Nitrous Oxide as Treatment for Fibromyalgia

NCT ID: NCT05357066

Last Updated: 2026-01-12

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

50 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-11-12

Study Completion Date

2027-12-01

Brief Summary

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

Detailed Description

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Investigators are conducting this trial to determine the efficacy of nitrous oxide on fibromyalgia, a chronic, debilitating, disorder typified by widespread musculoskeletal pain, accompanied by symptoms of fatigue, affected sleep, memory issues, and mood disorders.

Studies suggests that the chronic widespread pain seen in fibromyalgia patients has a neurogenic origin. Higher levels of ascending pathway neurochemicals, including nerve growth factor, substance P, and brain derived neurotrophic factor, are present in the cerebrospinal fluid (CSF) of fibromyalgia patients when compared to healthy controls. In addition, glutamate levels can be elevated in both the CSF and brain of fibromyalgia patients. Glutamate may play a central role, by acting on the NMDA-receptors to increase the central amplification of pain perception, which is thought to manifest as allodynia and hyperalgesia in fibromyalgia patients. NMDA-receptors are thus an attractive target for fibromyalgia therapeutic drug development.

In four other randomized controlled trial(s) to evaluate ketamine an NMDA-receptor antagonist; two demonstrated an acute reduction in VAS pain scores (20- to -25 points) 90- to 120-minutes following IV ketamine 0.3 mg/kg compared with placebo; while the other two using different drug concentrations and dose regimen (0.3 mg/kg over 30 minutes and 0.5 mg/kg for 3 hours) showed a 0.5- to 0.9-point reduction in pain scores (10-cm VAS) at 90 to 180 minutes following IV ketamine compared with placebo. Although all four trials demonstrated significant acute pain improvement during and immediately following the infusions, there were no sustained improvements.

Given nitrous oxide is another drug with known NMDA-receptor antagonism, this trial will evaluate the efficacy of inhaled 50% nitrous oxide compared to placebo (oxygen-air mixture). Study participants with a clinical diagnosis of fibromyalgia, meeting 2016-Fibromyalgia Diagnostic Criteria (2016-ACR) and neuropathic pain criterion will be randomly assigned to receive two, 60-minute inhalation sessions (50% nitrous oxide and placebo).

Treatment outcomes will be monitored using diagnostic tools measuring functionality, pain, and mood:

* Numeric Pain Rating Scale (NPRS)
* Revised Fibromyalgia Impact Questionnaire (FIQR)
* Patients Global Impression of Change Scale (PGIC)
* Hospital Anxiety and Depression Scale (HADS)
* Computerized Adaptive Test-Mental Health (CAT-MH)

Conditions

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Fibromyalgia Central Neuropathic Pain

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Participants are randomly assigned to a treatment group schedule, group-1 (nitrous, placebo), or group-2 (placebo, nitrous). Dosing consists of 50% Nitrous oxide in oxygen mixture (FiO2 0.5) vs placebo (oxygen-air mixture FiO2 ≈0.3).
Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Outcome Assessors
Patient and assessor blinded to study group assigned

Study Groups

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Treatment; Nitrous Oxide 50%

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

Group Type ACTIVE_COMPARATOR

Nitrous oxide gas for inhalation

Intervention Type DRUG

Administration of inhaled 50% nitrous oxide in oxygen (FiO2 0.5) will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.

Control; Oxygen-air mixture

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

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Administration of the placebo (oxygen-air mixture \[FiO2 ≈0.3\]), will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.

Interventions

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Nitrous oxide gas for inhalation

Administration of inhaled 50% nitrous oxide in oxygen (FiO2 0.5) will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.

Intervention Type DRUG

Placebo

Administration of the placebo (oxygen-air mixture \[FiO2 ≈0.3\]), will be under the direct supervision of a licensed practitioner who is experienced in the use and administration of the study drug, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken (MD, or CRNA); with study patient monitoring of pulse oximetry, heart rate, respiratory, non-invasive blood pressure, and end-tidal carbon dioxide.

Intervention Type DRUG

Other Intervention Names

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Nitrous Oxide Nitrous N2O Laughing gas Sham

Eligibility Criteria

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Inclusion Criteria

* 2016 American College of Rheumatology Revised criteria for fibromyalgia (2016-ACR)
* Subjects 18 -75 years of age.
* Self-reported pain of at least 4 on the Numeric Pain Rating Scale (NPRS) at screening and baseline.
* Subject receives and agrees to remain on their stable fibromyalgia treatment plan established at least 4 weeks prior to dosing. Stable means no change in dose or any pain medication.
* Ability to understand the requirements of the study, provide written informed consent, abide by the study restrictions, and agree to return for the required assessments
* If currently on psychotherapy, it must have been maintained at the same frequency for 4 weeks prior to treatment.

Exclusion Criteria

* Unstable doses of allowed antidepressants or muscle relaxants or dosages for any other medical condition.
* Pain due to concurrent autoimmune or inflammatory disease such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, or other chronic widespread pain condition(s) that may confound fibromyalgia pain.
* Psychiatric or cognitive disorder (e.g., current schizophrenia, severe depression, suicidal ideation, dementia, etc.) that the investigator or sponsor considers significant for this study.
* Clinically significant alcohol or other substance abuse within the last 2 years, in the opinion of the investigator.
* Current or recent history of medically inappropriate or illegal use of drugs of abuse including benzodiazepines, opiates, cocaine, cannabinoids, and amphetamines.
* Current treatment with N-methyl-D-aspartate receptor (NMDAR) ligands including ketamine, amantadine, dextromethorphan, memantine, methadone, or dextropropoxyphene.
* Subjects who are pregnant, breast feeding, or planning to become pregnant during the course of the study and for 28 days after the final administration of investigational product.
* Any other serious medical condition affecting heart, lung or any other organ system.
* Any impairment, activity or situation that in the judgment of the investigator would prevent satisfactory completion of the study protocol.
Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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University of Chicago

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Peter Nagele, MD, MSc

Role: PRINCIPAL_INVESTIGATOR

University of Chicago, Department of Anesthesia and Critical Care

Locations

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University of Chicago

Chicago, Illinois, United States

Site Status RECRUITING

Countries

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United States

Central Contacts

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Frank Brown Jr

Role: CONTACT

773-834-5778

Facility Contacts

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Clinical Trials Manager

Role: primary

773-834-5778

References

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Sorensen J, Bengtsson A, Ahlner J, Henriksson KG, Ekselius L, Bengtsson M. Fibromyalgia--are there different mechanisms in the processing of pain? A double blind crossover comparison of analgesic drugs. J Rheumatol. 1997 Aug;24(8):1615-21.

Reference Type BACKGROUND
PMID: 9263160 (View on PubMed)

Noppers I, Niesters M, Swartjes M, Bauer M, Aarts L, Geleijnse N, Mooren R, Dahan A, Sarton E. Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: a randomized, prospective, double blind, active placebo-controlled trial. Eur J Pain. 2011 Oct;15(9):942-9. doi: 10.1016/j.ejpain.2011.03.008. Epub 2011 Apr 11.

Reference Type BACKGROUND
PMID: 21482474 (View on PubMed)

Graven-Nielsen T, Kendall SA, Henriksson KG, Bengtsson M, Sorensen J, Johnson A, Gerdle B, Arendt-Nielsen L. Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain. 2000 Apr;85(3):483-491. doi: 10.1016/S0304-3959(99)00308-5.

Reference Type BACKGROUND
PMID: 10781923 (View on PubMed)

Jevtovic-Todorovic V, Todorovic SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski CF, Olney JW. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med. 1998 Apr;4(4):460-3. doi: 10.1038/nm0498-460.

Reference Type BACKGROUND
PMID: 9546794 (View on PubMed)

Nagele P, Metz LB, Crowder CM. Nitrous oxide (N(2)O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8791-6. doi: 10.1073/pnas.0402825101. Epub 2004 May 24.

Reference Type BACKGROUND
PMID: 15159532 (View on PubMed)

Arnold LM, Clauw DJ, Dunegan LJ, Turk DC; FibroCollaborative. A framework for fibromyalgia management for primary care providers. Mayo Clin Proc. 2012 May;87(5):488-96. doi: 10.1016/j.mayocp.2012.02.010.

Reference Type BACKGROUND
PMID: 22560527 (View on PubMed)

Clauw DJ, Arnold LM, McCarberg BH; FibroCollaborative. The science of fibromyalgia. Mayo Clin Proc. 2011 Sep;86(9):907-11. doi: 10.4065/mcp.2011.0206.

Reference Type BACKGROUND
PMID: 21878603 (View on PubMed)

Sorensen J, Bengtsson A, Backman E, Henriksson KG, Bengtsson M. Pain analysis in patients with fibromyalgia. Effects of intravenous morphine, lidocaine, and ketamine. Scand J Rheumatol. 1995;24(6):360-5. doi: 10.3109/03009749509095181.

Reference Type BACKGROUND
PMID: 8610220 (View on PubMed)

Other Identifiers

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IRB20-1169

Identifier Type: -

Identifier Source: org_study_id

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