Clinical Trial Results:
The study comprises two sub-studies: Study 1 (TME). Effect of High-dose Target-controlled Naloxone Infusion on Pain and Hyperalgesia in Patients following Recovery from Impacted Mandibular Third Molar Extraction. A Randomized, Placebo-controlled, Double-blind Crossover Study (n = 22) Study 2 (BI): Highdose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design (n = 80) Study 1 has not been published yet, however, study 2 was published 2020, containing all the data in a supplemental file. Study 1 included a main part (TME; n = 14) and a validation part (n = 8) Please, cf. attached paper: Springborg AD, Jensen EK, Kreilgaard M, Petersen MA, Papathanasiou T, Lund TM, Taylor BK, Werner MU. High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design. PLoS One. 2020 Nov 12;15(11):e0242169. doi: 10.1371/journal.pone.0242169. PMID: 33180816; PMCID: PMC7660513.)

Trial information Top of page
Trial identification
Sponsor protocol code	51237
Additional study identifiers
ISRCTN number	-
US NCT number	NCT02976337
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Rigshospitalet, Copenhagen University Hospitals
Sponsor organisation address	Blegdamsvej 9, Copenhagen, Denmark,
Public contact	Multidisciplinary Pain Center 7612,, Rigshospitalet, Copenhagen University Hospitals, +45 35457618,
Scientific contact	Multidisciplinary Pain Center 7612,, Rigshospitalet, Copenhagen University Hospitals, +45 35457618,
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	20 Mar 2025
Is this the analysis of the primary completion data?	Yes
Primary completion date	27 Nov 2023
Global end of trial reached?	Yes
Global end of trial date	27 Nov 2023
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	Study 1: The principal aim of the study is to investigate whether the administration of high-dose naloxone (3.25 mg/kg), a selective mu-opioid receptor (MOR) antagonist, can re-introduce pain (at rest, during mastication and during pressure-evoked condition) and hyperalgesia four to five weeks after unilateral, uncomplicated, impacted mandibular, third molar extraction. Study 2: Please, cf. attached paper: Springborg AD, Jensen EK, Kreilgaard M, Petersen MA, Papathanasiou T, Lund TM, Taylor BK, Werner MU. High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design. PLoS One. 2020 Nov 12;15(11):e0242169. doi: 10.1371/journal.pone.0242169. PMID: 33180816; PMCID: PMC7660513.)
Protection of trial subjects	In previous studies, naloxone given in doses of 2-4 mg/kg i.v. only caused mild side-effects in a minority of volunteers or patients (30%). These side-effects include: nausea, vomiting, weakness, fatigue, tremor, elevations of blood pressure and respiratory rate. During infusion of the drug, participants were monitored with ECG and measurements of pulse oximetry, blood pressure and respiratory rate. During the study a physician and a nurse were present to diagnose and manage development of adverse effects.
Background therapy	-
Evidence for comparator	An inactive i.v. comparator (0.9% NaCl solution) was used.
Actual start date of recruitment	01 Feb 2016
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: 102
Worldwide total number of subjects	102
EEA total number of subjects	102
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)	102
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	Study 1: Male participants with unilateral, primary, uncomplicated, impacted mandibular third molar extraction were included between 16-NOV-2017 and 28-NOV-2023 Study 2: Please, cf. attached paper: Springborg et. al. PLoS One. 2020 Nov 12;15(11):e0242169. doi: 10.1371/journal.pone.0242169.
Pre-assignment
Screening details	Inclusion criteria: Healthy male Age above 18 yrs and below 65 yrs Signed informed consent Participants submitted to unilateral, primary, impacted, uncomplicated mandibular third molar extraction 4 weeks (+/-3 days) prior to examination Day 1 Standardized surgical procedure Urin-sample without traces of opioids ASA I-II BMI: >18 +<30 kg/m2
Period 1
Period 1 title	Study 1: Main part (TME)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Data analyst
Blinding implementation details	This is a cross-over, block-randomized, double-blind study. Randomization (computer generated using Randomization.com; sequence-randomization in blocks of 4 subjects). Manufacturing, packaging and labelling of drugs were be performed by Skanderborg Hospital Pharmacy, Denmark. Two sets of non-transparent sealed envelopes with the complete randomization list were stored (one by the sponsor and one by the investigator).
Arms
Are arms mutually exclusive	No
Arm title	Placebo
Arm description	Placebo was normal saline (0.9% NaCl) delivered in vials of 100 ml.
Arm type	Placebo
Investigational medicinal product name	Saline (0.9% NaCl)
Investigational medicinal product code
Other name	Normal saline
Pharmaceutical forms	Infusion
Routes of administration	Infusion , Intravenous use, Intravenous bolus use
Dosage and administration details	Normal saline (0.9% NaCl) delivered by a target-controlled infusion.
Arm title	Naloxone
Arm description	Naloxone 4 mg/ml, dissolved in a 0.9% NaCl solution, was delivered in vials of 100 ml (manufactured by Skanderborg Hospital Pharmacy, Denmark).
Arm type	Experimental
Investigational medicinal product name	Naloxone 4 mg/ml
Investigational medicinal product code
Other name
Pharmaceutical forms	Infusion
Routes of administration	Infusion , Intravenous bolus use , Intravenous use
Dosage and administration details	Naloxone 4 mg/ml, dissolved in a 0.9% NaCl solution (manufactured by Skanderborg Hospital Pharmacy, Denmark), was delivered by a target-controlled infusion.
Number of subjects in period 1 Placebo Naloxone Started 14 14 Completed 14 14
Period 2
Period 2 title	Study 1: Test of validity
Is this the baseline period?	No
Allocation method	Not applicable
Blinding used	Not blinded
Blinding implementation details	To validate that the assessment methods used in determining the primary and secondary outcomes had sufficient power to measure: * primary outcomes: pain intensity scores (NRS 0-10) during rest, masticatory activities, and pressure algometry (100 kPa) * secondary outcomes: areas of secondary hyperalgesia/allodynia, online reaction time assessments, and Clinical Opiate Withdrawal Scale scores
Arms
Are arms mutually exclusive	Yes
Arm title	Study 1: Test of validity (pre-surgery)
Arm description	To validate that the assessment methods used in determining the primary and secondary outcomes had sufficient power to measure: * primary outcomes: pain intensity scores (NRS 0-10) during rest, masticatory activities, and pressure algometry (100 kPa) * secondary outcomes: areas of secondary hyperalgesia/allodynia, online reaction time assessments, and Clinical Opiate Withdrawal Scale scores
Arm type	No intervention
Investigational medicinal product name	No investigational medicinal product assigned in this arm
Arm title	Study 1: Test of validity (post-surgery)
Arm description	To validate that the assessment methods used in determining the primary and secondary outcomes had sufficient power to measure: * primary outcomes: pain intensity scores (NRS 0-10) during rest, masticatory activities, and pressure algometry (100 kPa) * secondary outcomes: areas of secondary hyperalgesia/allodynia, online reaction time assessments, and Clinical Opiate Withdrawal Scale scores
Arm type	No intervention
Investigational medicinal product name	No investigational medicinal product assigned in this arm
Number of subjects in period 2 Study 1: Test of validity (pre-surgery) Study 1: Test of validity (post-surgery) Started 8 8 Completed 8 8

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups [1]
Reporting group title	Study 1: Main part (TME)
Reporting group description	-
Notes [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: The number of subjects in the studies are: Study 1 (TME + validation): n = 14 (TME) + n = 8 (validation), as reported here. Study 2 (Burn Injury): n = 80 (Burn injury), as reported in the attached paper (Springborg et al. 2020). Total subjects in the studies: n = 102
Reporting group values Study 1: Main part (TME) Total Number of subjects 14 14 Age categorical Units: Subjects     In utero 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0     Newborns (0-27 days) 0 0     Infants and toddlers (28 days-23 months) 0 0     Children (2-11 years) 0 0     Adolescents (12-17 years) 0 0     Adults (18-64 years) 14 14     From 65-84 years 0 0     85 years and over 0 0 Age continuous Units: years     arithmetic mean (standard deviation) 25.9 ( 4.3 ) - Gender categorical Units: Subjects     Female 0 0     Male 14 14

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Placebo
Reporting group description	Placebo was normal saline (0.9% NaCl) delivered in vials of 100 ml.
Reporting group title	Naloxone
Reporting group description	Naloxone 4 mg/ml, dissolved in a 0.9% NaCl solution, was delivered in vials of 100 ml (manufactured by Skanderborg Hospital Pharmacy, Denmark).
Reporting group title	Study 1: Test of validity (pre-surgery)
Reporting group description	To validate that the assessment methods used in determining the primary and secondary outcomes had sufficient power to measure: * primary outcomes: pain intensity scores (NRS 0-10) during rest, masticatory activities, and pressure algometry (100 kPa) * secondary outcomes: areas of secondary hyperalgesia/allodynia, online reaction time assessments, and Clinical Opiate Withdrawal Scale scores
Reporting group title	Study 1: Test of validity (post-surgery)
Reporting group description	To validate that the assessment methods used in determining the primary and secondary outcomes had sufficient power to measure: * primary outcomes: pain intensity scores (NRS 0-10) during rest, masticatory activities, and pressure algometry (100 kPa) * secondary outcomes: areas of secondary hyperalgesia/allodynia, online reaction time assessments, and Clinical Opiate Withdrawal Scale scores

End points Top of page

Primary: Pain intensity score during rest Top of page
End point title	Pain intensity score during rest
End point description	Pain intensity score using the numerical rating scale (NRS 0-10) during rest
End point type	Primary
End point timeframe	At study day 1+2 (main study): *Baseline: 20-9 min. before infusion (target-controlled infusion (TCI)) *TCI 1:15-25 min. after infusion start *TCI 2: 39-49 min. after infusion start *TCI 3: 65-75 min. after infusion start
End point values Placebo Naloxone Study 1: Test of validity (pre-surgery) Number of subjects analysed 14 14 8 Units: NRS 0-10 14 14 8
Statistical analysis title	Pain at rest
Comparison groups	Placebo v Naloxone
Number of subjects included in analysis	28
Analysis specification	Post-hoc
Analysis type	superiority [1]
P-value	= 1
Method	ANOVA
Parameter type	Mean difference (final values)
Point estimate	0
Confidence interval
level	95%
sides	2-sided
lower limit	0
upper limit	0
Variability estimate	Standard deviation
Dispersion value	0
Notes [1] - None of the participants reported pain at rest at any of the measurement time points at any of the study days.

Primary: Pain intensity score during rest Top of page

Primary: Pain intensity score during masticatory activities Top of page
End point title	Pain intensity score during masticatory activities
End point description	Pain intensity score using the numerical rating scale (NRS 0-10) during masticatory activities
End point type	Primary
End point timeframe	At study day 1+2 (main study): *Baseline: 20-9 min. before infusion (target-controlled infusion (TCI)) *TCI 1:15-25 min. after infusion start *TCI 2: 39-49 min. after infusion start *TCI 3: 65-75 min. after infusion start
End point values Placebo Naloxone Study 1: Test of validity (pre-surgery) Number of subjects analysed 14 14 8 Units: NRS 0-10 14 14 8
Statistical analysis title	Pain intensity during masticatory activities
Comparison groups	Placebo v Naloxone
Number of subjects included in analysis	28
Analysis specification	Post-hoc
Analysis type	superiority [2]
P-value	= 0.2021
Method	ANOVA
Confidence interval
Notes [2] - ANOVA, where the pain intensity during masticatory activities, was the outcome variable and the measurement time points (baseline, TCI1, TCI2, TCI3) and treatment (Naloxone vs. Placebo) were the predictor variables.

Primary: Pain intensity score during masticatory activities Top of page

Primary: Pain intensity score applying an external algometry (100 kPa) Top of page
End point title	Pain intensity score applying an external algometry (100 kPa)
End point description	Pain intensity score using the numerical rating scale (NRS 0-10) when applying an external algometry (100 kPa) at the skin sites above the surgical area.
End point type	Primary
End point timeframe	At study day 1+2 (main study): *Baseline: 20-9 min. before infusion (target-controlled infusion (TCI)) *TCI 1:15-25 min. after infusion start *TCI 2: 39-49 min. after infusion start *TCI 3: 65-75 min. after infusion start
End point values Placebo Naloxone Study 1: Test of validity (pre-surgery) Number of subjects analysed 14 14 8 Units: NRS 0-10 14 14 8
Statistical analysis title	Pain intensity when applying external algometry
Comparison groups	Placebo v Naloxone
Number of subjects included in analysis	28
Analysis specification	Post-hoc
Analysis type	superiority [3]
P-value	= 0.3304
Method	ANOVA
Confidence interval
Notes [3] - ANOVA, where the pain intensity when applying external algometry was the outcome variable and the measurement time points (baseline, TCI1, TCI2, TCI3) and treatment (Naloxone vs. Placebo) were the predictor variables.

Primary: Pain intensity score applying an external algometry (100 kPa) Top of page

Secondary: Area of secondary hyperalgesia/allodynia Top of page
End point title	Area of secondary hyperalgesia/allodynia
End point description	Secondary outcomes included assessment of area of secondary hyperalgesia/allodynia at mandibular skin sites above the surgical area and on the contralateral side (by nylon monofilament testing)
End point type	Secondary
End point timeframe	At study day 1+2 (main study): *Baseline: 20-9 min. before infusion (target-controlled infusion (TCI)) *TCI 1:15-25 min. after infusion start *TCI 2: 39-49 min. after infusion start *TCI 3: 65-75 min. after infusion start
End point values Placebo Naloxone Study 1: Test of validity (pre-surgery) Number of subjects analysed 14 14 8 Units: 0-1 14 14 8
Statistical analysis title	Area of secondary hyperalgesia/allodynia
Comparison groups	Placebo v Naloxone
Number of subjects included in analysis	28
Analysis specification	Post-hoc
Analysis type	superiority [4]
P-value	= 1 [5]
Method	ANOVA
Parameter type	Mean difference (final values)
Point estimate	0
Confidence interval
level	95%
sides	2-sided
lower limit	0
upper limit	0
Variability estimate	Standard deviation
Dispersion value	0
Notes [4] - None of the participants reported an area of secondary hyperalgesia/allodynia at any of the measurement time points at any of the study days (1 or 2). [5] - None of the participants reported an area of secondary hyperalgesia/allodynia at any of the measurement time points at any of the study days (1 or 2).

Secondary: Area of secondary hyperalgesia/allodynia Top of page

Secondary: Online reaction time assessment Top of page
End point title	Online reaction time assessment
End point description	Online reaction time assessment
End point type	Secondary
End point timeframe	At study day 1+2 (main study) *Baseline: 20-9 min. before infusion (target-controlled infusion (TCI)) *TCI 1:15-25 min. after infusion start *TCI 2: 39-49 min. after infusion start *TCI 3: 65-75 min. after infusion start
End point values Placebo Naloxone Number of subjects analysed 14 14 Units: ms     number (not applicable) 14 14
Statistical analysis title	Online reaction time
Comparison groups	Placebo v Naloxone
Number of subjects included in analysis	28
Analysis specification	Post-hoc
Analysis type	superiority [6]
P-value	= 0.6993
Method	ANOVA
Confidence interval
Notes [6] - Two-way repeated measures ANOVA, where the online reaction time was the outcome variable and the measurement time points (baseline, TCI1, TCI2, TCI3) and treatment (Naloxone vs. Placebo) were the predictor variables.

Secondary: Online reaction time assessment Top of page

Secondary: Clinical Opiate Withdrawal Scale (COWS) scores Top of page
End point title	Clinical Opiate Withdrawal Scale (COWS) scores
End point description	Clinical Opiate Withdrawal Scale (COWS) scores
End point type	Secondary
End point timeframe	At study day 1+2 (main study): *Baseline: 20-9 min. before infusion (target-controlled infusion (TCI)) *TCI 1:15-25 min. after infusion start *TCI 2: 39-49 min. after infusion start *TCI 3: 65-75 min. after infusion start
End point values Placebo Naloxone Number of subjects analysed 14 14 Units: 0-48 14 14
Statistical analysis title	Clinical Opiate Withdrawal Scale
Comparison groups	Placebo v Naloxone
Number of subjects included in analysis	28
Analysis specification	Post-hoc
Analysis type	superiority [7]
P-value	= 0.3737
Method	ANOVA
Confidence interval
Notes [7] - Two-way repeated measures ANOVA, where the COWS was the outcome variable and the measurement time points (baseline, TCI1, TCI2, TCI3) and treatment (Naloxone vs. Placebo) were the predictor variables.

Secondary: Clinical Opiate Withdrawal Scale (COWS) scores Top of page

Post-hoc: Validity: pain at rest Top of page
End point title	Validity: pain at rest
End point description	Pain intensity score using the numerical rating scale (NRS 0-10) during rest
End point type	Post-hoc
End point timeframe	Immediately before and 24 hrs after the TME
End point values Study 1: Test of validity (pre-surgery) Study 1: Test of validity (post-surgery) Number of subjects analysed 8 8 Units: NRS 0-10 8 8
Statistical analysis title	Validity: pain at rest
Statistical analysis description	To validate that the assessment methods used in determining the primary and secondary outcomes had sufficient power to measure: * primary outcomes: pain intensity scores (NRS 0-10) during rest, masticatory activities, and pressure algometry (100 kPa) * secondary outcomes: areas of secondary hyperalgesia/allodynia, online reaction time assessments, and Clinical Opiate Withdrawal Scale scores
Comparison groups	Study 1: Test of validity (pre-surgery) v Study 1: Test of validity (post-surgery)
Number of subjects included in analysis	16
Analysis specification	Post-hoc
Analysis type	other [8]
P-value	= 0.0001
Method	t-test, 2-sided
Parameter type	Mean difference (final values)
Point estimate	3.876
Confidence interval
level	95%
sides	2-sided
lower limit	2.741
upper limit	5.009
Notes [8] - Paired sample t-test

Post-hoc: Validity: pain at rest Top of page

Post-hoc: Validity: pain during masticatory activities Top of page
End point title	Validity: pain during masticatory activities
End point description	To validate that the assessment methods used in determining the primary and secondary outcomes had sufficient power to measure: * primary outcomes: pain intensity scores (NRS 0-10) during rest, masticatory activities, and pressure algometry (100 kPa) * secondary outcomes: areas of secondary hyperalgesia/allodynia, online reaction time assessments, and Clinical Opiate Withdrawal Scale scores
End point type	Post-hoc
End point timeframe	Immediately before and 24 hours after the TME.
End point values Study 1: Test of validity (pre-surgery) Study 1: Test of validity (post-surgery) Number of subjects analysed 8 8 Units: NRS 0-10 8 8
Statistical analysis title	Validity: Pain during masticatory activities
Statistical analysis description	To ascertain that the assessment methods used in determining the primary and secondary outcome had sufficient power to measure the pain-related issues they intend to measure the validity of the assessment methods the primary outcome measures were tested immediately before and 24 hours after an elective uncomplicated third molar mandibular extraction.
Comparison groups	Study 1: Test of validity (pre-surgery) v Study 1: Test of validity (post-surgery)
Number of subjects included in analysis	16
Analysis specification	Post-hoc
Analysis type	other [9]
P-value	= 0.0008
Method	t-test, 2-sided
Parameter type	Mean difference (final values)
Point estimate	4.974
Confidence interval
level	95%
sides	2-sided
lower limit	2.806
upper limit	6.944
Notes [9] - Paired sample t-test

Post-hoc: Validity: pain during masticatory activities Top of page

Post-hoc: Validity: pain intensity during external algometry Top of page
End point title	Validity: pain intensity during external algometry
End point description	To validate that the assessment methods used in determining the primary and secondary outcomes had sufficient power to measure: * primary outcomes: pain intensity scores (NRS 0-10) during rest, masticatory activities, and pressure algometry (100 kPa) * secondary outcomes: areas of secondary hyperalgesia/allodynia, online reaction time assessments, and Clinical Opiate Withdrawal Scale scores
End point type	Post-hoc
End point timeframe	Immediately before and 24 hours after the TME.
End point values Study 1: Test of validity (pre-surgery) Study 1: Test of validity (post-surgery) Number of subjects analysed 8 8 Units: NRS 0-10 8 8
Statistical analysis title	Validity: Pain intensity external algometry
Statistical analysis description	To ascertain that the assessment methods used in determining the primary and secondary outcome had sufficient power to measure the pain-related issues they intend to measure the validity of the assessment methods the primary outcome measures were tested immediately before and 24 hours after an elective uncomplicated third molar mandibular extraction.
Comparison groups	Study 1: Test of validity (post-surgery) v Study 1: Test of validity (pre-surgery)
Number of subjects included in analysis	16
Analysis specification	Post-hoc
Analysis type	other [10]
P-value	< 0.0001
Method	t-test, 2-sided
Parameter type	Mean difference (final values)
Point estimate	5.875
Confidence interval
level	95%
sides	2-sided
lower limit	4.741
upper limit	7.008
Notes [10] - Paired sample t-test

Post-hoc: Validity: pain intensity during external algometry Top of page

Post-hoc: Validity: area of secondary hyperalgesia/allodynia Top of page
End point title	Validity: area of secondary hyperalgesia/allodynia
End point description	To validate that the assessment methods used in determining the primary and secondary outcomes had sufficient power to measure: * primary outcomes: pain intensity scores (NRS 0-10) during rest, masticatory activities, and pressure algometry (100 kPa) * secondary outcomes: areas of secondary hyperalgesia/allodynia, online reaction time assessments, and Clinical Opiate Withdrawal Scale scores
End point type	Post-hoc
End point timeframe	Immediately before and 24 hours after the TME.
End point values Study 1: Test of validity (pre-surgery) Study 1: Test of validity (post-surgery) Number of subjects analysed 8 8 Units: cm2 8 8
Statistical analysis title	Area of secondary hyperalgesia/allodynia
Statistical analysis description	To ascertain that the assessment methods used in determining the primary and secondary outcome had sufficient power to measure the pain-related issues they intend to measure the validity of the assessment methods the primary outcome measures were tested immediately before and 24 hours after an elective uncomplicated third molar mandibular extraction.
Comparison groups	Study 1: Test of validity (pre-surgery) v Study 1: Test of validity (post-surgery)
Number of subjects included in analysis	16
Analysis specification	Pre-specified
Analysis type	superiority [11]
P-value	< 0.0001
Method	t-test, 2-sided
Parameter type	Mean difference (final values)
Point estimate	14.625
Confidence interval
level	95%
sides	2-sided
lower limit	12.139
upper limit	17.111
Variability estimate	Standard deviation
Notes [11] - Paired sample t-test

Post-hoc: Validity: area of secondary hyperalgesia/allodynia Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Study1: During main study 15-OCT-2017-31-MAY-2018 Study 2: Please, cf. attached paper: Springborg et al. 2020 BI + Supplemental file: Springborg et al. 2020 Adverse events.
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	28.0
Reporting groups
Reporting group title	Naloxone
Reporting group description	Naloxone 4 mg/ml, dissolved in a 0.9% NaCl solution, was delivered in vials of 100 ml (manufactured by Skanderborg Hospital Pharmacy, Denmark).
Serious adverse events Naloxone Total subjects affected by serious adverse events      subjects affected / exposed 0 / 14 (0.00%)      number of deaths (all causes) 0      number of deaths resulting from adverse events 0
Frequency threshold for reporting non-serious adverse events: 1%
Non-serious adverse events Naloxone Total subjects affected by non serious adverse events      subjects affected / exposed 4 / 14 (28.57%) Nervous system disorders Anxiety      subjects affected / exposed 1 / 14 (7.14%)      occurrences all number 1 Cognitive dysfunction      subjects affected / exposed 1 / 14 (7.14%)      occurrences all number 1 Fatigue      subjects affected / exposed 1 / 14 (7.14%)      occurrences all number 1 Hyperacusis      subjects affected / exposed 1 / 14 (7.14%)      occurrences all number 1 Nausea      subjects affected / exposed 1 / 14 (7.14%)      occurrences all number 1 Pain      subjects affected / exposed 1 / 14 (7.14%)      occurrences all number 1 Paraesthesias      subjects affected / exposed 2 / 14 (14.29%)      occurrences all number 2 Soreness surgical area      subjects affected / exposed 1 / 14 (7.14%)      occurrences all number 1 Tachycardia      subjects affected / exposed 1 / 14 (7.14%)      occurrences all number 1 Transitory motor dysfunction      subjects affected / exposed 1 / 14 (7.14%)      occurrences all number 1 Vertigo      subjects affected / exposed 1 / 14 (7.14%)      occurrences all number 1 Xerostomia      subjects affected / exposed 1 / 14 (7.14%)      occurrences all number 1

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
14 Apr 2023	To validate that the assessment methods used in determining the primary and secondary outcomes had sufficient power to measure: * primary outcomes: pain intensity scores (NRS 0-10) during rest, masticatory activities, and pressure algometry (100 kPa) * secondary outcomes: areas of secondary hyperalgesia/allodynia, online reaction time assessments, and Clinical Opiate Withdrawal Scale scores
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

More information Top of page