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    Clinical Trial Results:
    METATONS - Intraoperative methadone for postoperative pain in patients undergoing tonsillectomy - a randomized controlled trial

    Summary
    EudraCT number
    		 2022-002496-11
    Trial protocol
    		 DK  
    Global end of trial date
    30 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 May 2025
    First version publication date
    28 May 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    07072022v1.0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05445856
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juels Jensens Boulevard, Aarhus, Denmark, 8200
    Public contact
    Kristian Dahl Friesgaard, Aarhus University Hospital, 0045 25113204,
    Scientific contact
    Kristian Dahl Friesgaard, Aarhus University Hospital, 0045 25113204,
    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
    15 Apr 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to investigate the effect of a single dose of intravenous intraoperative methadone on postoperative opioid consumption, pain and side effects in patients scheduled for tonsillectomy. A single dose of intravenous intraoperative fentanyl will be used as an active comparator.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and Guidelines for Good Clinical Practice (GCP) and monitored by the GCP unit at Aarhus University Hospital, Aarhus, Denmark. The study protocol was approved by the Danish Protection Agency, the Central Denmark Region Committees on Health Research Ethics , and the Danish Health and Medicines Authority
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Oct 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 120
    Worldwide total number of subjects
    120
    EEA total number of subjects
    120
    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)
    120
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were screened for inclusion at the first ambulatory contact at Randers Regional Hospital, Randers, Denmark, and informed oral and written consent was obtained before surgery. Adults scheduled for elective tonsillectomy were enrolled.

    Pre-assignment
    Screening details
    		 Patients were screened for inclusion at the first ambulatory contact at Randers Regional Hospital, Randers, Denmark, and informed oral and written consent was obtained before surgery. Adults scheduled for elective tonsillectomy were enrolled.

    Period 1
    Period 1 title
    Intervention (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 The study drug was given as an intravenous dose (methadone: 0.2 mg/kg) according to ideal body weight (definition: Height (cm) – 105 for females and height (cm) – 100 for males)).
    Arm type
    		 Experimental

    Investigational medicinal product name
    methadone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The study drug was given as an intravenous dose (methadone: 0.2 mg/kg) according to ideal body weight (definition: Height (cm) – 105 for females and height (cm) – 100 for males)).

    Arm title
    		 Control
    Arm description
    		 The study drug was given as an intravenous dose (fentanyl: 3 μg/kg) according to ideal body weight (definition: Height (cm) – 105 for females and height (cm) – 100 for males)).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    fentanyl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The study drug was given as an intravenous dose (fentanyl: 3 microgram/kg) according to ideal body weight (definition: Height (cm) – 105 for females and height (cm) – 100 for males)).

    Number of subjects in period 1
    		Intervention Control
    Started
    62
    58
    Completed
    62
    58

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 The study drug was given as an intravenous dose (methadone: 0.2 mg/kg) according to ideal body weight (definition: Height (cm) – 105 for females and height (cm) – 100 for males)).

    Reporting group title
    Control
    Reporting group description
    		 The study drug was given as an intravenous dose (fentanyl: 3 μg/kg) according to ideal body weight (definition: Height (cm) – 105 for females and height (cm) – 100 for males)).

    Reporting group values
    		 Intervention Control Total
    Number of subjects
    		 62 58 120
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 62 58 120
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 24 (20 to 30) 25.5 (22 to 30) -
    Gender categorical
    Units: Subjects
        Female
    		 45 41 86
        Male
    		 17 17 34

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 The study drug was given as an intravenous dose (methadone: 0.2 mg/kg) according to ideal body weight (definition: Height (cm) – 105 for females and height (cm) – 100 for males)).

    Reporting group title
    Control
    Reporting group description
    		 The study drug was given as an intravenous dose (fentanyl: 3 μg/kg) according to ideal body weight (definition: Height (cm) – 105 for females and height (cm) – 100 for males)).

    Primary: Pain intensity (NRS, 0-10)

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    End point title
    		 Pain intensity (NRS, 0-10)
    End point description
    End point type
    Primary
    End point timeframe
    on arrival at the post-anesthesia care unit
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: 0-10
        median (inter-quartile range (Q1-Q3))
    3 (2 to 5)
    4.5 (3 to 7)
    Statistical analysis title
    		 Mann-Whitney test
    Statistical analysis description
    Medians with interquartile ranges (IQR) are given for skewed data and compared with Mann-Whitney test.
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Total postoperative opioid consumption from extubation to 5 days after surgery

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    End point title
    		 Total postoperative opioid consumption from extubation to 5 days after surgery
    End point description
    End point type
    Primary
    End point timeframe
    from extubation to 5 days after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: mg
        median (inter-quartile range (Q1-Q3))
    30 (10 to 50)
    49 (29 to 80)
    Statistical analysis title
    		 Mann-Whitney test
    Statistical analysis description
    Medians with interquartile ranges (IQR) are given for skewed data and compared with Mann-Whitney test.
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Pain intensity (NRS 0-10) 1 day after surgery

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    End point title
    		 Pain intensity (NRS 0-10) 1 day after surgery
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 1 day after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: 0-10
        median (inter-quartile range (Q1-Q3))
    4 (2.5 to 5)
    5 (3 to 6)
    No statistical analyses for this end point

    Secondary: Pain intensity (NRS 0-10) 2 days after surgery

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    End point title
    		 Pain intensity (NRS 0-10) 2 days after surgery
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 2 days after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: 0-10
        median (inter-quartile range (Q1-Q3))
    4 (3 to 6)
    5 (4 to 6)
    No statistical analyses for this end point

    Secondary: Pain intensity (NRS 0-10) 3 days after surgery

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    End point title
    		 Pain intensity (NRS 0-10) 3 days after surgery
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 3 days after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: 0-10
        median (inter-quartile range (Q1-Q3))
    4.5 (3 to 6)
    5 (3 to 7)
    No statistical analyses for this end point

    Secondary: Pain intensity (NRS 0-10) 5 days after surgery

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    End point title
    		 Pain intensity (NRS 0-10) 5 days after surgery
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 5 days after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: 0-10
        median (inter-quartile range (Q1-Q3))
    5 (4 to 7)
    6 (4 to 7)
    No statistical analyses for this end point

    Secondary: Pain intensity (NRS 0-10) 7 days after surgery

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    End point title
    		 Pain intensity (NRS 0-10) 7 days after surgery
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 7 days after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: 0-10
        median (inter-quartile range (Q1-Q3))
    4 (3 to 6)
    4 (3 to 6)
    No statistical analyses for this end point

    Secondary: Total postoperative opioid consumption 24 hours after surgery

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    End point title
    		 Total postoperative opioid consumption 24 hours after surgery
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 24 hours after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: mg
        median (inter-quartile range (Q1-Q3))
    20 (10 to 35)
    35 (20 to 52)
    No statistical analyses for this end point

    Secondary: Total postoperative opioid consumption 7 days after surgery

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    End point title
    		 Total postoperative opioid consumption 7 days after surgery
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 7 days after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: mg
        median (inter-quartile range (Q1-Q3))
    36.5 (10 to 60)
    50 (30 to 92.5)
    No statistical analyses for this end point

    Secondary: Patient satisfaction 24 hours after extubation

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    End point title
    		 Patient satisfaction 24 hours after extubation
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 24 hours after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: 0-10
        median (inter-quartile range (Q1-Q3))
    9 (8 to 10)
    9 (8 to 10)
    No statistical analyses for this end point

    Secondary: Patient satisfaction 7 days after extubation

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    End point title
    		 Patient satisfaction 7 days after extubation
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 7 days after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: 0-10
        median (inter-quartile range (Q1-Q3))
    8 (6 to 9)
    8 (5 to 9)
    No statistical analyses for this end point

    Secondary: PONV (moderate to severe) 1 day after extubation

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    End point title
    		 PONV (moderate to severe) 1 day after extubation
    End point description
    End point type
    Secondary
    End point timeframe
    from extubation to 1 day after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: n
        number (not applicable)
    27
    8
    No statistical analyses for this end point

    Secondary: PONV (moderate to severe) 2 days after extubation

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    End point title
    		 PONV (moderate to severe) 2 days after extubation
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 2 days after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: n
        number (not applicable)
    26
    10
    No statistical analyses for this end point

    Secondary: PONV (moderate to severe) 3 days after extubation

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    End point title
    		 PONV (moderate to severe) 3 days after extubation
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 3 days after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: n
        number (not applicable)
    21
    10
    No statistical analyses for this end point

    Secondary: Time from arrival to discharge from PACU

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    End point title
    		 Time from arrival to discharge from PACU
    End point description
    End point type
    Secondary
    End point timeframe
    Time from arrival to discharge from PACU
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: Hours
        median (inter-quartile range (Q1-Q3))
    2.1 (1.7 to 2.4)
    2.1 (1.8 to 2.5)
    No statistical analyses for this end point

    Secondary: Time from arrival to discharge from hospital

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    End point title
    		 Time from arrival to discharge from hospital
    End point description
    End point type
    Secondary
    End point timeframe
    Time from arrival to discharge from hospital
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: Hours
        median (inter-quartile range (Q1-Q3))
    5.7 (3.8 to 6.9)
    4.7 (3.8 to 5.7)
    No statistical analyses for this end point

    Secondary: Level of sedation at the PACU 4 hours after extubation (normal level of consciousness according to Ramsay Sedation Scale)

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    End point title
    		 Level of sedation at the PACU 4 hours after extubation (normal level of consciousness according to Ramsay Sedation Scale)
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to 4 hours after surgery
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: n
        number (not applicable)
    47
    47
    No statistical analyses for this end point

    Secondary: Any adverse events (hypoventilation/hypoxemia) at the PACU

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    End point title
    		 Any adverse events (hypoventilation/hypoxemia) at the PACU
    End point description
    End point type
    Secondary
    End point timeframe
    From extubation to discharge from PACU
    End point values
    		 Intervention Control
    Number of subjects analysed
    62
    58
    Units: n
        number (not applicable)
    4
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From administration of study drug to 7 days after surgery
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    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: We have no non-serious adverse events reported.
    Serious adverse events
    		 Intervention Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 62 (8.06%)
    10 / 58 (17.24%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Bleeding after surgery
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 58 (8.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain after surgery
    Additional description: Pain requiring hospital admission
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Local swelling after surgery
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nausea and/or vomiting
    Additional description: Nausea and/or vomiting requiring hospital admission
         subjects affected / exposed
    3 / 62 (4.84%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Intervention Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 58 (0.00%)

    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
    For support, Contact us.
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