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    Clinical Trial Results:
    Intraoperative methadone for postoperative pain management in spinal fusion surgery: a prospective, double-blind, randomised controlled trial

    Summary
    EudraCT number
    		 2020-004826-47
    Trial protocol
    		 DK  
    Global end of trial date
    31 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2026
    First version publication date
    20 Mar 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    23956082
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04764825
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AUH
    Sponsor organisation address
    Palle Juul-Jensens Blvd 99, Aarhus , Denmark,
    Public contact
    Lone Nikolajsen, Aarhus University Hospital, 0045 78464317, lone.nikolajsen@clin.au.dk
    Scientific contact
    Lone Nikolajsen, Aarhus University Hospital, 0045 78464317, lone.nikolajsen@clin.au.dk
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensen Blvd. 99, Aarhus, Denmark, 8200
    Public contact
    MD, Ph.d. Camilla G Uhrbrand, Dept. of Anesthesia and Intensive Care, Aarhus University Hospital, 0045 23956082, camgaa@rm.dk
    Scientific contact
    Professor Lone Nikolajsen, Dept. of Anesthesia and Intensive Care, Aarhus University Hospital, 0045 23956082, loneniko@rm.dk
    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
    30 May 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Opioid consumption at 6 hours after extubation (mean cumulative opioid consumption) Opioid consumption at 24 hours after extubation (mean cumulative opioid consumption)
    Protection of trial subjects
    Informed written consent was obtained before surgery for all trial subjects. Criteria for exclusion included allergy to study drugs, preoperative opioid use [>60 mg oral morphine equivalents (OME) at least 7 days leading up to surgery], prolonged QTc-interval (>440 ms), planned postoperative epidural or ketamine infusion, American Society of Anesthesiologists Physical Status (ASA) IV or V, severe liver, kidney, lung or heart disease, pregnancy or breastfeeding, malignancy-related surgery or inability to provide informed consent. Doses was decided from commonn practice.
    Background therapy
    		 Anesthesia, surgery, and postoperative care followed standard protocols at our institution. Induction was achieved with propofol (1–3 mg/kg) and remifentanil (2–4 μg/ kg), followed by maintenance doses of 5 mg/kg/h and 30 μg/ kg/h, respectively. No fentanyl was administered after induction. Vasopressors and fluids were administered at the anesthetist’s discretion. Intraoperative monitoring included invasive blood pressure, continuous electrocardiogram, capnography, and oximetry. Spine fusion was performed using an instrumented posterior-only approach with patients in the prone position, adhering to international standards. Before closure, 100 mL ropivacaine 2 mg/mL, was infiltrated at the incision site. All patients were extubated in the operating theatre and transferred to the PACU. Discharge criteria from the PACU to the surgical ward were based on national recommendations.13 Pain management in the PACU was consistent with standard-ofcare. Intravenous alfentanil (0.25–0.5 μg) combined with intravenous fentanyl (0.1 mg/kg) was used as first-line treatment for Numeric Rating Scale (NRS, 0–10) ≥7. Intravenous morphine (0.05–1.0 μg/kg) was administered for NRS 4 to 6 and titrated every 5 to 10 minutes until NRS scores were below 4. Oxycodone was used as an alternative or supplement for moderate to severe pain in cases of morphine intolerance. Postoperative nausea and vomiting (PONV) treatment followed national guidelines.14 At extubation, all patients were equipped with a patient-controlled analgesia (PCA) pump for demandonly morphine (2.5 mg per dose, max four doses/hour, 7- minute lockout).
    Evidence for comparator
    		 The comparator in this trial was morphine. Morphine in this relation was pre trial our opioid of choice for this selected group of patients.
    Actual start date of recruitment
    01 Jan 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Scientific research
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 124
    Worldwide total number of subjects
    124
    EEA total number of subjects
    124
    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)
    62
    From 65 to 84 years
    62
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients aged 18 to 85 years scheduled for elective lumbar fusion surgery (<5 levels) were screened and at pre anesthesia consult asked to read information regarding the trial. They were able to ask follow up questions. At the day of surgery they were finally asked whether they wished to participate.

    Pre-assignment
    Screening details
    		 Between February 26, 2021, and March 19, 2024, 262 patients scheduled for spine fusion were screened for eligibility. Of these, 124 patients were enrolled and randomized to treatment groups. Eleven patients were excluded due to various reasons, leaving 113 patients in the final analysis

    Period 1
    Period 1 title
    Overall trial (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
    Blinding implementation details
    The Hospital Pharmacy managed study medication, randomization, and blinding. Patients were randomized in a 1:1:1 ratio using permuted blocks of sizes 3, 6, and 9. To ensure blinding, study personnel received two identical 10 mL syringes, marked by the pharmacy with either A or B according to treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MET pre
    Arm description
    		 receive methadone 0.15- 0.2 mg/kg ideal body weight (IBW) before incision
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methadone
    Investigational medicinal product code
    N07BC02
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Single bolus use.

    Arm title
    		 MET post
    Arm description
    		 Received methadone 0.15-0.2 mg/kg IBW before wound closure
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methadone
    Investigational medicinal product code
    N07BC02
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Single dose use.

    Arm title
    		 MOR post
    Arm description
    		 Received morphine 0.15- 0.2 mg/kg IBW before wound closure
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Single dose use.

    Number of subjects in period 1
    		MET pre MET post MOR post
    Started
    44
    41
    39
    Completed
    39
    38
    36
    Not completed
    5
    3
    3
         Surgery Cancelled
    1
    -
    -
         Consent withdrawn by subject
    2
    -
    1
         Physician decision
    -
    3
    -
         cancelled
    -
    -
    1
         Protocol deviation
    2
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MET pre
    Reporting group description
    		 receive methadone 0.15- 0.2 mg/kg ideal body weight (IBW) before incision

    Reporting group title
    MET post
    Reporting group description
    		 Received methadone 0.15-0.2 mg/kg IBW before wound closure

    Reporting group title
    MOR post
    Reporting group description
    		 Received morphine 0.15- 0.2 mg/kg IBW before wound closure

    Reporting group values
    		 MET pre MET post MOR post Total
    Number of subjects
    		 44 41 39 124
    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)
    		 64.9 ( 12.2 ) 63.7 ( 11.7 ) 63.8 ( 10.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 23 26 19 68
        Male
    		 21 15 20 56
    preoperative daily opioid use
    Units: Subjects
        yes
    		 14 14 13 41
        no
    		 30 27 26 83

    End points

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    End points reporting groups
    Reporting group title
    MET pre
    Reporting group description
    		 receive methadone 0.15- 0.2 mg/kg ideal body weight (IBW) before incision

    Reporting group title
    MET post
    Reporting group description
    		 Received methadone 0.15-0.2 mg/kg IBW before wound closure

    Reporting group title
    MOR post
    Reporting group description
    		 Received morphine 0.15- 0.2 mg/kg IBW before wound closure

    Primary: Cumulative opioid consumption at 24 hours

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    End point title
    		 Cumulative opioid consumption at 24 hours
    End point description
    End point type
    Primary
    End point timeframe
    Cumulative opioid requirements measured in oral morphine equivalents (OME) within 24 hours after extubation.
    End point values
    		 MET pre MET post MOR post
    Number of subjects analysed
    39
    38
    36
    Units: mg oral morphine equivalents (OME)
        median (inter-quartile range (Q1-Q3))
    141.5 (87.5 to 245.5)
    153.25 (102.5 to 239)
    183.8 (113.8 to 268.8)
    Statistical analysis title
    		 primary outcome
    Statistical analysis description
    Continuous variables were assessed for distribution and reported as medians with interquartile ranges (IQR) when not normally distributed. Comparisons of cumulative opioid consumption (oral morphine equivalents, OME) between the three treatment groups were performed using the Kruskal–Wallis test. Pairwise comparisons were performed using the Mann–Whitney U test when appropriate. A two-sided p-value <0.05 was considered statistically significant.
    Comparison groups
    MET pre v MET post v MOR post
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.518
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Cumulative opioid consumption (oral morphine equivalents) at 6 hours

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    End point title
    		 Cumulative opioid consumption (oral morphine equivalents) at 6 hours
    End point description
    End point type
    Secondary
    End point timeframe
    6 hours
    End point values
    		 MET pre MET post MOR post
    Number of subjects analysed
    39
    38
    36
    Units: mg oral morphine equivalents (OME)
        median (inter-quartile range (Q1-Q3))
    85 (27.5 to 112.5)
    77.8 (45 to 120)
    92.5 (48.8 to 146.3)
    No statistical analyses for this end point

    Secondary: Pain intensity at 24h

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    End point title
    		 Pain intensity at 24h
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours
    End point values
    		 MET pre MET post MOR post
    Number of subjects analysed
    39
    38
    36
    Units: NRS (0–10)
        arithmetic mean (standard deviation)
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    Attachments
    		 Untitled (Filename: 6E91B9A3.pdf)
    No statistical analyses for this end point

    Secondary: Patient satisfaction

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    End point title
    		 Patient satisfaction
    End point description
    Patient satisfaction with postoperative pain management measured on a Numeric Rating Scale (0–10).
    End point type
    Secondary
    End point timeframe
    24 hours
    End point values
    		 MET pre MET post MOR post
    Number of subjects analysed
    39
    38
    36
    Units: NRS (0 to 10)
        median (inter-quartile range (Q1-Q3))
    10 (9 to 10)
    9 (8 to 10)
    9 (7.5 to 10)
    No statistical analyses for this end point

    Secondary: Hypoventilation in PACU

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    End point title
    		 Hypoventilation in PACU
    End point description
    Hypoventilation in the post-anaesthesia care unit defined as respiratory rate <10 breaths per minute.
    End point type
    Secondary
    End point timeframe
    PACU time
    End point values
    		 MET pre MET post MOR post
    Number of subjects analysed
    39
    38
    36
    Units: No. of subjects
    2
    1
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    72 hours
    Adverse event reporting additional description
    Adverse events were assessed during the postoperatively and recorded according to the study protocol. The trial was monitored by the Good Clinical Practice (GCP) unit at Aarhus University Hospital.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTR
    Dictionary version
    2014
    Reporting groups
    Reporting group title
    overall trial population
    Reporting group description
    		 All randomized patients receiving study medication (methadone before incision, methadone before wound closure, or morphine before wound closure).

    Serious adverse events
    		 overall trial population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 113 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 overall trial population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 113 (9.73%)
    Respiratory, thoracic and mediastinal disorders
    Respiratory events
    Additional description: Respiratory events during postoperative stay in the PACU, including hypoventilation (respiratory rate <10/min) and hypoxemia (oxygen saturation <90%).
         subjects affected / exposed
    11 / 113 (9.73%)
         occurrences all number
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Apr 2023
    Changed the handling of study drugs and inclusion criterias (QTc on ECG).

    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.
    The study was terminated before reaching the planned sample size and may therefore be underpowered to detect smaller differences between groups. In addition, the single-centre design may limit the generalizability of the results.
    For support, Contact us.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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