doi: 10.1111/j.1526-4637.2007.00343.x.
Results Reference
background
PubMed Identifier
9286886
Citation
Yarmush J, D'Angelo R, Kirkhart B, O'Leary C, Pitts MC 2nd, Graf G, Sebel P, Watkins WD, Miguel R, Streisand J, Maysick LK, Vujic D. A comparison of remifentanil and morphine sulfate for acute postoperative analgesia after total intravenous anesthesia with remifentanil and propofol. Anesthesiology. 1997 Aug;87(2):235-43. doi: 10.1097/00000542-199708000-00009.
Results Reference
background
PubMed Identifier
9406321
Citation
Young T, Evans L, Finn L, Palta M. Estimation of the clinically diagnosed proportion of sleep apnea syndrome in middle-aged men and women. Sleep. 1997 Sep;20(9):705-6. doi: 10.1093/sleep/20.9.705.
Results Reference
background
PubMed Identifier
8464434
Citation
Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993 Apr 29;328(17):1230-5. doi: 10.1056/NEJM199304293281704.
Results Reference
background

Learn more about this trial

Morphine in Moderate Obstructive Sleep Apnoea

We'll reach out to this number within 24 hrs