Interaction Between Nitrous Oxide and Opioids May Improve Neuropathic Pain

A post hoc analysis of the ProtoTOP study found that the long-lasting analgesic effects of inhaled nitrous oxide administered in patients receiving treatment with opioids may be due to its anti-N-methyl-D-aspartate (NMDA) properties. These findings were published in Pain.

Patients with peripheral neuropathic pain, polyneuropathy, or postherpetic neuralgia were recruited at multiple sites in France and Germany to participate in the ProtoTOP study (ClinicalTrials.gov Identifier: NCT02957851). Patients were randomly assigned to receive 1 hour of treatment with inhaled nitrous oxide/oxygen in a 50%-50% equimolar mixture (EMONO; n=103) or placebo (n=138) for 3 consecutive days. Continuation of treatment with concomitant non-NMDA receptor analgesic medications was permitted. For this post hoc analysis, the change in pain scores from baseline was evaluated between patients who were (n=92) and were not (n=129) undergoing concomitant treatment with opioids.

The mean age of the entire study cohort ranged from 50.2 to 54.9 years, 58.1% to 65.3% had posttraumatic or postsurgical peripheral neuropathy, 25.0% to 30.2% had polyneuropathy, and the mean pain intensity ranged from 6.3 to 6.7 points.

Among opioid recipients, the most common medications used were tramadol (22.4%-41.9%), Papaver somniferum paracetamol (20.4%-20.9%), codeine-paracetamol (11.6%-14.3%), and tramadol-paracetamol (9.3%-10.2%). In addition, patients in both the opioid and nonopioid groups were also undergoing treatment with antiepileptic, antidepressant, and/or topical agents.

Among those being treated with opioids, response defined as a 50% improvement in numeric rating scale (NRS) score for pain was observed for more EMONO recipients compared with those receiving placebo at week 2 (14.0% vs 2.0%, respectively; P <.05). Response defined as a 30% improvement in NRS score was documented in more of the EMONO recipients compared with those receiving placebo at weeks 2 (32.6% vs 4.1%; P <.001), 3 (33.3% vs 8.2%; P <.01), and 4 (28.6% vs 10.4%; P <.05). Opioid recipients also reported significantly greater improvement in bodily pain as defined by the short-form 12 (SF-12) instrument compared with those receiving placebo (change from baseline, 5.0 vs 1.0; P <.01).

Among patients who were not undergoing treatment with opioids, EMONO was not associated with any significant changes compared with placebo.

Among EMONO recipients, the most common nervous system adverse event was somnolence (81.9%-83.3%), and the most common psychiatric adverse event was euphoric mood (80.6%-83.3%). In addition, EMONO caused a sensation of feeling drunk among 36.1% to 41.7% of patients, nausea among 27.8% to 35.4% of patients, and fatigue among 8.3% to 13.9% of patients.

A major limitation of this study was the small size of each cohort.

Results of this study suggested that there may be an EMONO-opioid interaction resulting in a beneficial analgesic effect among patients with peripheral neuropathic pain. The authors conclude that “[a]s suggested by experimental studies, the long-lasting effects of EMONO administration reported in this study may depend on the anti-NMDA properties of N₂O.” However, additional study is needed to evaluate the biologic mechanism of this potential interaction.

Disclosure: This study was sponsored by Air Liquide Sante International. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.