Safety and efficacy of an equimolar mixture of oxygen and nitrous oxide (EMONO): a randomized controlled trial in patients with peripheral neuropathic pain.

Nitrous oxide (N2O) is an odorless and colorless gas routinely used as an adjuvant of anesthesia and for short duration analgesia in various clinical settings mostly in the form of a N2O/O2 50%-50% equimolar mixture (EMONO). Experimental studies have suggested that EMONO could also induce long lasting analgesic effects related to the blockade of NMDA receptors. We designed the first international multicenter proof of concept randomized, placebo-controlled study to assess the efficacy and safety of a one hour administration of EMONO or placebo (medical air) on three consecutive days up to one month after the last administration in patients with chronic peripheral neuropathic pain. A total of 240 patients were recruited in 22 centers in France and Germany and randomly assigned to one study group (120 per group). Average pain intensity (primary outcome), neuropathic pain characteristics (NPSI), patient global impression of change (PGIC), anxiety, depression and quality of life were systematically assessed before and after treatment. The changes in average pain intensity between baseline and seven days after the last administration were not significantly different between the two groups. However, evoked pain intensity (predefined secondary endpoint) and PGIC (exploratory endpoint), were significantly improved in the EMONO group and these effects were maintained up to four weeks after the last treatment administration. Mostly transient side effects were reported during the treatment administration. These encouraging results provide a basis for further investigation of the long term analgesic effects of EMONO in neuropathic pain patients.