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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine the effects of acute pain on long-term memory and conditioned physiologic responses in the presence and absence of low dose nitrous oxide. Functional magnetic resonance imaging will be used to identify the neural correlates of these phenomena. The study will occur over 2 visits and involves no long-term follow up.

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.

What evidence supports the effectiveness of the drug nitrous oxide for pain relief?

Nitrous oxide is commonly used as a safe anesthetic in medical settings like dentistry and childbirth, and it is appreciated for its ability to reduce anxiety. However, its effectiveness specifically for pain relief in children during medical procedures is limited, as studies show that it may not significantly reduce pain scores. ^{1 2 3 4 5}

Is nitrous oxide safe for use in humans?

Nitrous oxide is generally considered safe when used medically, but heavy or prolonged use can lead to vitamin B12 deficiency, which may cause nerve damage and anemia. It is important to be aware of these risks, especially with recreational use, and to use it under medical supervision when possible. ^{4 6 7 8 9}

How does nitrous oxide differ from other pain treatments?

Nitrous oxide is unique because it acts like an opiate (a type of pain-relieving drug) but is inhaled, allowing for continuous adjustment during use. This makes it a flexible and safe option for pain relief, especially in settings like dental procedures and emergency departments, where quick and adjustable pain management is needed. ^{2 6 10 11 12}

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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 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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

Limited analgesic efficacy of nitrous oxide for painful procedures in children. [2022]

3. United States 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. [2020]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Recreational nitrous oxide use: Prevalence and risks. [2022]

5. United Arab Emirates pubmed.ncbi.nlm.nih.gov

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

6. Netherlands pubmed.ncbi.nlm.nih.gov

Update on nitrous oxide and its use in anesthesia practice. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Case report of an acute myocardial infarction after high-dose recreational nitrous oxide use: a consequence of hyperhomocysteinaemia? [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Nitrous oxide-induced reproductive risks: Should recreational nitrous oxide users worry? [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

[Not Available]. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Nitrous oxide analgesia in selected dental patients. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Entonox® inhalation to reduce pain in common diagnostic and therapeutic outpatient urological procedures: a review of the evidence. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Nitrous oxide: effective analgesic for vascular and interventional procedures. [2013]