Using L-NAC to reverse breathing problems caused by opioid medication
| ISRCTN | ISRCTN16683564 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN16683564 |
| EudraCT/CTIS number | 2023-503912-34 |
| Secondary identifying numbers | P23.033 |
- Submission date
- 15/05/2023
- Registration date
- 31/05/2023
- Last edited
- 31/05/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Signs and Symptoms
Plain English summary of protocol
Background and study aims
Opioid-induced respiratory depression (OIRD) is a serious problem that can occur when using opioids for medical treatment or when misusing them. Naloxone, a commonly used medication, is not very effective in reversing OIRD caused by powerful opioids like high-dose fentanyl. This means there is a need for alternative medications that can stimulate breathing without being specific to certain opioids. L-NAC (N-acetyl-N-cysteine or fluimicil) is a drug that is approved for treating paracetamol overdose, and it also has the ability to stimulate breathing. In this study, we will investigate whether giving L-NAC through an intravenous infusion can help reverse OIRD caused by fentanyl. We will conduct a randomized controlled trial where some participants will receive intravenous L-NAC while others will receive a placebo, and we will observe the effects on fentanyl-induced respiratory depression.
Who can participate?
Healthy volunteers aged 18 - 40 years.
What does the study involve?
The main goal of the study is to determine how L-NAC affects the amount of air a person breathes in and out (minute ventilation) when they receive an individualized intravenous dose of fentanyl. This specific dose of fentanyl is designed to cause a 40% decrease in breathing by the end of a 2-hour infusion of L-NAC or placebo.
First, the individualized intravenous fentanyl infusion will begin with the aim of achieving a 40% decrease in breathing compared to the person's normal breathing rate. Once the 40% decrease is achieved, either the L-NAC or placebo infusion will start and last for 1 hour with a dose of 75 mg/kg. Then, a second administration of L-NAC or placebo will be given over the next hour with a dose of 150 mg/kg. The dose of L-NAC may be adjusted based on the observations from previous participants, with a maximum increase of two times the initial dose.
Three hours after the start of the first infusion of L-NAC or placebo, the experiment will end, and all infusions will be stopped.
What are the possible benefits and risks of participating?
The healthy volunteers in this trial will not gain benefit from participating in this study. The benefit lies within the gained knowledge in our ability to treat, reverse and prevent opioid-inducted respiratory depression observed in patients treated with opioids and persons with an opioid use disorder. The burden of the study is related to the measurements and interventions. The used drugs have side effects. The application of iv lines could cause short-lasting pain and might result in a temporary, self-resolving hematoma.
Where is the study run from?
Leiden University Medical Center (the Netherlands)
When is the study starting and how long is it expected to run for?
April 2023 to January 2024
Who is funding the study?
Leiden University Medical Center (the Netherlands)
Who is the main contact?
Dr Monique van Velzen, m.van_velzen@lumc.nl
Contact information
Scientific
Albinusdreef 2
H5-P
Leiden
2333 ZA
Netherlands
 ORCID ID |
0000-0002-0289-6432 |
|---|---|
| Phone | +31 715262301 |
| m.van_velzen@lumc.nl |
Study information
| Study design | Single center randomized placebo-controlled double-blind |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | University/medical school/dental school |
| Study type | Safety, Efficacy |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet. |
| Scientific title | L-NAC (N-acetyl-N-cysteine or fluimicil) for reversal of opioid-induced respiratory depression |
| Study acronym | ORNAC |
| Study objectives | L-NAC (N-acetyl-N-cysteine or fluimicil) is a drug, registered for treatment of paracetamol intoxication, that has also respiratory stimulatory effects. In the current study, we will investigate the ability of an intravenous infusion of L-NAC on OIRD induced by fentanyl. |
| Ethics approval(s) | Approved 12/05/2023, Medical Research Ethics Committee Leiden the Hague Delft (Albinusdreef 2, 2333 ZA Leiden, the Netherlands; +31-71-5263241; metc-ldd@lumc.nl), ref: P23.033 |
| Health condition(s) or problem(s) studied | Reversal of opioid-induced respiratory depression |
| Intervention | Randomization (1:1) will be done by generating an electronic randomization list in R by an independent member of the department and sent to the pharmacy. The pharmacy is responsible for blinding the L-NAC/placebo syringes Individualized intravenous fentanyl infusion will be initiated aimed at 40% respiratory depression compared to baseline. After 40% respiratory depression is attained, the L-NAC or placebo infusion will start over 1 h with dose 75 mg/kg. A second administration of L-NAC or placebo will be administered over hour the next hour with dose 150 mg/kg. The L-NAC dose may be adapted based on the results observed in previous subjects (max. increase with a factor of 2). Three hours after the first infusion of L-NAC or placebo, the experiment will end, and all infusions will be terminated. Measurements made are: minute ventilation on a breath-to-breath basis through a facemask for 3 hours, end-tidal carbon dioxide partial pressure, respiratory frequency, tidal volume, oxygen saturation (all obtained on a breath-to-breath basis), arterial blood gas analysis: pH, pO2, pCO2, oxygen saturation (obtained at 15 min intervals), blood pressure by cuff (at 30 min interval) and plasma concentrations of fentanyl and L-NAC (at regular intervals). Total volume of blood drawn is 125 mL. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacokinetic, Pharmacodynamic |
| Phase | Phase III/IV |
| Drug / device / biological / vaccine name(s) | L-NAC (N-acetyl-N-cysteine or fluimicil), fentanyl |
| Primary outcome measure | Minute ventilation during exposure measured through a facemask during the exposure period |
| Secondary outcome measures | 1. End-tidal carbon dioxide partial pressure obtained on a breath-to-breath basis during the exposure period using pneumotachograph 2. Respiratory frequency obtained on a breath-to-breath basis during the exposure period using pneumotachograph 3. Tidal volume obtained on a breath-to-breath basis during the exposure period using pneumotachograph 4. Arterial blood gas analysis: pH, pO2, pCO2, oxygen saturation obtained at 15 min intervals during the exposure period using blood gas analyzer 5. Plasma concentrations of fentanyl and L-NAC measured using a blood sample at regular intervals using LC-MS/MS methods 6. Blood pressure measured by cuff (at 30 min interval) during the exposure period |
| Overall study start date | 01/04/2023 |
| Completion date | 01/01/2024 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 40 Years |
| Sex | Both |
| Target number of participants | 18 |
| Key inclusion criteria | 1. Aged 18 - 40 years 2. Body mass index 19-30 kg/m² 3. Ability to read and understand the subject information in the Dutch language |
| Key exclusion criteria | 1. A medical history of medical or psychiatric disease; 2. Any allergy to food or medication; 3. Weekly ethanol intake of more than 3 units/day or more than 21 units/week in women and 5 units/day and 35 units/week in men; 4. Pregnancy; 5. 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 urine 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; Acceptable means of contraception include: hormonal methods (birth control pills), barrier 6. Methods (condoms, diaphragm), intrauterine devices, sterilization; 7. Participation in an investigational drug trial in the 3 months before the current study; 8. Illicit drug use in the 30 days before the current study; 9. A positive drug urine dipstick on the screening or study days, including benzodiazepines. |
| Date of first enrolment | 01/06/2023 |
| Date of final enrolment | 01/11/2023 |
Locations
Countries of recruitment
- Netherlands
Study participating centre
Albinusdreef 2
Leiden
2333 ZA
Netherlands
Sponsor information
University/education
Albinusdreef 2
H5-P
Leiden
2333 ZA
Netherlands
| Phone | +31 715262301 |
|---|---|
| m.van_velzen@lumc.nl | |
| Website | https://www.lumc.nl/?setlanguage=English&setcountry=en |
"ROR" |
https://ror.org/05xvt9f17 |
Funders
Funder type
Hospital/treatment centre
Government organisation / Local government
- Alternative name(s)
- Leiden University Medical Center, LUMC
- Location
- Netherlands
Results and Publications
| Intention to publish date | 01/06/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The data will be published in a peer-reviewed scientific journal as soon as the data have been analyzed and the manuscript has been written, without any restrictions. This is in agreement with the CCMO statement that (https://english.ccmo.nl/publications/publications/2002/03/01/ccmostatement- on-publication-policy) |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be available upon request from Albert Dahan a.dahan@lumc.nl |
Editorial Notes
17/05/2023: Trial's existence confirmed by Medical Research Ethics Committee Leiden the Hague Delft.
