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    Clinical Trial Results:
    The Effect of Morphine on the Human Central Nervous System

    Summary
    EudraCT number
    		 2016-002623-29
    Trial protocol
    		 DK  
    Global end of trial date
    22 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jul 2018
    First version publication date
    21 Jul 2018
    Other versions
    Summary report(s)
    		 EudraCT Results Report

    Trial information

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    Trial identification
    Sponsor protocol code
    Lundbeckstudy2016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aalborg University Hospital
    Sponsor organisation address
    Mølleparkvej 4, Aalborg, Denmark, 9000
    Public contact
    Mech-Sense, Mech-Sense, Aalborg University Hospital, dilelic@gmail.com
    Scientific contact
    Mech-Sense, Mech-Sense, Aalborg University Hospital, dilelic@gmail.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The project aims to investigate the effect of I.V. morphine on the central nervous system (including spinal cord and the brain) and to observe whether these effects are reversed by an opioid-receptor blocker (naloxone).
    Protection of trial subjects
    A doctor was available during every experimental visit for immediate assistance if needed. Moreover, heart rate, noninvasive blood pressure, and peripheral oxygen saturation were continuously monitored and documented every 15 minutes. Additionally, 3 L of oxygen was continuously supplied by a nasal cannula. The infusion would be stopped if the oxygen saturation decreased to less than 92%. If the morphine side effects were too intolerable for the subjects, the morphine IV infusion would immediately be stopped and naloxone would be given. Furthermore, metoloperamide was present in the laboratory and administered to the subjects in case these asked for it. Metoloperamide treats nausea and vomiting. The volunteers were instructed to contact us if there are any issues/side effects/adverse events after the experiment. Moreover, the volunteers were monitored for at least one hour after the experiment until the medical personnel deems they were ready to leave the lab.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The subjects were recruited in Denmark from website www.forsoegsperson.dk website between December 1, 2016 and July 3, 2017.

    Pre-assignment
    Screening details
    		 27 subjects were screened. Each healthy volunteer was asked to meet at The Department of Gastroenterology, Aalborg Hospital for all visits (provided that a healthy volunteer fulfills the criteria to participate and wishes to take part in the study). The initial visit was the screening visit where the volunteers were explained what the study is

    Period 1
    Period 1 title
    Placebo
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The treatment medication was mixed by someone on the research staff not otherwise involved in the study. All study medications were similarly mixed in the same amount of saline solution so that the subject and the experimenter were blinded to study drug.

    Arms
    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline Solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    Route of administration: intravenous Dosage: 10ml saline over ten minutes followed by 50 ml saline for the next hour and 45 minutes (to mimic the morphine infusion) Dosage: 10ml saline bolus followed by 50 ml saline infusion for 45 minutes (to mimic the naloxone infusion) Administered once, on first or second experimental day (the placebo day)

    Number of subjects in period 1
    		Placebo
    Started
    20
    Completed
    20
    Period 2
    Period 2 title
    Morphine
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The treatment medication was mixed by someone on the research staff not otherwise involved in the study. All study medications were similarly mixed in the same amount of saline solution so that the subject and the experimenter were blinded to study drug.

    Arms
    Arm title
    		 Morphine and Naloxone
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    Route of administration: intravenous Dosage: 0.15mg/kg mixed with 10ml saline over ten minutes in the first 7 subjects and 0.12mg/kg mixed with 10ml saline over ten minutes in the last 13 subjects. Thereafter 0.05mg/kg/hr mixed with 50ml saline for the next hour and 45 minutes Administered once, on the first or second experimental visit on the morphine day

    Investigational medicinal product name
    Naloxone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    Route of administration: intravenous Dosage: 2mg mixed with 10ml saline bolus in the first 7 volunteers and 1mg mixed with 10ml saline bolus in the remaining 13 volunteers. This was followed by 4mg/hr mixed with 50ml saline infusion for 45 minutes. Naloxone infusion was initiated 60 minutes after morphine infusion was initiated. When naloxone was given, both morphine and naloxone were infused simultaneously.

    Number of subjects in period 2
    		Morphine and Naloxone
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Placebo Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 23 ± 2 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 20 20
    Subject analysis sets

    Subject analysis set title
    Placebo Group - placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This is placebo treatment in placebo period. This was a cross-over study, so each subject participated in period 1 and period 2. Data between the two periods were compared.

    Subject analysis set title
    Morphine Group - morphine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This is morphine treatment in the morphine period. This was a cross-over study so all subjects participated in Period 1 and Period 2. Data from the two periods were compared.

    Subject analysis set title
    Placebo Group - baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    THis is baseline for placebo period in this cross-over study.

    Subject analysis set title
    Placebo group - placebo + placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This is double placebo infusion during placebo period. This is to mimic the moprhine + naloxone infusion in the morphine period.

    Subject analysis set title
    Morphine Group - baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This is baseline in the morphine period.

    Subject analysis set title
    Morphine Group - morphine + naloxone
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This is morphine and naloxone simultaneous administration during the morphine visit.

    Subject analysis sets values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects
    20
    20
    20
    20
    20
    20
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    0
    0
    0
    0
    0
    0
        Male
    20
    20
    20
    20
    20
    20

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    Morphine and Naloxone
    Reporting group description
    		 -

    Subject analysis set title
    Placebo Group - placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This is placebo treatment in placebo period. This was a cross-over study, so each subject participated in period 1 and period 2. Data between the two periods were compared.

    Subject analysis set title
    Morphine Group - morphine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This is morphine treatment in the morphine period. This was a cross-over study so all subjects participated in Period 1 and Period 2. Data from the two periods were compared.

    Subject analysis set title
    Placebo Group - baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    THis is baseline for placebo period in this cross-over study.

    Subject analysis set title
    Placebo group - placebo + placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This is double placebo infusion during placebo period. This is to mimic the moprhine + naloxone infusion in the morphine period.

    Subject analysis set title
    Morphine Group - baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This is baseline in the morphine period.

    Subject analysis set title
    Morphine Group - morphine + naloxone
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This is morphine and naloxone simultaneous administration during the morphine visit.

    Primary: Reflex EMG

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    End point title
    		 Reflex EMG
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: AUC
        arithmetic mean (standard error)
    34.1 ± 7.3
    28.1 ± 6.4
    31.9 ± 7.1
    34.8 ± 8.7
    40.7 ± 8.1
    43.4 ± 9.3
    Statistical analysis title
    		 Reflex EMG
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Reflex EEG latency peak 1

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    End point title
    		 Reflex EEG latency peak 1
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: uV
        arithmetic mean (standard error)
    111.8 ± 3.7
    111 ± 4.0
    115.4 ± 3.3
    113.5 ± 4
    113.2 ± 3.4
    113.8 ± 4.4
    Statistical analysis title
    		 Reflex EEG latency peak 1
    Comparison groups
    Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone v Placebo Group - placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Reflex EEG latency peak 2

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    End point title
    		 Reflex EEG latency peak 2
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: ms
        arithmetic mean (standard error)
    253.4 ± 7.6
    258.8 ± 8.6
    257.7 ± 8.4
    251.9 ± 8.1
    261.1 ± 8.1
    258.1 ± 8.3
    Statistical analysis title
    		 Reflex EEG latency peak 2
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Reflex EEG amplitude peak 1

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    End point title
    		 Reflex EEG amplitude peak 1
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: uV
        arithmetic mean (standard error)
    19.2 ± 1.7
    19.9 ± 2.0
    20.9 ± 1.8
    19.5 ± 1.9
    21.3 ± 1.8
    20.0 ± 1.8
    Statistical analysis title
    		 Reflex EEG amplitude peak 1
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Reflex EEG amplitude peak 2

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    End point title
    		 Reflex EEG amplitude peak 2
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: uV
        arithmetic mean (standard error)
    26.2 ± 1.7
    24.6 ± 2.1
    27.1 ± 1.7
    25.3 ± 2.1
    27.4 ± 1.8
    26.2 ± 2
    Statistical analysis title
    		 Reflex EEG amplitude peak 2
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Spinal EEG peak 1 latency

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    End point title
    		 Spinal EEG peak 1 latency
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: ms
        arithmetic mean (standard error)
    11.3 ± 0.8
    11.1 ± 0.7
    11.2 ± 0.8
    11.1 ± 0.7
    11 ± 0.6
    11.1 ± 0.7
    Statistical analysis title
    		 Spinal EEG peak 1 latency
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Spinal EEG peak 2 latency

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    End point title
    		 Spinal EEG peak 2 latency
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: ms
        arithmetic mean (standard error)
    13.9 ± 1.1
    14.1 ± 0.8
    14.2 ± 1
    13.9 ± 1
    13.8 ± 0.7
    14 ± 0.8
    Statistical analysis title
    		 Spinal peak 2 latency
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Spinal EEG amplitude peak 1

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    End point title
    		 Spinal EEG amplitude peak 1
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: uV
        arithmetic mean (standard deviation)
    11.3 ± 0.8
    11.2 ± 0.8
    11.1 ± 0.7
    11.1 ± 0.7
    11 ± 0.6
    11.1 ± 0.7
    Statistical analysis title
    		 spinal peak 1 amplitude
    Comparison groups
    Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone v Placebo Group - placebo
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Spinal EEG amplitude peak 2

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    End point title
    		 Spinal EEG amplitude peak 2
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: uV
        arithmetic mean (standard error)
    2.2 ± 0.7
    2.4 ± 0.6
    2.2 ± 0.9
    2.2 ± 1.2
    2.3 ± 0.9
    2.2 ± 0.6
    Statistical analysis title
    		 Spinal EEG peak 2 amplitude
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Somatosensory Evoked Potentials p14 latency

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    End point title
    		 Somatosensory Evoked Potentials p14 latency
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: ms
        arithmetic mean (standard error)
    15.5 ± 0.9
    15.3 ± 0.8
    15.4 ± 0.7
    15.3 ± 0.8
    15.5 ± 0.6
    15.6 ± 0.7
    Statistical analysis title
    		 P14 latency
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: somatosensory evoked potentials N20 latency

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    End point title
    		 somatosensory evoked potentials N20 latency
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: ms
        arithmetic mean (standard error)
    20.6 ± 0.9
    20.9 ± 1.1
    20.7 ± 1.1
    20.6 ± 1
    20.8 ± 0.8
    20.7 ± 0.8
    Statistical analysis title
    		 N20 latency
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Somatosensory evoked potentials P14 amplitude

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    End point title
    		 Somatosensory evoked potentials P14 amplitude
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: uV
        arithmetic mean (standard deviation)
    0.6 ± 0.3
    0.7 ± 0.3
    0.6 ± 0.2
    0.7 ± 0.2
    0.6 ± 0.3
    0.7 ± 0.2
    Statistical analysis title
    		 P14 amplitude
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Somatosensory evoked potentials N20 amplitude

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    End point title
    		 Somatosensory evoked potentials N20 amplitude
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: uV
        arithmetic mean (standard error)
    1.2 ± 0.6
    1.2 ± 0.6
    1.1 ± 0.5
    1.2 ± 0.6
    1.2 ± 0.4
    1.2 ± 0.6
    Statistical analysis title
    		 N20 amplitude
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Resting EEG Delta

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    End point title
    		 Resting EEG Delta
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: uV
        arithmetic mean (standard error)
    17.5 ± 1.1
    16.9 ± 0.8
    17.7 ± 1.2
    17.4 ± 1
    17.9 ± 1
    16.9 ± 0.8
    Statistical analysis title
    		 Resting EEG Delta
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Resting EEG Theta

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    End point title
    		 Resting EEG Theta
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: uV
        arithmetic mean (standard deviation)
    16.9 ± 0.7
    17 ± 0.7
    17.5 ± 0.8
    16.6 ± 0.7
    17 ± 0.6
    17.4 ± 0.8
    Statistical analysis title
    		 Resting EEG Theta
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Resting EEG Alpha

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    End point title
    		 Resting EEG Alpha
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: uV
        arithmetic mean (standard error)
    29.6 ± 1.6
    29.5 ± 1.5
    29.3 ± 1.6
    30.2 ± 1.6
    29 ± 1.4
    30.2 ± 1.4
    Statistical analysis title
    		 Resting EEG Alpha
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Resting EEG Beta

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    End point title
    		 Resting EEG Beta
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: uV
        arithmetic mean (standard error)
    16 ± 0.4
    16.3 ± 0.5
    16.1 ± 0.4
    15.9 ± 0.4
    16.2 ± 0.5
    16 ± 0.4
    Statistical analysis title
    		 Resting EEG Beta
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Tonic Pain EEG Delta

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    End point title
    		 Tonic Pain EEG Delta
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: uV
        arithmetic mean (standard error)
    25.7 ± 1.4
    23.5 ± 1.1
    26.3 ± 1.2
    25.2 ± 1.4
    25.6 ± 1.1
    25.4 ± 1.4
    Statistical analysis title
    		 Tonic Pain EEG Delta
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Tonic Pain EEG Theta

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    End point title
    		 Tonic Pain EEG Theta
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: uV
        arithmetic mean (standard error)
    17.4 ± 0.7
    16.6 ± 0.6
    17.5 ± 0.7
    17.8 ± 0.8
    17.6 ± 0.6
    17.6 ± 0.8
    Statistical analysis title
    		 Tonic Pain EEG Theta
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Tonic Pain EEG Alpha

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    End point title
    		 Tonic Pain EEG Alpha
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: uV
        arithmetic mean (standard error)
    21.9 ± 1.9
    22.8 ± 1.6
    21.4 ± 1.7
    22 ± 1.8
    21.1 ± 1.4
    21.8 ± 1.9
    Statistical analysis title
    		 Tonic Pain EEG Alpha
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Tonic Pain EEG Beta

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    End point title
    		 Tonic Pain EEG Beta
    End point description
    End point type
    Primary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    19
    19
    19
    19
    19
    19
    Units: uV
        arithmetic mean (standard error)
    15.2 ± 0.5
    14.8 ± 0.3
    15.2 ± 0.4
    15.4 ± 0.4
    15.0 ± 0.5
    15.1 ± 0.5
    Statistical analysis title
    		 Tonic Pain EEG Beta
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: Reflex Pain Rating

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    End point title
    		 Reflex Pain Rating
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: cm
        arithmetic mean (standard error)
    2.7 ± 0.4
    2.5 ± 0.4
    2.5 ± 0.4
    3.0 ± 0.4
    3 ± 0.5
    3.2 ± 0.5
    Statistical analysis title
    		 Reflex Pain Scores
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: Reflex Unpleasantness Rating

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    End point title
    		 Reflex Unpleasantness Rating
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: cm
        arithmetic mean (standard error)
    4.6 ± 0.4
    3.6 ± 0.5
    4.6 ± 0.4
    4.5 ± 0.4
    4.6 ± 0.5
    4.7 ± 0.4
    Statistical analysis title
    		 Reflex Unpleasantness Scores
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: Cold-Pressor Pain Rating

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    End point title
    		 Cold-Pressor Pain Rating
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: cm
        arithmetic mean (standard error)
    6.7 ± 0.4
    5.4 ± 0.5
    6.5 ± 0.3
    7 ± 0.3
    6.4 ± 0.3
    6.7 ± 0.3
    Statistical analysis title
    		 Cold-Pressor Pain Scores
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: Cold-Pressor Unpleasantness Rating

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    End point title
    		 Cold-Pressor Unpleasantness Rating
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: cm
        arithmetic mean (standard error)
    8 ± 0.4
    6.3 ± 0.4
    7.9 ± 0.3
    8.2 ± 0.3
    7.7 ± 0.3
    8.1 ± 0.3
    Statistical analysis title
    		 Cold-Pressor Unpleasantness Scores
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: Heat Pain Tolerance Threshold

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    End point title
    		 Heat Pain Tolerance Threshold
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: Celcius
        arithmetic mean (standard error)
    48 ± 0.5
    48.4 ± 0.4
    48.4 ± 0.4
    48.5 ± 0.4
    48.5 ± 0.3
    47.7 ± 0.4
    Statistical analysis title
    		 Heat pain tolerance threshold
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: Electrical Pain Tolerance Threshold

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    End point title
    		 Electrical Pain Tolerance Threshold
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: mA
        arithmetic mean (standard error)
    19.1 ± 2.3
    23.4 ± 3
    18.8 ± 2.1
    18.8 ± 2.3
    17.7 ± 1.9
    18.7 ± 2.2
    Statistical analysis title
    		 Electrical Pain Tolerance Threshold
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: Bone Pressure Pain Tolerance Threshold

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    End point title
    		 Bone Pressure Pain Tolerance Threshold
    End point description
    End point type
    Secondary
    End point timeframe
    Period 1 and Period 2
    End point values
    		 Placebo Group - placebo Morphine Group - morphine Placebo Group - baseline Placebo group - placebo + placebo Morphine Group - baseline Morphine Group - morphine + naloxone
    Number of subjects analysed
    20
    20
    20
    20
    20
    20
    Units: kPa
        arithmetic mean (standard error)
    6735 ± 435
    8678 ± 843
    7504 ± 506
    6434 ± 407
    7506 ± 445
    6572 ± 416
    Statistical analysis title
    		 Bone Pressure Pain Tolerance Threshold
    Comparison groups
    Placebo Group - placebo v Morphine Group - morphine v Placebo Group - baseline v Placebo group - placebo + placebo v Morphine Group - baseline v Morphine Group - morphine + naloxone
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Period 1 and Period 2
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Morphine
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Morphine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Morphine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no adverse events. There were side effects such as drowsiness, nausea and vomitting.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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