Complex Regional Pain Syndrome
Conditions
Brief summary
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.
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.
Interventions
DRUGNitrous 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.
DRUGOxygen
A total of three inhalation treatments with 50% oxygen (6 total exposure hours) over one week with 2 or 3 days between each session.
Sponsors
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Patients and other involved providers will be blinded to the treatment type. Research investigators administering the treatments will not be blinded.
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Score | one-week and one-month follow-up time points | scales ranging from 0 - no pain to 10 - worst pain ever based on the PROMIS-29 v2.0 questionnaire. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score | one-week and one-month follow-ups after treatments were ended | 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. |
| PGIC Scale | one-week and one-month follow-ups. | 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 20 |
| The Control Group Control group will receive 50% oxygen, inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit.
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. | 24 |
| Total | 44 |
Baseline characteristics
| Characteristic | The Nitrous Oxide Group | The Control Group | Total |
|---|---|---|---|
| Age, Continuous | 44.4 years STANDARD_DEVIATION 12.3 | 46.3 years STANDARD_DEVIATION 13.4 | 45.4 years STANDARD_DEVIATION 12.8 |
| Duration of disease | 53.5 months | 108.0 months | 89.5 months |
| Extremity affected Multiple locations | 12 Participants | 19 Participants | 31 Participants |
| Extremity affected Single location | 8 Participants | 5 Participants | 13 Participants |
| Pain score at baseline | 7.3 units on a scale STANDARD_DEVIATION 1.7 | 6.8 units on a scale STANDARD_DEVIATION 1.5 | 7.0 units on a scale STANDARD_DEVIATION 1.6 |
| Race/Ethnicity, Customized Race Black/African American | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Hispanic/Latino | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Multicultural | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White/Caucasian | 20 Participants | 21 Participants | 41 Participants |
| Sex: Female, Male Female | 16 Participants | 22 Participants | 38 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
| Spinal cord stimulators used | 5 Participants | 7 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 24 |
| other Total, other adverse events | 0 / 20 | 0 / 24 |
| serious Total, serious adverse events | 0 / 20 | 0 / 24 |
Outcome results
Primary
Pain Score
scales ranging from 0 - no pain to 10 - worst pain ever based on the PROMIS-29 v2.0 questionnaire.
Time frame: one-week and one-month follow-up time points
Population: A few patients had missing primary outcome measurements. The Mean (SD) values presented here was based on available raw data. In our formal analysis of treatment effect on primary outcome, we used multiple imputation procedures to impute missing primary outcome values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| The Nitrous Oxide Group | Pain Score | one-week follow-up | 5.9 score on a scale | Standard Deviation 1.5 |
| The Nitrous Oxide Group | Pain Score | one-month follow-up | 6.5 score on a scale | Standard Deviation 2 |
| The Control Group | Pain Score | one-week follow-up | 6.0 score on a scale | Standard Deviation 2.5 |
| The Control Group | Pain Score | one-month follow-up | 6.8 score on a scale | Standard Deviation 2.2 |
Comparison: Null hypothesis: Mean of pain score assessed at one-week and one-month follow-up after end of treatment for Nitrous Oxide group equals that assessed at same time points for the Control group.p-value: 0.1995% CI: [-1.42, 0.28]Mixed Models Analysis
Secondary
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).
Time frame: one-week and one-month follow-ups.
Population: A few patients had missing values due to withdrawal from the study or study participants can not be reached for follow-up with phone calls.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| The Nitrous Oxide Group | PGIC Scale | PGIC scale at one-week follow-up | 2 score on a scale |
| The Nitrous Oxide Group | PGIC Scale | PGIC scale at one-month follow-up | 2 score on a scale |
| The Control Group | PGIC Scale | PGIC scale at one-week follow-up | 4 score on a scale |
| The Control Group | PGIC Scale | PGIC scale at one-month follow-up | 2 score on a scale |
Comparison: Null hypothesis: Mean of PGIC scale assessed at one-week and one-month follow-up time points for Nitrous Oxide patients is equal to that assessed at the same time points for Control patients.p-value: 0.2395% CI: [-1.85, 0.46]Mixed Models Analysis
Secondary
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.
Time frame: one-week and one-month follow-ups after treatments were ended
Population: A few patients had missing values due to withdrawal from the study or failure of follow-up contact.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| The Nitrous Oxide Group | PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score | Physical health Z-score at one-week follow-up | -1.4 z-score | Standard Deviation 0.71 |
| The Nitrous Oxide Group | PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score | Physical health Z-score at one-month follow-up | -1.4 z-score | Standard Deviation 0.58 |
| The Nitrous Oxide Group | PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score | Mental health Z-score at one-week follow-up | -1.01 z-score | Standard Deviation 0.81 |
| The Nitrous Oxide Group | PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score | Mental health Z-score at one-month follow-up | -1.2 z-score | Standard Deviation 0.88 |
| The Control Group | PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score | Mental health Z-score at one-month follow-up | -1.1 z-score | Standard Deviation 0.91 |
| The Control Group | PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score | Physical health Z-score at one-week follow-up | -1.4 z-score | Standard Deviation 0.78 |
| The Control Group | PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score | Mental health Z-score at one-week follow-up | -0.91 z-score | Standard Deviation 1 |
| The Control Group | PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score | Physical health Z-score at one-month follow-up | -1.5 z-score | Standard Deviation 0.68 |
Comparison: Null hypothesis for testing difference in means of physical health Z-score between two study groups: mean of physical health Z-score assessed at one-week and one-month follow-ups for Nitrous Oxide group was equal to that assessed at the same follow-up time points for Control group.p-value: 0.3695% CI: [-0.16, 0.43]Mixed Models Analysis
Comparison: Null hypothesis for testing difference in means of mental health Z-score between two study groups: mean of mental health Z-score assessed at one-week and one-month follow-ups for Nitrous Oxide group was equal to that assessed at the same follow-up time points for Control group.p-value: 0.6695% CI: [-0.31, 0.48]Mixed Models Analysis