Morphine in Moderate Obstructive Sleep Apnoea

NCT03127800 | Terminated Phase 3 DMC

• 1 other identifier: P01911
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Change in Apnoea-Hypopnea Index (AHI)

  Change in the mean number of apnoeas and hypopneas.

  Change in AHI from baseline Respiratory Polygraphy (rPSG) through to completion of study at overnight visit, within 4 months of baseline

Secondary Outcomes (2)

• Change in arterial oxygen desaturations

  Change in arterial oxygen desaturations from baseline Respiratory Polygraphy (rPSG) through to completion of study at overnight visit, within 4 months of baseline

• Change in the percentage of time spent with nocturnal saturations

  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

Study Arms (1)

Morphine sulphate

EXPERIMENTAL

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

Drug: Morphine sulphate

Interventions

Morphine sulphate DRUG

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.

Also known as: Morphine sulphate 10mg/ml

Morphine sulphate

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Papworth Hospital NHS Foundation Trust: lead

Study Sites (1)

Papworth Hospital NHS Foundation Trust

Papworth Everard, Cambridgeshire, CB23 3RE, United Kingdom

Location

Related Publications (23)

• 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.

  PMID: 14742377 BACKGROUND

• 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.

  PMID: 19104169 BACKGROUND

• Boldt J, Thaler E, Lehmann A, Papsdorf M, Isgro F. RETRACTED: 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.

  PMID: 9854662 BACKGROUND

• 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.

  PMID: 15087614 BACKGROUND

• 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.

  PMID: 4014768 BACKGROUND

• 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.

  PMID: 17557450 BACKGROUND

• 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.

  PMID: 11254524 BACKGROUND

• 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.

  PMID: 2530406 BACKGROUND

• 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.

  PMID: 16645462 BACKGROUND

• 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.

  PMID: 21836134 BACKGROUND

• Koo, CY. Respiratory effects of opioids in perioperative medicine. The Open Anesthesiology Journal (Suppl 1-M6):23-4. 2011.

  BACKGROUND

• 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.

  PMID: 16171294 BACKGROUND

• 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.

  PMID: 18683000 BACKGROUND

• Scottish Intercollegiate Guidelines Network. Management of Obstructive Sleep Apnoea/Hypopnoea Syndrome in Adults. A national clinical guideline. (Guideline Number 73). 2003.

  BACKGROUND

• 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.

  PMID: 9249130 BACKGROUND

• 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.

  PMID: 16477954 BACKGROUND

• American Pain Society. Principles of analgesic use in the treatment of acute pain and cancer pain. 1999.

  BACKGROUND

• 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.

  PMID: 12753355 BACKGROUND

• 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.

  PMID: 16162728 BACKGROUND

• 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.

  PMID: 18489633 BACKGROUND

• 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.

  PMID: 9286886 BACKGROUND

• 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.

  PMID: 9406321 BACKGROUND

• 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.

  PMID: 8464434 BACKGROUND

MeSH Terms

Conditions

Sleep Apnea, Obstructive; Sleep Apnea Syndromes; Sleep Apnea, Central; Hypoxia; Hypercapnia; Cheyne-Stokes Respiration; Agnosia; Respiratory Aspiration

Interventions

Morphine

Condition Hierarchy (Ancestors)

Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Perceptual Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Pathologic Processes

Intervention Hierarchy (Ancestors)

Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Study Officials

• Ian Smith, MBBS

  Papworth Hospital NHS Foundation Trust

  STUDY DIRECTOR

• Martina Mason, MBBS

  Papworth Hospital NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2016
• First Posted: April 25, 2017
• Study Start: May 20, 2016
• Primary Completion: November 4, 2017
• Study Completion: June 6, 2018
• Last Updated: November 29, 2018

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)