Perspectives in Biology and Medicine

OPIOID PROPERTIES OF PSYCHOTROPIC ANALGESIC NITROUS OXIDE (LAUGHING GAS) MARK A. GILLMAN* and FREDERICKJ. LICHTIGFELDt Introduction Nitrous oxide (N2O) is a natural constituent of the atmosphere in trace quantities. The history of the original synthesis and identification of the gas in 1772 by Priestley has been well documented [I]. In 1799 Humphry Davy began his celebrated experiments with the gas, which culminated in the publication of his observations of the effects of the gas on animals and man. Among his findings were that analgesic concentrations of the gas alleviated toothache and, at times, also produced pleasurable sensations of exhilaration and merriment. He also suggested its possible role in surgery to eliminate pain. However, at no time, did he specify the concentrations of nitrous oxide for this indication [2]. It is therefore clear that, even from the very beginning of the use of the gas in human experimentation, the effects were very closely linked to the concentration. At low doses it produced analgesia and emotional effects, while at much higher doses it could produce unconsciousness. Once the analgesic dose has been titrated for a particular patient, that concentration is so much lower than the dose that would produce pre-anesthetic excitation, let alone anesthesia, that analgesic and anesthetic doses are extremely far from one another; i.e., there is virtually no overlap. They are therefore easily determined clinically, because they are so concentration-dependent, ensuring a wide margin of safety when analgesic concentrations are used. The clear distinction between analgesic and anesthetic nitrous oxide has been established without doubt [3] even since the earliest times [2]. To avoid any future confusion we have introduced the term psychotropic analgesic nitrous oxide (PAN) for The authors gratefully acknowledge support for their work from the Anglo-American and De Beers Chairman's Fund and the South African Medical Research Council. *Executive director, South African Brain Research Institute, 6 Campbell Street, Waverley 2090, Johannesburg, South Africa. tDirector, South African Brain Research Institute.© 1994 by The University of Chicago. AU rights reserved. 0031-5982/94/3801-0896$01.00 Perspectives in Biology and Medicine, 38, 1 ¦ Autumn 1994 125 these non-anesthetic concentrations [4]. In this paper, we intend to concentrate on the unique non-anesthetic, analgesic, and psychotropic properties of nitrous oxide termed PAN. At these low concentrations the subject is always conscious and cooperative [5]. The subjective effects of PAN have been described as pleasant, with euphoria and a sense of well-being, sometimes accompanied by fantasies [2, 5]. Emotional lability occasionally manifests as laughing or crying, which rapidly disappears even while the gas is inhaled. PAN is also an extremely valuable anxiolytic agent [5]. LINK BETWEEN PAN AND THE EXOGENOUS OPIOIDS PRIOR TO THE DISCOVERY OF THE ENDOGENOUS OPIOID (ENDORPHIN) SYSTEM IN THE BRAIN Seevers and colleagues conclusively established that analgesia at low doses of N2O produced a dose-related elevation of pain thresholds in volunteers which was independent of hypoxia. These experiments demonstrated that the analgesic effects of the gas were completely independent of its anesthetic properties, which only manifested themselves at much higher concentrations [6]. Chapman and colleagues extended this work by showing that N2O in low concentrations ("consciousness not impaired beyond a slight euphoria") relieved pain comparable to the analgesic effects of morphine, without the undesirable side effects of morphine [7]. The latter authors found that PAN at 20 percent concentration in oxygen was as effective as 15mg of subcutaneous morphine. They also noticed what Seevers, et al. had shown in two separate papers, namely that 20 percent N2O was more effective than 10mg of morphine [7]. It is significant that Seevers and colleagues had also raised the possibility that aspects of the actions of PAN resembled the subjective effects described after injection of opioids [6]. To confirm that analgesia was a property of low concentrations of the gas, with the subject retaining consciousness, Chapman, et al., went on to show that none of their subjects retained consciousness above 75 percent N2O with 25 percent oxygen, and most became unconscious at 60 percent N2O [7]. These observations confirmed those of Seevers, et al., and were also later repeated by others [8]. This work emphasized the uniqueness of the analgesic effects...