Opioid Induced Respiratory DepressionPhase 1ROARNCT05338632
Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists
A Phase 1 study testing Narcan 40 MG/ML Nasal Spray, Naloxone Hydrochloride and Nalmefene HCl injection in people with Opioid Induced Respiratory Depression and Chronic Opioid Use, run by Leiden University Medical Center at 1 site in Netherlands.
Trial summary
n this pharmacokinetic/pharmacodynamic modelling study we will determine the ability of intranasal and intravenous naloxone and intravenous nalmefene to reverse opioid (fentanyl and sufentanil)- induced respiratory depression in healthy volunteers and chronic opioid users to develop dosing recommendations in case of… Read more about this study
- Who is it for?
- Ages 18 to 70 yearsHealthy volunteers can take part
- Conditions the study is for
- Opioid Induced Respiratory Depression, Chronic Opioid Use
- What is being tested?
- Narcan 40 MG/ML Nasal Spray, Naloxone Hydrochloride and Nalmefene HCl injection
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 58 participants
- Where
- 1 siteNetherlands
- Study dates
- 24 Jun 2022to 23 Mar 2026
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Healthy volunteers
- Signed the informed consent form (ICF) and able to comply with the study requirements and restrictions listed therein;
- Male and female subjects, age 18 to 70 years, inclusive;
- Women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative serum pregnancy test prior to enrolment and must agree to use a medically acceptable means of contraception from screening through at least 1 month after the last dose of study drug;
- Body Mass Index (BMI) 18 to 30 kg/m2, inclusive;
- Healthy as defined by the Investigator, based on a medical evaluation that includes the subject's medical and surgical history, physical examination, vital signs, lab chemistry: estimated glomerular filtration rate >60 mL/min as estimated by the CKD-EPI equation, and AST or ALT levels < 3.0 times the upper limit of normal at screening, and negative serology tests for HIV, acute hepatitis B, or acute hepatitis C;
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- No history of substance use disorder;
- Chronic opioid users
- Signed the consent form and able to comply with the requirements and restrictions listed therein;
- Males or females age 18 to 70 years, inclusive;
- Women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative serum pregnancy test prior to enrolment and must agree to use a medically acceptable means of contraception from screening through at least 1 3 month after the last dose of study drug.
- BMI 18 to 32 kg/m2, inclusive;
- Opioid tolerant patients administered prescription opioids at daily doses ≥ 60 mg oral morphine equivalents (See Table 3);
- Stable as defined by the Investigator, based on a medical evaluation that includes the subject's medical and surgical history, physical examination, vital signs, 12-lead ECG, hematology, and blood chemistry;
Who cannot join
- Healthy volunteers
- Currently meet the criteria for diagnosis of substance use disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria on any substance;
- Any other active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints;
- Consume, on average, >27 20 units/week of alcohol in men and > 20 13 units/week of alcohol in women (1 unit = 1 glass (250 mL) beer, 125 mL glass of wine or 25 mL of 40% spirit);
- Previous or current treatment with opioid agonist, partial agonist, or antagonist treatment within 30 days prior to the first study drug administration;
- Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;
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- History of suicidal ideation within 30 days prior to informed consent or history of a suicide attempt in the 6 months prior to informed consent;
- Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;
- History or presence of allergic response to fentanyl, sufentanil or naloxone;
- Subjects who have demonstrated allergic reactions (e.g., food, drug, atopic reactions or asthmatic episodes) which, in the opinion of the Investigator and sponsor, interfere with their ability to participate in the trial;
- Treatment with another investigational drug within 3 months prior to dosing or having participated in more than 4 investigational drug studies within 1 year prior to screening;
- Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study;
- Chronic opioid users
- Currently meet the criteria for diagnosis of moderate or severe substance use disorder according to the DSM-5 criteria on any substances other than opioids, caffeine, or nicotine;
- Any active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints;
- Consume, on average, >27 units/week of alcohol in men and >20 units/week of alcohol in women (1 unit = 1 glass (250 mL) beer, 125 mL glass of wine or 25 mL of 40% spirit);
- Currently receiving medication-assisted treatment for the treatment of opioid-use disorder;
- Significant traumatic injury, major surgery, or open biopsy within the prior 4 weeks of informed consent;
- History of suicidal ideation within 30 days prior to informed consent or history of a suicide attempt in the 6 months prior to informed consent;
- Measured systolic blood pressure greater than 160 or less than 95 mmHg or diastolic pressure greater than 95 mmHg at screening;
- History or presence of allergic response to study medication;
- Opioid tolerant patients who have demonstrated allergic reactions (e.g., food, drug, atopic reactions or asthmatic episodes) which, in the opinion of the Investigator and sponsor, interfere with their ability to participate in the trial.
- Estimated glomerular filtration rate <60 mL/min as estimated by the CKD-EPI equation;
- Anemia at screening or donation of > 250 mL of blood or plasma within the last 3 months;
- Positive serology tests for HIV, acute hepatitis B, or acute hepatitis C (OT patients with asymptomatic hepatitis B or C infection may be enrolled);
- AST or ALT levels >3.0 times the upper limit of normal at screening;
- Treatment with another investigational drug within 3 months prior to dosing or having participated in more than 4 investigational drug studies within 1 year prior to screening;
- Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Leiden University Medical Center
Leiden, South Holland, 2333 ZA
About this study
Official title: Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists - a Study in Opioid naïve Individuals and Chronic Opioid Users Under Real-life Conditions
n this pharmacokinetic/pharmacodynamic modelling study we will determine the ability of intranasal and intravenous naloxone and intravenous nalmefene to reverse opioid (fentanyl and sufentanil)- induced respiratory depression in healthy volunteers and chronic opioid users to develop dosing recommendations in case of opioid-induced respiratory depression from an opioid overdose in clinical practice and in the out-of-hospital overdose.
Read the detailed description
Primary objective:
To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on ventilation of intranasal and intravenous naloxone and intravenous nalmefene in its ability to reverse respiratory depression (important model parameters include C50, a measure of potency and t½ke0). The results of these studies will allow us to perform simulation studies aimed at optimizing dosing regimens for intranasal and intramuscular naloxone in individuals that overdosed on potent opioids, with respiratory depression ranging from moderate to severe.
Secondary objectives:
To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on pupil diameter and intranasal and intravenous naloxone and intravenous nalmefene in its ability to reverse miosis (important model parameters include C50, a measure of potency and t½ke0). The results of these studies will allow us to compare the ventilatory and pupil effects of the opioids and of naloxone.
Study design:
This is an open-label, randomized, crossover study in a mixed population
Study population:
We will study 12 healthy individuals of either sex aged 18-55 years and 12 individuals that are chronic opioids users (> 60 daily oral morphine equivalents; 18-55 years).
Intervention:
Study 1: Infusion of low-dose fentanyl and sufentanil whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation > 85%), intranasal naloxone (IN, 4 mg) will be administered twice with a maximum of 180 minutes in between. At the end of each experiment 0.4 mg naloxone will be administered intravenously to determine its effect on ventilation and to allow calculation of naloxone intranasal bioavailability.
Study 2: Infusion of low-dose fentanyl whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation > 85%), intravenous naloxone (IV, 0.4mg/mL) or intravenous nalmefene (IV, 1 mg/mL) will be administered at 5 min intervals with each bolus is 0.08 mg.
At regular intervals blood will be drawn for measurement of drug concentration; at regular intervals pupil diameter will be measured.
Main study parameters:
The main study measurement is minute ventilation. Together with the plasma concentration of the opioid and naloxone and nalmefene), ventilation is inputted in the PKPD model to get meaningful model parameters such as C50 and t½ke0, measures of potency and the speed of onset/offset of effect, respectively.
The secondary study measurement is pupil diameter. Together with the plasma concentration of the opioid and naloxone and nalmefene), the pupil diameter is inputted in the PKPD model to get meaningful model parameters such as C50 and t½ke0, measures of potency and the speed of onset/offset of effect, respectively. See Data analysis below. Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
In this pharmacokinetic-pharmacodynamic modeling study, the effect of intravenous and intranasal naloxone and intravenous nalmefene is studied during infusion of two opioids, fentanyl and sufentanil, in mixed population of healthy volunteers and chronic opioid users. The PK/PD analysis will yield important information regarding dosing regimens of IM and IN naloxone at fentanyl and sufentanil doses much higher than we will administer here, but that may represent doses in case of an overdose both in clinical patients and opioid abusers. Side effects related to the medication will be mild to moderate with most common side effects: nausea, vomiting, dizziness, somnolence, dry mouth and respiratory depression (from the opioids), and possibly mild withdrawal symptoms from naloxone. Side effects will dissipate over time while severe occurrences of nausea and vomiting will be treated with an antiemetic; severe occurrence of withdrawal symptoms will be treated with clonidine.
- Being tested
- Narcan 40 MG/ML Nasal Spray, Naloxone Hydrochloride, Nalmefene HCl injection
- Keywords
- Reversal of opioid induced respiratory depression, Intranasal naloxone
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Narcan 40 MG/ML Nasal SprayDrug
Also called Intranasal naloxone
naloxone 4mg/0.1 mL intranasal spray, up to 4 doses intranasally, followed by 1ml 0.4 mg/ml naloxone hydrochloride intravenously
Naloxone HydrochlorideDrug
Also called IV naloxone
Naloxone 0.4mg/mL
Nalmefene HCl injectionDrug
Also called Nalmefene IV
Nalmefene 1 ng/mL
| Study group | Role | What they receive |
|---|---|---|
| Intravenous fentanyl year 1 | Experimental | continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression. Receives: Drug: Narcan 40 MG/ML Nasal Spray |
| Intravenous sufentanil year 1 | Experimental | continuous intravenous infusion of sufentanil to induce 40-60% respiratory depression. Receives: Drug: Narcan 40 MG/ML Nasal Spray |
| Intravenous fentanyl year 2 | Experimental | continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression. Receives: Drug: Naloxone Hydrochloride; Drug: Nalmefene HCl injection |
| IV fentanyl year 2 | Experimental | continuous intravenous infusion of fentanyl to induce 40-60% respiratory depression. Receives: Drug: Naloxone Hydrochloride; Drug: Nalmefene HCl injection |
What is being measured
The primary outcome is the main question the study is designed to answer.
Minute ventilation
Minute ventilation (liters/minute)
Measured: Minute ventilation will be measured for up to 180 minutes following the start of opioid infusion
Plasma concentration sufentanil/fentanyl
50 samples of 2ml arterial blood
Measured: at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intravenous naloxone or nalmefene
Plasma concentration naloxone
50 samples of 2ml arterial blood
Measured: at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intravenous naloxone or nalmefene
Secondary outcomes (1)
Pupil diameter
Pupil diameter in millimeters
Measured: at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intramuscular/intravenous naloxone. After discontinuation of infusion every 20 min. up to 6 hrs. following the start of opioid infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Apr 2022
- Study start24 Jun 2022
- Primary completion23 Mar 2026
- Study completion23 Mar 2026
Why it stopped: Recruitment of chronic opioid users was substantially lower than anticipated despite extensive recruitment efforts; the study was therefore closed before reaching the planned sample size.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for Opioid Induced Respiratory DepressionStudies of the same condition, open and under way.
- More trials run by Leiden University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Model description
- This is an open-label, randomized (IM versus IN naloxone), crossover study in a mixed population.
- Masking
- None (open label)
- Enrolment
- 58 participants (actual)
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Food and Drug Administration (FDA)
- Responsible party
- Principal investigator, Albert Dahan, Leiden University Medical Center
- Investigators
- Rutger van der Schrier, MD, Principal investigator, LUMC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05338632
- Sponsor's protocol ID
- P21.112
- Acronym
- ROAR
- Status last verified
- Jul 2026
- First submitted
- 14 Apr 2022
- Last updated
- 29 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie the results reported in this article, after deidentification (texts, tables, figures and appendices)
Publications
Algera MH, Kamp J, van der Schrier R, van Velzen M, Niesters M, Aarts L, Dahan A, Olofsen E. Opioid-induced respiratory depression in humans: a review of pharmacokinetic-pharmacodynamic modelling of reversal. Br J Anaesth. 2019 Jun;122(6):e168-e179. doi: 10.1016/j.bja.2018.12.023. Epub 2019 Feb 1.
PubMed 30915997Algera MH, Olofsen E, Moss L, Dobbins RL, Niesters M, van Velzen M, Groeneveld GJ, Heuberger J, Laffont CM, Dahan A. Tolerance to Opioid-Induced Respiratory Depression in Chronic High-Dose Opioid Users: A Model-Based Comparison With Opioid-Naive Individuals. Clin Pharmacol Ther. 2021 Mar;109(3):637-645. doi: 10.1002/cpt.2027. Epub 2020 Oct 5.
PubMed 32865832Dahan A, Aarts L, Smith TW. Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression. Anesthesiology. 2010 Jan;112(1):226-38. doi: 10.1097/ALN.0b013e3181c38c25.
PubMed 20010421Olofsen E, van Dorp E, Teppema L, Aarts L, Smith TW, Dahan A, Sarton E. Naloxone reversal of morphine- and morphine-6-glucuronide-induced respiratory depression in healthy volunteers: a mechanism-based pharmacokinetic-pharmacodynamic modeling study. Anesthesiology. 2010 Jun;112(6):1417-27. doi: 10.1097/ALN.0b013e3181d5e29d.
PubMed 20461002Olofsen E, Boom M, Nieuwenhuijs D, Sarton E, Teppema L, Aarts L, Dahan A. Modeling the non-steady state respiratory effects of remifentanil in awake and propofol-sedated healthy volunteers. Anesthesiology. 2010 Jun;112(6):1382-95. doi: 10.1097/ALN.0b013e3181d69087.
PubMed 20461001van Dorp E, Yassen A, Dahan A. Naloxone treatment in opioid addiction: the risks and benefits. Expert Opin Drug Saf. 2007 Mar;6(2):125-32. doi: 10.1517/14740338.6.2.125.
PubMed 17367258Yassen A, Olofsen E, van Dorp E, Sarton E, Teppema L, Danhof M, Dahan A. Mechanism-based pharmacokinetic-pharmacodynamic modelling of the reversal of buprenorphine-induced respiratory depression by naloxone : a study in healthy volunteers. Clin Pharmacokinet. 2007;46(11):965-80. doi: 10.2165/00003088-200746110-00004.
PubMed 17922561Gepts E, Shafer SL, Camu F, Stanski DR, Woestenborghs R, Van Peer A, Heykants JJ. Linearity of pharmacokinetics and model estimation of sufentanil. Anesthesiology. 1995 Dec;83(6):1194-204. doi: 10.1097/00000542-199512000-00010.
PubMed 8533912van Lemmen MA, Florian J, Li Z, van Velzen M, Olofsen E, Dahan A, Niesters M, Sarton E, van der Schrier R. Intranasal Naloxone Reversal of Opioid-induced Respiratory Depression in Opioid-naive Individuals and Self-reported Daily Opioid Users. Anesthesiology. 2026 May 1;144(5):1160-1172. doi: 10.1097/ALN.0000000000005931. Epub 2026 Feb 5.
PubMed 41642634
Study at a glance
From the registry record, last updated by the sponsor on 29 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Reversal of Opioid-induced Respiratory Depression With Opioid Antagonists - a Study in Opioid naïve Individuals and Chronic Opioid Users Under Real-life Conditions
- ClinicalTrials.gov ID
- NCT05338632
- Acronym / sponsor ID
- ROAR / P21.112
- Keywords
- Reversal of opioid induced respiratory depression, Intranasal naloxone
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Recruitment of chronic opioid users was substantially lower than anticipated despite extensive recruitment efforts; the study was therefore closed before reaching the planned sample size.
- Enrolment
- 58 participants (actual)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Collaborators
- Food and Drug Administration (FDA)
- Study start
- 24 Jun 2022 (actual)
- Primary completion
- 23 Mar 2026 (actual)
- Study completion
- 23 Mar 2026 (actual)
- First posted
- 21 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
n this pharmacokinetic/pharmacodynamic modelling study we will determine the ability of intranasal and intravenous naloxone and intravenous nalmefene to reverse opioid (fentanyl and sufentanil)- induced respiratory depression in healthy volunteers and chronic opioid users to develop dosing recommendations in case of opioid-induced respiratory depression from an opioid overdose in clinical practice and in the out-of-hospital overdose.
Detailed description
Primary objective:
To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on ventilation of intranasal and intravenous naloxone and intravenous nalmefene in its ability to reverse respiratory depression (important model parameters include C50, a measure of potency and t½ke0). The results of these studies will allow us to perform simulation studies aimed at optimizing dosing regimens for intranasal and intramuscular naloxone in individuals that overdosed on potent opioids, with respiratory depression ranging from moderate to severe.
Secondary objectives:
To describe the pharmacokinetics and pharmacodynamics of intravenous fentanyl and sufentanil on pupil diameter and intranasal and intravenous naloxone and intravenous nalmefene in its ability to reverse miosis (important model parameters include C50, a measure of potency and t½ke0). The results of these studies will allow us to compare the ventilatory and pupil effects of the opioids and of naloxone.
Study design:
This is an open-label, randomized, crossover study in a mixed population
Study population:
We will study 12 healthy individuals of either sex aged 18-55 years and 12 individuals that are chronic opioids users (> 60 daily oral morphine equivalents; 18-55 years).
Intervention:
Study 1: Infusion of low-dose fentanyl and sufentanil whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation > 85%), intranasal naloxone (IN, 4 mg) will be administered twice with a maximum of 180 minutes in between. At the end of each experiment 0.4 mg naloxone will be administered intravenously to determine its effect on ventilation and to allow calculation of naloxone intranasal bioavailability.
Study 2: Infusion of low-dose fentanyl whilst measuring minute ventilation and pupil diameter. When ventilation has dropped by 40-60% (Saturation > 85%), intravenous naloxone (IV, 0.4mg/mL) or intravenous nalmefene (IV, 1 mg/mL) will be administered at 5 min intervals with each bolus is 0.08 mg.
At regular intervals blood will be drawn for measurement of drug concentration; at regular intervals pupil diameter will be measured.
Main study parameters:
The main study measurement is minute ventilation. Together with the plasma concentration of the opioid and naloxone and nalmefene), ventilation is inputted in the PKPD model to get meaningful model parameters such as C50 and t½ke0, measures of potency and the speed of onset/offset of effect, respectively.
The secondary study measurement is pupil diameter. Together with the plasma concentration of the opioid and naloxone and nalmefene), the pupil diameter is inputted in the PKPD model to get meaningful model parameters such as C50 and t½ke0, measures of potency and the speed of onset/offset of effect, respectively. See Data analysis below. Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
In this pharmacokinetic-pharmacodynamic modeling study, the effect of intravenous and intranasal naloxone and intravenous nalmefene is studied during infusion of two opioids, fentanyl and sufentanil, in mixed population of healthy volunteers and chronic opioid users. The PK/PD analysis will yield important information regarding dosing regimens of IM and IN naloxone at fentanyl and sufentanil doses much higher than we will administer here, but that may represent doses in case of an overdose both in clinical patients and opioid abusers. Side effects related to the medication will be mild to moderate with most common side effects: nausea, vomiting, dizziness, somnolence, dry mouth and respiratory depression (from the opioids), and possibly mild withdrawal symptoms from naloxone. Side effects will dissipate over time while severe occurrences of nausea and vomiting will be treated with an antiemetic; severe occurrence of withdrawal symptoms will be treated with clonidine.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 4
- Model description
- This is an open-label, randomized (IM versus IN naloxone), crossover study in a mixed population.
| Arm | Type | Receives |
|---|---|---|
| Intravenous fentanyl year 1 | Experimental | Drug: Narcan 40 MG/ML Nasal Spraycontinuous intravenous infusion of fentanyl to induce 40-60% respiratory depression. |
| Intravenous sufentanil year 1 | Experimental | Drug: Narcan 40 MG/ML Nasal Spraycontinuous intravenous infusion of sufentanil to induce 40-60% respiratory depression. |
| Intravenous fentanyl year 2 | Experimental | Drug: Naloxone Hydrochloride, Drug: Nalmefene HCl injectioncontinuous intravenous infusion of fentanyl to induce 40-60% respiratory depression. |
| IV fentanyl year 2 | Experimental | Drug: Naloxone Hydrochloride, Drug: Nalmefene HCl injectioncontinuous intravenous infusion of fentanyl to induce 40-60% respiratory depression. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Healthy volunteers
- Signed the informed consent form (ICF) and able to comply with the study requirements and restrictions listed therein;
- Male and female subjects, age 18 to 70 years, inclusive;
- Women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative serum pregnancy test prior to enrolment and must agree to use a medically acceptable means of contraception from screening through at least 1 month after the last dose of study drug;
- Body Mass Index (BMI) 18 to 30 kg/m2, inclusive;
Key exclusion criteria (28 listed)
- Healthy volunteers
- Currently meet the criteria for diagnosis of substance use disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria on any substance;
- Any other active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints;
- Consume, on average, >27 20 units/week of alcohol in men and > 20 13 units/week of alcohol in women (1 unit = 1 glass (250 mL) beer, 125 mL glass of wine or 25 mL of 40% spirit);
- Previous or current treatment with opioid agonist, partial agonist, or antagonist treatment within 30 days prior to the first study drug administration;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Narcan 40 MG/ML Nasal SprayAlso: Intranasal naloxonenaloxone 4mg/0.1 mL intranasal spray, up to 4 doses intranasally, followed by 1ml 0.4 mg/ml naloxone hydrochloride intravenously | Drug | Intravenous fentanyl year 1, Intravenous sufentanil year 1 |
| Naloxone HydrochlorideAlso: IV naloxoneNaloxone 0.4mg/mL | Drug | IV fentanyl year 2, Intravenous fentanyl year 2 |
| Nalmefene HCl injectionAlso: Nalmefene IVNalmefene 1 ng/mL | Drug | IV fentanyl year 2, Intravenous fentanyl year 2 |
Primary outcome
Minute ventilation
Time frame: Minute ventilation will be measured for up to 180 minutes following the start of opioid infusion
Minute ventilation (liters/minute)
Plasma concentration sufentanil/fentanyl
Time frame: at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intravenous naloxone or nalmefene
50 samples of 2ml arterial blood
Plasma concentration naloxone
Time frame: at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intravenous naloxone or nalmefene
50 samples of 2ml arterial blood
1 secondary outcome
Pupil diameter
Time frame: at 2,5,10,15,20 and 30 minutes following opioid infusion and following every administration of intranasal/intramuscular/intravenous naloxone. After discontinuation of infusion every 20 min. up to 6 hrs. following the start of opioid infusion
Results and safety
The study was stopped early (reason given: Recruitment of chronic opioid users was substantially lower than anticipated despite extensive recruitment efforts; the study was therefore closed before reaching the planned sample size.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jul 2026.
- Background: PubMed 30915997Algera MH, Kamp J, van der Schrier R, van Velzen M, Niesters M, Aarts L, Dahan A, Olofsen E. Opioid-induced respiratory depression in humans: a review of pharmacokinetic-pharmacodynamic modelling of reversal. Br J Anaesth. 2019 Jun;122(6):e168-e179. doi: 10.1016/j.bja.2018.12.023. Epub 2019 Feb 1.
- Background: PubMed 32865832Algera MH, Olofsen E, Moss L, Dobbins RL, Niesters M, van Velzen M, Groeneveld GJ, Heuberger J, Laffont CM, Dahan A. Tolerance to Opioid-Induced Respiratory Depression in Chronic High-Dose Opioid Users: A Model-Based Comparison With Opioid-Naive Individuals. Clin Pharmacol Ther. 2021 Mar;109(3):637-645. doi: 10.1002/cpt.2027. Epub 2020 Oct 5.
- Background: PubMed 20010421Dahan A, Aarts L, Smith TW. Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression. Anesthesiology. 2010 Jan;112(1):226-38. doi: 10.1097/ALN.0b013e3181c38c25.
- Background: PubMed 20461002Olofsen E, van Dorp E, Teppema L, Aarts L, Smith TW, Dahan A, Sarton E. Naloxone reversal of morphine- and morphine-6-glucuronide-induced respiratory depression in healthy volunteers: a mechanism-based pharmacokinetic-pharmacodynamic modeling study. Anesthesiology. 2010 Jun;112(6):1417-27. doi: 10.1097/ALN.0b013e3181d5e29d.
- Background: PubMed 20461001Olofsen E, Boom M, Nieuwenhuijs D, Sarton E, Teppema L, Aarts L, Dahan A. Modeling the non-steady state respiratory effects of remifentanil in awake and propofol-sedated healthy volunteers. Anesthesiology. 2010 Jun;112(6):1382-95. doi: 10.1097/ALN.0b013e3181d69087.
- Background: PubMed 17367258van Dorp E, Yassen A, Dahan A. Naloxone treatment in opioid addiction: the risks and benefits. Expert Opin Drug Saf. 2007 Mar;6(2):125-32. doi: 10.1517/14740338.6.2.125.
- Background: PubMed 17922561Yassen A, Olofsen E, van Dorp E, Sarton E, Teppema L, Danhof M, Dahan A. Mechanism-based pharmacokinetic-pharmacodynamic modelling of the reversal of buprenorphine-induced respiratory depression by naloxone : a study in healthy volunteers. Clin Pharmacokinet. 2007;46(11):965-80. doi: 10.2165/00003088-200746110-00004.
- Background: PubMed 8533912Gepts E, Shafer SL, Camu F, Stanski DR, Woestenborghs R, Van Peer A, Heykants JJ. Linearity of pharmacokinetics and model estimation of sufentanil. Anesthesiology. 1995 Dec;83(6):1194-204. doi: 10.1097/00000542-199512000-00010.
- Derived from this study: PubMed 41642634van Lemmen MA, Florian J, Li Z, van Velzen M, Olofsen E, Dahan A, Niesters M, Sarton E, van der Schrier R. Intranasal Naloxone Reversal of Opioid-induced Respiratory Depression in Opioid-naive Individuals and Self-reported Daily Opioid Users. Anesthesiology. 2026 May 1;144(5):1160-1172. doi: 10.1097/ALN.0000000000005931. Epub 2026 Feb 5.
- Individual participant dataSharing planned: Yes. Individual participant data that underlie the results reported in this article, after deidentification (texts, tables, figures and appendices)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rutger van der Schrier, MD principal investigator
LUMC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Narcan 40 MG/ML Nasal Spray, Naloxone Hydrochloride and Nalmefene HCl injection in people with Opioid Induced Respiratory Depression and Chronic Opioid Use, run by Leiden University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 29 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Recruitment of chronic opioid users was substantially lower than anticipated despite extensive recruitment efforts; the study was therefore closed before reaching the planned sample size.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Minute ventilation (time frame: Minute ventilation will be measured for up to 180 minutes following the start of opioid infusion). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05338632, which also lists 9 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jul 2026.