Morphine in Moderate Obstructive Sleep Apnoea

Study Overview
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Brief Summary
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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
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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.

Official Title
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The Effect of Acute Intravenous Morphine Administration on Sleep Disordered Breathing (SDB) in Patients With Moderate Obstructive Sleep Apnoea (OSA): A Paired Design Trial

Conditions
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Obstructive Sleep Apnoea

Intervention / Treatment
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* Drug: Morphine sulphate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Morphine sulphate<br>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<br>* 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.<br>* Other names: Morphine sulphate 10mg/ml;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 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 | Percentage of time spent with nocturnal saturations of less than or equal to 90% measured by pulse oximetry during the rPSG | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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