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Nitrous Oxide as Treatment for Fibromyalgia

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ClinicalTrials.gov Identifier: NCT05357066
Recruitment Status : Recruiting
First Posted : May 2, 2022
Last Update Posted : May 2, 2022
Sponsor:
Information provided by (Responsible Party):
University of Chicago

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

Condition or disease Intervention/treatment Phase
Fibromyalgia Central Neuropathic Pain Drug: Nitrous oxide gas for inhalation Drug: Placebo Phase 2

Detailed Description:

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)

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: 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).
Masking: Double (Participant, Outcomes Assessor)
Masking Description: Patient and assessor blinded to study group assigned
Primary Purpose: Treatment
Official Title: Nitrous Oxide as Treatment for Fibromyalgia
Actual Study Start Date : November 12, 2021
Estimated Primary Completion Date : April 30, 2023
Estimated Study Completion Date : July 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fibromyalgia

Arm Intervention/treatment
Active Comparator: Treatment; Nitrous Oxide 50%
A single 60-minute session of inhaled 50% nitrous oxide.
Drug: 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.
Other Names:
  • Nitrous Oxide
  • Nitrous
  • N2O
  • Laughing gas

Placebo Comparator: Control; Oxygen-air mixture
A single 60-minute session of inhaled Oxygen-air mixture
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.
Other Name: Sham




Primary Outcome Measures :
  1. Monitor changes in NPRS score [ Time Frame: Over 8-weeks from baseline (length of study participation) ]

    Monitoring changes in 'Numeric Pain Rating Scale' (NPRS) diagnostic score to determine effectiveness a 60-minute session of inhaled 50% nitrous oxide vs placebo has on symptoms associated with fibromyalgia.

    The NPRS is a validated self-report diagnostic asking patients to indicate the intensity of current, best, and worst pain levels over the past 24 hours on a scale of 0 (no pain) to 10 (worst pain imaginable).

    Response and remission will be based on a 30% improvement in average daily mean (max and min) NPRS score.



Secondary Outcome Measures :
  1. Changes in FIQR [ Time Frame: Over 8-weeks from baseline (length of study participation) ]

    Evaluation of response and remission will be based on 'Fibromyalgia Impact Questionnaire-Revised' (FIQR).

    This validated self-report diagnostic contains 21-questions to rate fibromyalgia effects over the prior 7-days.

    Domain 1: 9-questions rating function: 'No difficulty = 0' to 'Very difficult = 10' Domain 2: 2-questions rating overall impact: 'Never = 0' to 'Always = 10' Domain 3: 10-questions rating symptom intensity: 'None = 0' to 'Worst = 10'

    • First: Sum the scores for each of the 3 domains (function, overall, and symptoms).
    • Second: Divide domain 1 score by 3, leave domain 2 score unchanged, and divide domain 3 score by 2.
    • Third: Add the 3 resulting domain scores to obtain the total FIQR score.

  2. Changes in Global Impression of Change Scale [ Time Frame: Over 8-weeks from baseline (length of study participation) ]

    The Global Impression of Change Scale (PGI-C), a two question, self-report diagnostic evaluating the patients belief of treatment efficacy.

    - Patients rate their neuropathic pain ['No pain = 0' to 'Worst = 10'], and evaluate treatment effectiveness ['Very Much Improved'; 'Much Improved'; 'Minimally'; 'Improved'; 'No Change'; 'Minimally Worse'; 'Much Worse'; 'Very Much Worse']


  3. Computerize Adaptive Testing - Mental Health (CAT-MH) measurements [ Time Frame: Over 8-weeks from baseline ]

    This CAT-MH is a validated self-reporting diagnostic that adaptively selects a small optimal set of items from a large bank of approximately 1,500 items, targeted to individuals current or historical level of severity and likelihood of 'depression'.

    Generated scores include severity and liklihood percentile:

    depression = (%) normal, mild, moderate, severe


  4. Hospital Anxiety and Depression Scale [ Time Frame: Over 8-weeks from baseline (length of study participation) ]

    The Hospital Anxiety and Depression Scale (HADS) is a self-report questionnaire comprising of 14-questions (7-anxiety and 7-depression), with response scores ranging: '0' to '3'

    • Sum Depression scores = 0 to 21
    • Sum Anxiety scores = 0 to 21

    Score range for each item (depression and anxiety):

    0-7 = Normal 8-10 = Borderline abnormal (mild) 11-14 = Abnormal (moderate) 15-21 = Severe



Other Outcome Measures:
  1. Adverse events [ Time Frame: Over 8-weeks (length of study participation) ]

    AEs such as nausea and vomiting; or any other AEs determined probably, possibly, or unrelated to the study intervention.

    Study patient safety is monitored by the investigators (MD) with experience in critical care anesthesia, as well as an experienced clinical research team responsible for recording and reporting events.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05357066


Contacts
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Contact: Clinical Trial Manager 773-834-5778 fbrown@dacc.uchicago.edu

Locations
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United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: Clinical Trials Manager    773-834-5778    fbrown@dacc.uchicago.edu   
Principal Investigator: Peter Nagele, MD, MSc         
Sub-Investigator: Tariq Malik, MD         
Sub-Investigator: Kourosh Rezania, MD         
Sponsors and Collaborators
University of Chicago
Investigators
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Principal Investigator: Peter Nagele, MD, MSc University of Chicago, Department of Anesthesia and Critical Care
Publications:

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Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT05357066    
Other Study ID Numbers: IRB20-1169
First Posted: May 2, 2022    Key Record Dates
Last Update Posted: May 2, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by University of Chicago:
Fibromyalgia
Pain
Additional relevant MeSH terms:
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Fibromyalgia
Myofascial Pain Syndromes
Neuralgia
Muscular Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Neuromuscular Diseases
Nervous System Diseases
Peripheral Nervous System Diseases
Pain
Neurologic Manifestations
Nitrous Oxide
Anesthetics, Inhalation
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents