No Improvement in Pain Scores With Nitrous Oxide for CRPS

SAN FRANCISCO—Clinicians looking for pain treatments for patients with complex regional pain syndrome (CRPS) may not find an effective option in nitrous oxide, according to the results of a new study.

Researchers at Cleveland Clinic concluded that compared with a placebo of air and oxygen, two hours of nitrous oxide and oxygen exposure for three sessions did not decrease pain scores or opioid consumption in such patients.

“Treating CRPS is very difficult, and ketamine infusion is one of the last options for these patients,” said Fabio Rodriguez-Patarroyo, MD, the chief research fellow at Cleveland Clinic, in Cleveland. “However, ketamine infusions are costly and require intravenous access and monitoring because of their neurologic and cardiovascular side effects.

“Nitrous oxide is also an NMDA receptor antagonist, and some studies suggest that nitrous oxide can reduce the incidence of chronic postsurgical pain,” he continued. “But what is more important is that nitrous oxide has minimal side effects and can be quickly eliminated after inhalation. So, we tested the hypothesis that brief breathing sessions of nitrous oxide can decrease pain scores in people with CRPS.”

The researchers enrolled 44 patients into the trial, all of whom had been diagnosed with CRPS for at least six months. Participants were randomized to treatment on three alternating days with either two hours of nitrous oxide (n=20) or a placebo air/oxygen mixture (n=24). The study’s primary outcome was patient-reported pain scores at one week and one month after treatment. The researchers also tested the average daily opioid use (in IV morphine milligram equivalents) at these same time points.

“You might ask why we thought nitrous oxide may cause an improvement in CRPS patients,” Rodriguez-Patarroyo commented. “This is because we based our protocol on previous studies made in mice, which found improvement after exposure to nitrous oxide in models of neuropathic pain.”

Reporting at the 2023 annual meeting of the American Society of Anesthesiologists (abstract A2227), Rodriguez-Patarroyo said mean pain scores were comparable between groups at both time points. At one week, those in the nitrous oxide group had a mean score of 5.9±1.5, compared with 6.0±2.5 for controls. These scores were 6.5±2.0 and 6.8±2.2 at one month after treatment, respectively.

Of note, nitrous oxide patients with high baseline pain scores (=7.0) demonstrated statistically significant improvements at both one week (6.3±1.6 vs. 7.4±1.7) and one month (7.3±1.6 vs. 8.3±0.8). However, similar differences were not observed among individuals with low baseline pain scores (<7.0).

Patients treated with nitrous oxide did not demonstrate any decreases in opioid consumption, according to the researchers. Specifically, the 75th percentile of average daily opioid consumption at baseline was 10.6 mg in the nitrous oxide group and 3.0 mg in the placebo group. These changed to 11.3 and 0.0 mg, respectively, one week after treatment, and 10.0 and 2.5 mg, respectively, one month after treatment. The investigators also did not find any differences between groups with respect to functional or mental health improvements at either time point.

As Rodriguez-Patarroyo discussed, the findings may be the product of several factors.

“The study’s participants already had very high pain scores at baseline and a long history of CRPS,” he told Pain Medicine News. “That may explain why the intervention didn’t have any effect. Additionally, we used a relatively low small concentration of nitrous oxide, since our patients went home after each treatment session.”

—Michael Vlessides

Rodriguez-Patarroyo reported no relevant financial disclosures.