THE ANALGETIC EFFECTS OF LOW CONCENTRATIONS OF NITROUS OXIDE COMPARED IN MAN WITH MORPHINE SULPHATE William P. Chapman, … , Julia G. Arrowood, Henry K. Beecher J Clin Invest. 1943;22(6):871-875. https://doi.org/10.1172/JCI101461. Research Article Find the latest version: https://jci.me/101461/pdf THE ANALGETIC EFFECTS OF LOW CONCENTRATIONS OF NITROUS OXIDE COMPARED IN MAN WITH MORPHINE SULPHATE1 By WILLIAM P. CHAPMAN, JULIA G. ARROWOOD, AND HENRY K. BEECHER (From the Anesthesia Laboratory of the Harvard Medical School at the Massachusetts General Hospital, Boston) (Received for publication May 22, 1943) In a study of the loss of consciousness under tion, has on many occasions been used effectively nitrous oxide, Cobb and Beecher (1) found that for pain relief, without loss of consciousness, but it was desirable to have information on changes wider usefulness of the agent for this purpose has in the pain threshold level during this process. A been limited for several reasons, one of which is few measurements were attempted; but it was the lack of objective data to prove its value in clearly not practicable to include the necessary low concentration. Moreover, several statements tests with the work already in progress, so the in the literature on the subject have also tended observations reported here were made separately. to discourage the use of really low concentrations. It can be observed that nitrous oxide, although For example, Brown, Lucas, and Henderson (3) widely employed, is used in the majority of cases state that no analgesia resulted when 85 per cent in concentrations nearly great enough, if not great nitrous oxide with 15 per cent oxygen was used. enough, to cause loss of consciousness and even It seems unlikely that adequate time could have anoxia. It is our belief that this agent also should elapsed for even approximate equilibration of their be much more widely used as an analgetic agent subjects with this gas mixture; at least none of than is now the case. The purpose of this study our patients retained consciousness beyond 75 per is to report, on the basis of quantitative studies, cent nitrous oxide (with 25 per cent oxygen) and that nitrous oxide in low concentration (con- most of them lost consciousness at 60 per cent sciousness not impaired, beyond a slight euphoria) (with 40 per cent oxygen). Our findings on this has power to relieve pain comparable to that of score agree with the interesting observations of morphine and yet does not have the undesirable Seevers, Bennett, Pohle, and Reinardy (4). Not side effects which limit the use of morphine. only analgesia but anesthesia is produced by this Since 1799,2 nitrous oxide, in low concentra- high concentration of nitrous oxide. ISupported by a grant from Mr. Edward Mallinckrodt. PROCEDURE 2 In Sir Humphry Davy's report of his superb in- vestigation of nitrous oxide (2), made in 1799, at the age The subjects. Fifteen healthy male subjects, varying of 20, he describes repeatedly the use of nitrous oxide to in age from 18 to 34 years, were used in the heat radia- produce analgesia with little or no disturbance of con- tion studies. All of these had been used in the morphine sciousness. For example, on page 464, ". when I had study of Chapman and Jones (5). The same subjects head-ache from indigestion, it was immediately removed were used here in order to minimize the effects of indi- by the effects of a large dose of gas. ." "The power vidual variations, and 10 of these same subjects were of the immediate operation of the gas in removing in- used in the muscle ischemia observations. All deter- tense physical pain, I had a very good opportunity of minations were made with the subject lying comfortably ascertaining," for on being disturbed by a painful dental in the supine position. The nose was closed with a clamp infection, he breathed nitrous oxide and "The pain al- and breathing was carried out through a "basal metabo- ways diminished after the first four or five inspirations lism" rubber mouth piece. The subject did not know ... and ... was ... swallowed up in pleasure." Later what he was breathing. Seven control tests were run (p. 481), as an experiment he "drank a bottle of wine in with 100 per cent oxygen, and 3, with air from a tank. large draughts in less than eight minutes." Subsequently he "was awakened by head-ache and painful nausea." may properly be used with advantage during surgical op- On breathing nitrous oxide, he reports that he "was un- erations. ." It can be recalled only with chagrin that conscious of head-ache after the third inspiration... close to a half century went by before Davy's well-in- and continued for some minutes much exhilarated." He formed suggestion was acted on by the medical profes- concluded (p. 556), "As nitrous oxide in its extensive op- sion, and even now his great work is often not adequately erations appears capable of destroying physical pain, it acknowledged. 871 872 WILLIAM P. CHAPMAN, JULIA G. ARROWOOD, AND HENRY K. BEECHER Nitrous oxide was administered (see below) without the all concentrations used, with constant respiratory minute subject's knowledge. volume and the cardiac output constant (assumed).4 At the completion of the experiment, questions were After the position of the plateau was clearly estab- asked to determine the presence of any side reactions not lished, the administration of the nitrous oxide was stopped evident to the observer, such as possible nausea. Careful (without the subject being aware of this) and the pain notes were kept of any alterations in behavior. threshold followed until the base-line level had been Pain production and measurement. Two types of pain reached. Further controls were occasionally run with air production have been studied: (a) Pain arising from heat or oxygen, the subject believing that the gas administered radiation of the skin of the forehead. Our principal con- was nitrous oxide. clusions are based upon these observations. (b) Pain (b) Muscle ischemia pain. In order to study a sus- arising from muscle ischemia as a result of exercise of tained type of aching pain, muscle ischemia was produced the hand under conditions of vascular occlusion by a cuff by having the subject clench his fist at 1-second intervals tourniquet on the arm (5). Here, the observations are with the circulation as completely occluded as possible highly subjective and have been used only as supple- just above the elbow by a blood pressure cuff, inflated mentary support for our conclusions. and maintained at a pressure of 200 mm. Hg (5). The Two components of the pain experience were meas- vascular occlusion was maintained for 600 seconds. As ured, the threshold of pain perception, and as far as was soon as the blood pressure cuff was inflated to 200 mm. possible, the pain reaction.3 The observations under ni- Hg, the subject began clenching his fist and continued trous oxide were compared in the same subjects with until his grip showed the first signs of weakening. At effects previously produced by morphine sulphate (gr. 'A, 200 seconds, this was repeated and again at 450 seconds. 15 mgm., administered subcutaneously), Chapman and The cuff was released at 600 seconds. The time of these Jones (5). 3 different periods of contraction was recorded by a stop- (a) Cutaneous pain. The technic employed here uti- watch. As it was assumed that the amount of pain pro- lizes the Hardy, Wolff, and Goodell apparatus (6) and duced was directly related to the amount of work done follows their procedure with a minor exception, in that by the contractions, it was necessary that the degree of we have used a somewhat stronger and, as a result, more each contraction be kept uniform. This factor was con- definite end-point, as described (5). Briefly, the method trolled by having the subject squeeze the 2 extended consists in focusing the heat from a 1000 watt Mazda fingers of an assistant, making sure that before each con- lamp on the midline of the forehead, already blackened traction the subject's fingers were fully extended and with India ink. The exposure was kept constant for 3 that each grip exerted a uniform pressure. The same seconds and then interrupted by a shutter operated by a number of contractions was repeated for each period of telechron motor. The heat intensity was varied with a exercise during the gas inhalation. Since each subject wire rheostat. The quantity of heat needed to produce showed a tendency to have a more forceful grip during the sharp piercing end-point of pain was measured di- the breathing of nitrous oxide, as a result of diminished rectly by a radiometer and potentiometer. The quantity pain, any error was on the side of more exercise when the of heat was expressed in absolute end-point values of nitrous oxide was used than otherwise. The effect of the gram calories per second per square centimeter of skin nitrous oxide was evaluated by asking the subject the fol- surface. lowing questions at the completion of the tests: 1. Dur- The usual procedure was to establish first the base-line ing which test (nothing or nitrous oxide) was the pain of the normal pain perception threshold and the threshold more severe? If, on either of the tests, the pain was less of pain reaction while the subject breathed room air but severe, estimate how much less intense it was than in the with the respiratory apparatus in place. (This plan was other case. 2. How did each test compare in the time it varied often enough so that the subject did not know took to complete it? what he was breathing.) After establishment of the nor- As already pointed out, the evaluation of the effect of mal pain threshold, nitrous oxide was administered (see the nitrous oxide was so much less accurate here than in below).