Nitrous Oxide for Fibromyalgia

Overseen By Peter Nagele, MD, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Chicago

Must not be taking: NMDAR ligands, Benzodiazepines

Disqualifiers: Autoimmune diseases, Severe depression, others

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 2

Duration: 2 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether nitrous oxide, a gas often used for pain relief during dental procedures, can reduce pain in people with fibromyalgia. Participants will inhale either nitrous oxide or a placebo (a non-active treatment) for 60 minutes. The trial seeks individuals who have experienced fibromyalgia pain for an extended period, are on a stable treatment plan, and have significant pain. The goal is to determine if nitrous oxide can provide new pain relief options for those with fibromyalgia. As a Phase 2 trial, this research measures how well nitrous oxide works in an initial, smaller group, offering a chance to explore new pain relief options.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that nitrous oxide, commonly known as "laughing gas," is generally safe under medical supervision and does not cause long-term problems when administered correctly. However, frequent exposure, such as in certain occupations, can be risky.

In medical settings, nitrous oxide is typically safe for short-term use, such as during dental procedures. This trial is in an early stage, meaning previous studies have demonstrated its safety in humans, allowing it to be tested for fibromyalgia. This suggests it is considered safe enough to explore for this new purpose. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for fibromyalgia?

Unlike standard treatments for fibromyalgia, which often include medications like antidepressants, anticonvulsants, or pain relievers, nitrous oxide offers a novel approach. Nitrous oxide is administered through inhalation, providing a non-invasive option that could deliver rapid relief. Researchers are excited because it works differently by potentially modulating pain pathways in the brain, offering hope for faster symptom relief and fewer side effects compared to current drug therapies. This unique mechanism and delivery method make nitrous oxide a promising candidate for improving the quality of life for those with fibromyalgia.

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

Research has shown that nitrous oxide might help reduce pain for people with fibromyalgia. One study with 92 patients who had nerve pain found that breathing in nitrous oxide provided significant pain relief. This effect may occur by influencing certain brain areas involved in pain perception. Another study discovered that a mix containing 50% nitrous oxide could reduce pain by 45% in just a few minutes. In this trial, participants will receive either a single 60-minute session of inhaled 50% nitrous oxide or a control session with an oxygen-air mixture. These findings suggest that nitrous oxide could be a promising option for managing fibromyalgia pain. ^{1 3 6 7 8}

Who Is on the Research Team?

Peter Nagele, MD, MSc

Principal Investigator

University of Chicago, Department of Anesthesia and Critical Care

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Nitrous oxide gas for inhalation
• Placebo

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.

How Is the Trial Designed?

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 United States, European Union, Canada for the following indications:

Approved in United States as Nitrous Oxide for:

• Anesthesia
• Pain relief

Approved in European Union as Nitrous Oxide for:

• Anesthesia
• Pain relief

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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 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]

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]

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]

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]

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]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05357066?term=NITROUS%20OXIDE&rank=9

NCT05357066 | Nitrous Oxide as Treatment for Fibromyalgia

Investigators are conducting this trial to determine the efficacy of nitrous oxide on fibromyalgia, a chronic, debilitating, disorder typified by widespread ...

2.

centerwatch.com

centerwatch.com/clinical-trials/listings/NCT05357066/nitrous-oxide-as-treatment-for-fibromyalgia

Nitrous Oxide as Treatment for Fibromyalgia

The purpose of this study is to explore a potential role of nitrous oxide in treating pain associated with fibromyalgia.

3.

withpower.com

withpower.com/trial/phase-2-myofascial-pain-syndromes-10-2021-0c1b9

Nitrous Oxide for Fibromyalgia

In a study involving 92 patients with neuropathic pain who were also receiving opioids, inhaled nitrous oxide/oxygen (EMONO) significantly reduced pain ...

4.

thevillatreatmentcenter.com

thevillatreatmentcenter.com/new-nitrous-oxide-research/

New Research Applications for Nitrous Oxide in Clinical ...

You can achieve 45% pain reduction within 5 minutes through NMDA receptor modulation, while 50% N2O mixtures show promise for treatment-resistant depression.

5.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/33044394/

Safety and efficacy of an equimolar mixture of oxygen and ...

Mostly transient side effects were reported during the treatment administration. These encouraging results provide a basis for further ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05357066

NCT05357066 | Nitrous Oxide as Treatment for Fibromyalgia

Investigators are conducting this trial to determine the efficacy of nitrous oxide on fibromyalgia, a chronic, debilitating, disorder typified by widespread ...

7.

my.clevelandclinic.org

my.clevelandclinic.org/health/treatments/nitrous-oxide-laughing-gas

Nitrous Oxide (Laughing Gas): Uses, Side Effects & Safety

Laughing gas doesn't cause any long-term complications when given under the care of a healthcare provider. But frequent nitrous oxide exposure (for multiple- ...

8.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5157143/

The Effect of Various Concentrations of Nitrous Oxide and ...

The purpose of this study was to compare the effectiveness of various concentrations of N2O/O2 on obtunding a hypersensitive gag reflex.