Nitrous Oxide for Pain

(NONI Trial)

Overseen By Keith M Vogt, MD, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Keith M Vogt

Must not be taking: Antiepileptics, Antidepressants, Antipsychotics, others

Disqualifiers: Pregnancy, Chronic pain, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 1 day

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates how acute pain affects long-term memory and body responses, both with and without low-dose nitrous oxide (commonly known as laughing gas). Researchers will use MRI scans to observe brain activity during the trial. Participants will receive nitrous oxide and experience controlled, mild pain. This trial may suit individuals without chronic pain who can safely undergo MRI scans. As an Early Phase 1 trial, this research aims to understand how nitrous oxide affects the brain, offering participants a chance to contribute to groundbreaking scientific knowledge.

Will I have to stop taking my current medications?

The trial requires that you do not regularly take certain medications, including pain medications, antiepileptics, antidepressants, antipsychotics, antihistamines, anti-anxiety medications, stimulants, or sleep-aids. If you are taking any of these, you may need to stop before participating.

Is there any evidence suggesting that nitrous oxide is likely to be safe for humans?

Research has shown that nitrous oxide is generally safe for managing pain and has been used worldwide for many years, particularly during childbirth. Studies have found that it is safe and lacks the serious risks associated with other pain relief methods. A large study of over 22,000 patients found that nitrous oxide did not increase the risk of death or major complications after surgery. While it might not completely eliminate pain, its side effects are usually minor, making it a well-tolerated choice for many people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for pain relief, which often includes medications like opioids and NSAIDs that can have significant side effects and risk dependencies, nitrous oxide offers a unique approach. Researchers are excited about nitrous oxide because it provides rapid pain relief by acting directly on the nervous system, potentially reducing the need for drugs with more severe side effects. This gas has a long history of safe use in medical settings, like dental procedures, making it a promising alternative for managing acute pain with fewer complications.

What evidence suggests that nitrous oxide might be an effective treatment for pain?

Studies have shown that nitrous oxide reduces pain by blocking pain signals in the brain, providing relief similar to other pain treatments. Research indicates it is particularly helpful during labor, offering safe pain management for both mothers and babies. Some studies suggest that lower amounts of nitrous oxide can be as effective as higher amounts, with fewer side effects like dizziness and nausea. Although nitrous oxide is commonly used in dental procedures and childbirth, its use for treating sudden pain conditions remains under study. In this trial, participants will receive nitrous oxide alongside painful electric nerve stimulation to evaluate its effectiveness in managing acute pain. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for individuals experiencing amnesia or pain who can undergo two visits with no long-term follow-up. Specific eligibility details are not provided, but typically participants must be in good health and meet certain age and condition severity criteria.

Inclusion Criteria

Have none of the specific exclusion criteria

I have a working email and phone number.

Free from any non-MRI compatible implants

Exclusion Criteria

Being claustrophobic

Have metal implants or non-removable metal piercings

Having a history of adverse reaction to anesthetics

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Baseline Assessment

Participants undergo baseline functional MRI scans without nitrous oxide to assess brain activity and connectivity

1 day

1 visit (in-person)

Treatment

Participants receive nitrous oxide and undergo functional MRI scans to assess the effects on pain processing and memory encoding

1 day

1 visit (in-person)

Follow-up

Participants are monitored for memory performance 24 hours after the learning experiment

1 day

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Nitrous Oxide

Trial Overview The study tests the effects of low dose nitrous oxide on memory and body responses to acute pain using brain imaging (fMRI). It also explores how peripheral nerve stimulation impacts these outcomes over two separate visits.

How Is the Trial Designed?

Group I: Nitrous Oxide + Pain Experimental Treatment 2 Interventions

Single-arm study. All subjects receive nitrous oxide and painful electric nerve stimulation, as described in the interventions.

Who Is Running the Clinical Trial?

Keith M Vogt

Lead Sponsor

Trials

4

Recruited

210+

National Institute of General Medical Sciences (NIGMS)

Collaborator

Trials

315

Recruited

251,000+

Published Research Related to This Trial

In a study of 124 children aged 1-17 undergoing procedures in the emergency department, nitrous oxide (N2O) was used for analgesia, but pain scores showed that 34% of patients experienced significant pain (scores of 70 mm or greater) during procedures, indicating limited efficacy for very painful interventions.

Despite the pain management limitations, both parents (96% satisfaction) and staff (92% rated sedation and analgesia as adequate) reported high satisfaction with the use of N2O for procedural sedation in the emergency department.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Limited analgesic efficacy of nitrous oxide for painful procedures in children. Babl, FE., Oakley, E., Puspitadewi, A., et al.[2022]

A case study revealed that very high-dose nitrous oxide use, especially when combined with cannabis, can lead to serious health issues like acute myocardial infarction due to thrombus formation in the coronary artery.

The patient exhibited low vitamin B12 levels and hyperhomocysteinaemia, suggesting that nitrous oxide abuse may cause vitamin deficiencies that increase the risk of blood clotting, challenging the perception of nitrous oxide as a safe recreational drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report of an acute myocardial infarction after high-dose recreational nitrous oxide use: a consequence of hyperhomocysteinaemia? Oomens, T., Riezebos, RK., Amoroso, G., et al.[2022]

Entonox(®), a mixture of 50% nitrous oxide and 50% oxygen, has been shown to significantly reduce pain during various urological procedures, including prostate biopsies and flexible cystoscopies, based on a systematic review of five randomized controlled trials.

The studies indicate that Entonox(®) is not only effective in pain management but also safe and well-accepted by patients, suggesting its potential for broader use in clinical practice due to its cost-effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entonox® inhalation to reduce pain in common diagnostic and therapeutic outpatient urological procedures: a review of the evidence. Young, A., Ismail, M., Papatsoris, AG., et al.[2022]

In a study of 173 vascular and interventional procedures over 2 years, nitrous oxide was found to be a safe and effective analgesic, providing adequate pain relief in 74% of patients without premedication and 61% of those with premedication.

Minor complications such as nausea and vomiting were reported in a small number of patients, but these were easily managed by adjusting the nitrous oxide concentration, highlighting its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide: effective analgesic for vascular and interventional procedures. Braun, SD., Miller, GA., Ford, KK., et al.[2013]

Nitrous oxide (N2O) is an effective analgesic and sedative used in dentistry, offering benefits like rapid onset and both pain relief and anxiety reduction.

Despite its advantages, nitrous oxide can lead to vitamin B12 deficiency and has potential risks such as infertility and neurological issues, highlighting the importance of using scavenger systems to reduce occupational exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Not Available]. Liakoni, E., Liechti, ME.[2019]

A systematic review of 34 studies on recreational nitrous oxide (N2O) use highlights a concerning increase in its use and associated harms, particularly among young people, yet there is a lack of awareness about these risks.

The review calls for improved harm reduction strategies, emphasizing the need for both policy changes and service delivery improvements to better address the growing issue of N2O use and its potential dangers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review of Recreational Nitrous Oxide Use: Implications for Policy, Service Delivery and Individuals. Allan, J., Cameron, J., Bruno, J.[2023]

Nitrous oxide (N2O) is a safe and effective anesthetic and analgesic gas that can be used in various medical situations due to its low incidence of adverse effects.

It can be administered by trained medical providers or even self-administered by patients, making it a versatile option in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on nitrous oxide and its use in anesthesia practice. Zafirova, Z., Sheehan, C., Hosseinian, L.[2019]

Nitrous oxide (N2O) is widely used as a safe anesthetic and has a rapid onset of euphoric effects when inhaled recreationally, particularly among clubbers and festival-goers, with usage rates between 40% and 80%.

While N2O is generally considered safe for moderate use, heavy or sustained use can lead to vitamin B12 deficiency and associated neurological issues, highlighting the need for user education about these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recreational nitrous oxide use: Prevalence and risks. van Amsterdam, J., Nabben, T., van den Brink, W.[2022]

Healthcare professionals exposed to high levels of nitrous oxide (N2O) in the past faced significant reproductive risks, including congenital anomalies and reduced fertility rates, but these risks have been reduced due to occupational safety measures.

Recreational users of N2O often exceed safe exposure limits by a large margin, putting themselves at risk for similar reproductive issues, highlighting the need for increased awareness about these dangers among users, especially those who are pregnant or planning to become pregnant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide-induced reproductive risks: Should recreational nitrous oxide users worry? van Amsterdam, J., van den Brink, W.[2022]

Nitrous oxide (N2O) is an effective analgesic that mimics the action of opiates like morphine, making it a preferred choice for pain relief in medically compromised patients and during dental procedures.

Its inhalation method allows for adjustable dosing and minimal side effects, making it particularly suitable for managing anxiety in children and patients with health concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide analgesia in selected dental patients. Kaufman, E., Kadari, A., Galili, D., et al.[2018]

Nitrous oxide (N2O) has a long history of use, initially discovered in 1772 and later recognized for its psychotropic properties in the late 18th century, leading to its application in dentistry and psychiatry.

At low doses, N2O mixed with oxygen is used safely in modern dentistry to avoid adverse effects, and it has been explored for treating psychiatric conditions since the 1980s, highlighting its potential beyond just anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mini-Review: A Brief History of Nitrous Oxide (N2O) Use in Neuropsychiatry. Gillman, MA.[2020]

A systematic review identified 59 cases of nitrous oxide (N2O) use disorder and 17 cases of EMONO use disorder, highlighting the potential for addiction, especially when used in larger quantities and for longer durations than intended.

The study suggests that N2O use disorder can develop not only from recreational use but also from medical exposure, indicating a need for careful monitoring of its use in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide: What do we know about its use disorder potential? Results of the French Monitoring Centre for Addiction network survey and literature review. Fidalgo, M., Prud'homme, T., Allio, A., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7755562/

Nitrous Oxide for Labor Analgesia: What We Know to Date N 2 O has been shown to be a safe option for both mom and baby during labor and delivery. Studies support N 2 O as an analgesic for laboring.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0735675722001863

Analgesic efficacy of nitrous oxide in adults in the ... The present meta-analysis suggested that N2O could provide better analgesia than placebo and similar analgesia to other methods with more vomiting and dizziness ...

3. evidencebasedbirth.com evidencebasedbirth.com/nitrous-oxide-during-labor/

Nitrous Oxide During Labor Now, about half of the studies examined the effectiveness of nitrous oxide for labor pain relief, and they concluded that there is some poor quality evidence ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06661005

Nitrous Oxide for Pain Management During In-Office ... The purpose of this study is to evaluate the pain control, patient satisfaction, and efficiency of nitrous oxide used for anesthesia during ...

5. emedicine.medscape.com emedicine.medscape.com/article/1413427-overview

Nitrous Oxide Administration: Overview, Indications, ... Compared with a 50% concentration of nitrous oxide, the 25% concentration was similarly effective but posed a lower risk of adverse effects, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3594866/

Nitrous Oxide for Labor Analgesia: Expanding Analgesic ... N2O administration is noninvasive and does not carry the serious (although rare) risks associated with regional analgesia. Indeed, in patients in whom regional ...

7. apsf.org apsf.org/article/safety-and-utility-of-nitrous-oxide-for-labor-analgesia/

Safety and Utility of Nitrous Oxide for Labor Analgesia Much of the available data suggests a modest analgesic effect at best. One study found no decrease in pain scores with nitrous oxide compared to placebo in ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01738672

NCT01738672 | Inhaled Nitrous Oxide and Labor Analgesia Hypothesis: The administration of nitrous oxide for labor analgesia will decrease the labor epidural anesthesia rate by 15%.

9. asahq.org asahq.org/about-asa/governance-and-committees/asa-committees/committee-on-obstetric-anesthesia/nitrous-oxide

​Nitrous Oxide | American Society of Anesthesiologists ... Nitrous oxide has been used throughout the world for labor pain control for many decades and is considered safe.

10. sciencedirect.com sciencedirect.com/science/article/pii/S0007091224000734

Influence of nitrous oxide added to general anaesthesia on ... The current meta-analysis included 71 RCTs, totalling 22 147 patients, and found that nitrous oxide did not influence postoperative mortality and major ...