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.

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.

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.

1 month

limitations include the purely subjective nature of pain which was our primary outcome. Validity of the trial thus depends critically on adequacy of blinding. Because many patients can detect inhaled nitrous oxide, we gave all participants midazolam which has similar effects. But it remains possible that some patients could distinguish nitrous oxide from air, and were thus biased.

Patients and other involved providers will be blinded to the treatment type. Research investigators administering the treatments will not be blinded.