Nitrous Oxide for Fibromyalgia

Overseen by Peter Nagele, MD, MSc

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Chicago

Must not be taking: NMDAR ligands, Benzodiazepines

Disqualifiers: Autoimmune diseases, Severe depression, others

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing if inhaling nitrous oxide can help people with fibromyalgia by blocking certain brain signals that make pain feel worse. It focuses on patients who have not found relief from other treatments.

Will I have to stop taking my current medications?

You can continue taking your current fibromyalgia medications as long as they have been stable for at least 4 weeks before the study. However, you cannot be on certain drugs like ketamine or methadone.

What data supports the effectiveness of the drug nitrous oxide for fibromyalgia?

Research shows that nitrous oxide, when combined with opioids, can significantly reduce pain in patients with neuropathic pain, suggesting it may have potential for pain relief in fibromyalgia as well. ^{1 2 3 4 5}

Is nitrous oxide generally safe for humans?

Nitrous oxide is generally considered safe when used under medical supervision, but long-term exposure, especially in occupational settings, may pose risks such as vitamin B12 deficiency, reproductive issues, and neurological effects. Safety standards and preventive measures are in place to minimize these risks. ^{3 6 7 8 9}

How is nitrous oxide different from other drugs for fibromyalgia?

Nitrous oxide, commonly known as 'laughing gas,' is unique because it is inhaled and has been traditionally used as an anesthetic and analgesic (pain reliever) in medical settings, unlike most fibromyalgia treatments which are oral medications. Its potential use for fibromyalgia is novel, as it may offer pain relief through a different mechanism compared to standard treatments. ^{1 10 11 12 13}

Research Team

Peter Nagele, MD, MSc

Principal Investigator

University of Chicago, Department of Anesthesia and Critical Care

Eligibility Criteria

This trial is for adults aged 18-75 with fibromyalgia experiencing pain of at least a moderate level. Participants must have been on a stable treatment plan for fibromyalgia for four weeks prior to the study and meet specific diagnostic criteria. Pregnant individuals, those with significant psychiatric conditions or substance abuse history, or those using certain medications are excluded.

Inclusion Criteria

Meet the 2016 American College of Rheumatology Revised criteria for fibromyalgia (2016-ACR)

My pain level is at least 4 out of 10.

Ability to understand study requirements, provide written informed consent, abide by study restrictions, and agree to return for required assessments

Exclusion Criteria

Clinically significant alcohol or other substance abuse within the last 2 years, in the opinion of the investigator

I do not have any serious conditions affecting my heart, lungs, or other organs.

I have chronic pain from conditions like rheumatoid arthritis or lupus that might be confused with fibromyalgia pain.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive two 60-minute inhalation sessions of 50% nitrous oxide or placebo

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 weeks

Regular assessments (in-person and virtual)

Treatment Details

Interventions

• Nitrous oxide gas for inhalation (Inhalational Anesthetic)
• Placebo (Other)

Trial Overview The trial is testing whether inhaling nitrous oxide gas can help manage pain in fibromyalgia patients compared to a placebo. It aims to determine if this common anesthetic could be repurposed as a pain relief method for chronic conditions like fibromyalgia.

Participant Groups

Group I: Treatment; Nitrous Oxide 50% Active Control 1 Intervention

A single 60-minute session of inhaled 50% nitrous oxide.

Group II: Control; Oxygen-air mixture Placebo Group 1 Intervention

A single 60-minute session of inhaled Oxygen-air mixture

Nitrous oxide gas for inhalation is already approved in Canada for the following indications:

Approved in Canada as Nitrous Oxide for:

• Anesthesia
• Pain relief

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Pete Salzmann

University of Chicago

Chief Executive Officer since 2018

MD from University of Chicago’s Pritzker School of Medicine, MBA from Stanford University’s Graduate School of Business

Anh Nguyen

University of Chicago

Chief Medical Officer

MD from Rutgers New Jersey Medical School, MBA from University of Chicago

Findings from Research

This case report highlights that nitrous oxide (N2O) can lead to serious spinal cord myelopathy, resulting in impairments in lower limb strength and coordination, as seen in two patients who experienced ataxic ambulation.

Both patients were treated with vitamin B12 and underwent a structured rehabilitation program, leading to significant improvements, including independent walking by discharge and full functional recovery in one case after 9 months, demonstrating the importance of timely medical and rehabilitation interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of the Rehabilitation Treatment Specification System (RTSS) in the management of nitrous oxide (N2O)-induced spinal cord injury. Buttery, C., Birns, J., Gibson, J., et al.[2023]

In a study involving 92 patients with neuropathic pain who were also receiving opioids, inhaled nitrous oxide/oxygen (EMONO) significantly reduced pain intensity compared to placebo, with effects lasting for four weeks after treatment.

The findings suggest that the analgesic effects of EMONO may be enhanced in patients taking opioids, potentially due to its interaction with opioid mechanisms and anti-NMDA properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of inhaled nitrous oxide and oral opioids induces long-lasting analgesic effects in patients with neuropathic pain: ProtoTOP study post hoc exploratory analyses. Bouhassira, D., Perrot, S., Attal, N., et al.[2022]

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]

In two trials with eight healthy volunteers, flumazenil at a supraclinical dose (5.0 mg/70 kg) significantly reduced the subjective feeling of being 'high' from nitrous oxide, suggesting it can counteract some of nitrous oxide's effects.

Flumazenil did not affect the psychomotor performance impairments caused by nitrous oxide, indicating that while it may alter subjective experiences, it does not improve cognitive or motor function affected by nitrous oxide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flumazenil may attenuate some subjective effects of nitrous oxide in humans: a preliminary report. Zacny, JP., Yajnik, S., Coalson, D., et al.[2019]

In a study of 2,328 patients from the ENIGMA II trial, nitrous oxide anesthesia was associated with a 19.3% lower incidence of lung atelectasis compared to air, suggesting it may help prevent lung collapse after major surgery.

However, there was no significant difference in the incidence of pneumonia between the nitrous oxide and air groups, indicating that while nitrous oxide may reduce atelectasis, it does not appear to affect the risk of pneumonia post-surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative Pulmonary Complications in the ENIGMA II Trial: A Post Hoc Analysis. Peyton, PJ., Liskaser, G., Ho, A., et al.[2023]

Nitrous oxide is effective in reducing dental anxiety and pain, leading to a more cooperative and satisfied patient during dental procedures.

Chronic exposure to nitrous oxide poses significant health risks to dental personnel, including potential reproductive, neurological, and other systemic effects, highlighting the need for preventive measures to ensure workplace safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Environmental health risk of chronic exposure to nitrous oxide in dental practice. Szymańska, J.[2013]

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 commonly used in dental offices as a sedative to help reduce anxiety and pain, but long-term exposure to high concentrations can pose health risks to medical staff.

While regulations exist in the U.S. and Europe to manage nitrous oxide pollution, there is a lack of uniform detection measures and insufficient research on its health effects in countries like China.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Detection and prevention of nitrous oxide iatrogenic pollution in dental treatments]. Wang, Y., Wan, K.[2019]

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]

Two patients developed serious neurological issues, including limb weakness and numbness, after long-term recreational use of nitrous oxide (N2O), leading to a diagnosis of subacute combined degeneration (SCD).

Treatment involved stopping N2O use and administering vitamin B supplements, which significantly improved their symptoms, highlighting the need for awareness of N2O's neurotoxic effects and the importance of early diagnosis to prevent irreversible damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subacute combined degeneration induced by nitrous oxide inhalation: Two case reports. Zhao, B., Zhao, L., Li, Z., et al.[2022]

A 22-year-old woman developed severe health issues, including polyneuropathy and pancytopenia, due to recreational nitrous oxide use, which caused a functional vitamin B12 deficiency and increased homocysteine levels.

After receiving vitamin B12 supplementation and rehabilitation, the patient showed significant recovery, highlighting the importance of recognizing and treating the serious complications associated with nitrous oxide abuse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide-induced polyneuropathy, pancytopenia and pulmonary embolism: a case report. Parein, G., Bollens, B.[2023]

A case study of a young woman who regularly inhaled nitrous oxide for pain relief revealed that it can lead to serious neurological issues, such as subacute myelopathy, especially in individuals with poor nutrition.

The patient improved significantly after stopping nitrous oxide, receiving high-dose vitamin B12, and undergoing physiotherapy, highlighting the importance of recognizing nitrous oxide-related complications in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An unusual cause of falls in a young woman. Sleeman, I., Wiblin, L., Burn, D.[2017]

A case study revealed that recreational use of nitrous oxide can lead to subacute combined degeneration (SCD) due to vitamin B12 deficiency, highlighting a serious health risk associated with its misuse.

The patient showed significant improvement after receiving vitamin B12 supplementation, indicating that timely treatment can reverse the neurological effects caused by nitrous oxide-induced deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Case Report of Subacute Combined Degeneration Due to Nitrous Oxide-Induced Vitamin B12 Deficiency. Nadal Bosch, J., Malcolm, J., Moya, M., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Use of the Rehabilitation Treatment Specification System (RTSS) in the management of nitrous oxide (N2O)-induced spinal cord injury. [2023]

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

Combination of inhaled nitrous oxide and oral opioids induces long-lasting analgesic effects in patients with neuropathic pain: ProtoTOP study post hoc exploratory analyses. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Flumazenil may attenuate some subjective effects of nitrous oxide in humans: a preliminary report. [2019]

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

Postoperative Pulmonary Complications in the ENIGMA II Trial: A Post Hoc Analysis. [2023]

6. Poland pubmed.ncbi.nlm.nih.gov

Environmental health risk of chronic exposure to nitrous oxide in dental practice. [2013]

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

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

8. China pubmed.ncbi.nlm.nih.gov

[Detection and prevention of nitrous oxide iatrogenic pollution in dental treatments]. [2019]

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

[Not Available]. [2019]

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

Subacute combined degeneration induced by nitrous oxide inhalation: Two case reports. [2022]

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

Nitrous oxide-induced polyneuropathy, pancytopenia and pulmonary embolism: a case report. [2023]

12. England pubmed.ncbi.nlm.nih.gov

An unusual cause of falls in a young woman. [2017]

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

A Case Report of Subacute Combined Degeneration Due to Nitrous Oxide-Induced Vitamin B12 Deficiency. [2023]