Nitrous Oxide for the Treatment of Complex Regional Pain Syndrome

A Prospective Randomized Controlled Pilot Study Nitrous Oxide for the Treatment of Complex Regional Pain Syndrome

Patients will then be randomized via a web-based randomization system Redcap Allocation will be stratified based on the presence of a pre-existing spinal cord stimulator to either the nitrous oxide study group or the oxygen control group.

The nitrous oxide group will receive 50% nitrous oxide mixed with 50% oxygen, and the control group will receive 50% oxygen (oxygen plus air mixture). Both groups will undergo inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit. Vital signs (blood pressure, respiratory rate, heart rate) will be monitored every 30 minutes. Pulse oximetry monitoring will be continuous. Patients will be monitored for side effects including nausea, vomiting, desaturation, sedation, respiratory depression, and dizziness. Patients and other involved providers will be blinded to the treatment type.

Study Overview

• Status: Completed
• Conditions: Complex Regional Pain Syndrome
• Intervention / Treatment: Drug: Nitrous Oxide; Drug: Oxygen

Detailed Description

Daily opioid consumption data will be collected by having patients record and report their daily opioid use before and after treatment. Oral and transdermal opioids will be converted to standardized morphine equivalents and adjusted for bioavailability.

Patients will present for the first scheduled treatment and they will fill out the PROMIS-29 v2 survey and the SF-MPQ-2 (6 neuropathic pain items). Patients will also turn in their opioid use log.

Vital signs will be obtained. Patients with significantly abnormal vital signs or vital signs that are significantly deviated from baseline will be referred to appropriate medical care.

Patients will then be randomized via a web-based randomization system Redcap. Group allocation will be stratified based on the presence of a pre-existing spinal cord stimulator to either the nitrous oxide study group or the oxygen control group.

The nitrous oxide group will receive 50% nitrous oxide mixed with 50% oxygen, and the control group will receive 50% oxygen. Both groups will undergo inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit. Active Control, because patients may be able to tell if they are receiving nitrous oxide, patient blinding may be compromised. Therefore, we plan to utilize an active control. Both groups will receive 2 mg of intravenous midazolam, to infuse over 5 minutes, at the start of each breathing treatment session. IVs will be removed at the conclusion of each breathing treatment. Vital signs (blood pressure, respiratory rate, heart rate) will be monitored every 30 minutes. Pulse oximetry monitoring will be continuous. Patients will be monitored for side effects including nausea, vomiting, desaturation, sedation, respiratory depression, and dizziness. Patients and other involved providers will be blinded to the treatment type. Research investigators administering the treatments will not be blinded.

At the conclusion of inhalation therapy, the gas will be turned off and patients will breathe room air. All patients will be monitored for an additional 30 minutes. This recovery time is more than sufficient to ensure nitrous oxide is completely eliminated in those patients who receive it. Patients will be monitored and asked about side effects.

Patients will receive a total of three treatments (6 total exposure hours) over one week with 2 or 3 days between each session. Possible treatment schedules: Monday-Wednesday-Friday, Wednesday-Friday-Monday, or Friday-Monday-Wednesday. After the conclusion of the third treatment, patients will be followed with phone calls as detailed in the Measurement section below.

1. Drug Handling Instructions

a. Nitrous oxide for the study will be stored at room temperature in appropriately labeled E-cylinder tanks.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Pain Management

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must be diagnosed with CRPS based on the revised International Association for the Study of Pain criteria.
2. Duration of disease must be at least 6 months.
3. Written informed consent.

Exclusion Criteria:

1. Patients who had no subjective benefit from ketamine infusions, as determined by interview during the recruitment process.
2. Patients taking more than 60mg of morphine equivalents or more daily for an alternative chronic pain condition.
3. Patients with both coronary artery disease (as determined by cardiac catheterization) and a functional status of less than 4 metabolic equivalents. The limited functional status must be secondary to cardiopulmonary symptoms (angina, dyspnea on exertion). Patients with coronary artery disease and a limited functional status (<4 METS) secondary to chronic pain can be included.
4. Patients with congestive heart failure of any etiology that are NYHA Class III or IV
5. Patients with moderate or severe pulmonary hypertension as determined by echocardiogram or right heart catheterization.
6. Patients with intraocular surgery within the past 14 days
7. Patients with worker's compensation claims and active litigation.
8. Patients who have been diagnosed with COPD.
9. Patients who use home oxygen therapy for any condition.
10. Diagnosis of Alcohol Use Disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).
11. Illicit drug use within the past three months (not including marijuana).
12. Pregnant patients or patients with upcoming planned pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: The nitrous oxide group; Nitrous oxide group will receive 50% nitrous oxide mixed with 50% oxygen, inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit.	Drug: Nitrous Oxide; A total of three inhalation treatments with 50% Nitrous Oxide plus 50% oxygen (6 total exposure hours) over one week with 2 or 3 days between each session.; Other Names: 50 % Nitrous Oxide plus 50% Oxygen
Placebo Comparator: The Control Group; Control group will receive 50% oxygen, inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit.	Drug: Oxygen; A total of three inhalation treatments with 50% oxygen (6 total exposure hours) over one week with 2 or 3 days between each session.; Other Names: 50% Oxygen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Score	scales ranging from 0 - "no pain" to 10 - "worst pain ever" based on the PROMIS-29 v2.0 questionnaire.	one-week and one-month follow-up time points

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score	As intermediate scores, T-scores for each of the 7 domains used in the survey need to be estimated from raw data in order to obtain final summary Z-scores measuring physical and mental health. T-scores were obtained from an on-line service provided by the HealthMeasures Scoring Service (https://www.assessmentcenter.net/ac_scoringservice). Physical and mental summary Z-scores were calculated using the formulas given in the document titled "Calculating physical and mental health summary scores for PROMIS-29 v2.0 and v2.1" (dated on August 8, 2018) by Karen L. Spritzer and Ron D. Hays from the website HealthMeasures.net. High T-scores indicates more of the concept being measured which can be either desirable or undesirable outcome, e.g., high T-score on fatigue is undesirable whereas desirable for physical function. Z-scores are standard scores with mean of 0 and SD of 1 in reference population. High Z-scores are desirable for either physical or mental health.	one-week and one-month follow-ups after treatments were ended
PGIC Scale	patient disease perception as measured by the Patient's Global Impression of Change (PGIC) survey (a seven-point scale ranging from 1 - "no change or condition has gotten worse" to 7 - "very much improve").	one-week and one-month follow-ups.

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Investigators: Principal Investigator: Jason Hale, MD, Anesthesiologist

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2019
• Primary Completion (Actual): July 28, 2022
• Study Completion (Actual): July 28, 2022

Study Registration Dates

• First Submitted: January 31, 2019
• First Submitted That Met QC Criteria: March 15, 2019
• First Posted (Actual): March 18, 2019

Study Record Updates

• Last Update Posted (Actual): February 9, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Disease; Neuromuscular Diseases; Peripheral Nervous System Diseases; Autonomic Nervous System Diseases; Syndrome; Complex Regional Pain Syndromes; Reflex Sympathetic Dystrophy; Somatoform Disorders; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Anesthetics, Inhalation; Nitrous Oxide
• Other Study ID Numbers: 19-150

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No