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Use of Drugs in the Prevention of Motion Sickness CHARLES D. WOOD Shreveport Medical School Louisiana State University SUMMARY The most potent drugs for the prevention of motion sickness are those with central autonomic activity. Drugs which block parasympathetic or stimulate sympathetic activity are most effective. Drugs such as the phenothiazines, phenoxybenzamine, or meprobamate, which reduce sympathetic activity, appear to increase susceptibility to motion sickness. Scopolamine was the most effective single drug, and when combined with </-amphetamine, it was even more effective in prevention of motion sickness. The antihistamines appeared to be more suitable for use with exposure to mild forms of motion. In highly susceptible individuals, or during exposure to more intense motion, the combination of scopolamine with ^-amphetamine was the most effective preparation tested. INTRODUCTION A large number of anti-motion-sickness drugs are currently available, and these can be classi- fied as belladonnas, antihistamines, pheno- thiazines, or as a large miscellaneous group (refs. 1 and 2). Based on reports in the literature, the various classes of drugs would appear to have approximately equal efficacy in preventing motion sickness. This impression seems to be due to the fact that the drugs were not tested under identical conditions or in a controlled environment (ref. 3). The slow rotation room (SRR) at the Naval Aerospace Medical Institute has provided a laboratory setting in which to compare the effectiveness of drugs under controlled and reproducible conditions (refs. 4 and 5). Re- sults obtained from laboratory experiments have been validated by comparing them with those obtained during field studies (unpub- lished observations). In this way a more exact comparison of the relative effectiveness of each individual drug and each class of drug could be made. This report summarizes our data regarding the study of 16 drugs with 8 variations in dosage and 3 different combinations of drugs; selection was based on the reported effectiveness of drugs in different categories as revealed by the review of the relevant literature (ref. 2). PROCEDURE Fifty Navy enlisted men 17 to 23 years of age were volunteer subjects. A comprehensive medical evaluation revealed that all were in good health. With regard to the sensory organs of the inner ear, none had any significant loss of (1) hearing as revealed by audiometry, (2) otolith function as revealed by ocular counter- rolling (ref. 6), or (3) canal function as revealed by the threshold caloric test (ref. 7). The Coriolis accelerations were generated by requiring the subject, while seated, to flex his head and upper part of the body out of the plane of the room's rotation. These "head movements" were standardized (ref. 8) by requiring the sub- ject to set the needle of five dials to different locations according to taped instructions; the sequential order of the dial settings was varied in a random fashion. A series of five head movements followed by a pause was termed a "sequence" and required 30 seconds. Thus, 101
102 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION the duration of stress in minutes was equivalent to 10 head movements, or two sequences, and the severity of the stress increased as a function of the room's angular velocity. By individualizing the level of stress, persons with varying susceptibility to motion sickness could serve as their own controls in an experi- ment. As part of the initial workup, subjects were "calibrated" in terms of the number of head movements at a given rpm necessary to pro- duce a level of motion sickness termed "severe malaise" (M III). This endpoint has been pre- cisely defined (ref. 9), and here it is sufficient to describe it as mild motion sickness to which sub- jects do not object. Independent estimates of the M HI endpoint indicated close agreement among experimenters with previously shared ex- periences. The double-blind technique was used. Drugs and placebo (lactose) were in matched oral cap- sules and administered using a Latin-square de- sign. In each of 5 experiments, 7 drugs and 3 placebos (4 placebos on one occasion) were given to 10 subjects, each participating in 10 experi- mental trials. In all, the 50 subjects were exposed to stress on 500 occasions. The capsules were given 1 to 2 hours prior to exposure in the SRR. Only one subject was ex- posed at a time. The number of head move- ments was recorded when the M III endpoint was reached, and then the room was brought to a stop. Habituation was taken into account by establish- ing the mean placebo level of susceptibility which was used as the baseline in measuring the effects of the drugs. It should be emphasized that the procedure made it possible to demonstrate in- creased as well as decreased susceptibility. RESULTS The results are summarized in figure 1 where the drugs and combinations of drugs are ranked according to their effectiveness in reducing susceptibility to acute SRR sickness. Among drugs with either a sympatholytic ac- tion or a tranquilizing effect, some caused a slight decrease and others an increase in susceptibility to SRR sickness. Phenoxybenzamine HC1 and thiethylperazine maleate in the usual doses, as well as a triple dose of the latter, were found to reduce the subjects' tolerance to the stressful Coriolis accelerations. Trimethobenzamide HC1 in a triple dose and meprobamate ranked just be- low the placebo level, while a single dose of the former was effective just above that level. A new drug known as Experimental 999 was the most effective, although its level of effectiveness was below that of all antihistaminic drugs tested with the exception of meclizine in the usual dose. When 2j times the usual dose of Exp 999 was administered, its effectiveness decreased. All six of the antihistaminic agents tested caused a decrease in susceptibility to SRR sickness, although the difference between the least and most effective was large. The effec- tiveness of meclizine was not increased when given in combination with dextroamphetamine sulfate. The effectiveness of the sympathomimetic drugs was a chance finding and is thus explained: Amphetamine was given to counter the drowsi- ness caused by /-scopolamine hydrobromide and then administered alone for purposes of experimental control. In a 10-mg dose it was found to rank in effectiveness near the middle of the antihistamine group. It was unique among drugs tested in that a larger than the "recommended" dose increased its effectiveness, but the side effect (nervousness) contraindicated this dose for routine use. Scopolamine with a parasympatholytic action was the single most effective drug. When the usual dose of 0.6 mg was doubled, its effective- ness was not increased, the actual number of head movements decreasing slightly. Drowsi- ness and "dry mouth" were prominent side effects. The combination of the sympathomimetic drugs and scopolamine, a parasympatholytic drug, was additive in case of ephedrine and synergistic in the case of amphetamine 20 mg plus scopolamine 1.2 mg. The only troublesome side effect was "dry mouth." The same combi- nation in half the doses was nearly as effective. DISCUSSION It has been stated that all persons with normal vestibular and neural responses are susceptible to motion sickness. The level of this sus-
DRUGS IN PREVENTION OF MOTION SICKNESS 103 ceptibility varies greatly among individuals; some are highly susceptible while others are very resistant. If the stimulus is strong enough and lasts long enough, however, all normal persons apparently will respond. The anti- motion-sickness drugs raise this individual base line so that an increased percentage of persons are then able to withstand a given exposure to motion. None of the drugs is completely effective, being dependent on the individual's susceptibility and the strength and duration of the stimulus. The medications with central autonomic activity appeared to have the greatest effect on susceptibility to motion sickness in the SRR. The drugs that blocked sympathetic activity increased susceptibility to motion sickness. Preparations with sympathetic stimulating activity and those with parasympathetic blocking activity were most effective in preventing the development of motion sickness. Phenoxybenzamide, which is a sympathetic blocking agent with some central action, in- creased susceptibility to motion sickness. This drug was also reported to increase susceptibility in a large study at sea. In acrobatic studies at Pensacola the tolerated motion with this drug was below that of the placebo trials. Mepro- bamate is another preparation with adrenolytic activity which reduced tolerance to motion. Another group of drugs with sympathetic blocking activity is the phenothiazines. These 3I0 200 I90 I80 170 i/i id 60 Z uj 150 5 -1 Â§ SM0 O S 130 2 g â¢^ i20 LJ O or 90 Â« s ao y S 70 P H 60 50 > 40 [ ^ I0 t 0 -o -20 -30 -4O -SO EFFECTIVENESS OF ANTIMOTION SICKNESS DRUGS IN PREVENTING MOTION SICKNESS IN 50 SUBJECTS EXPOSED ON 500 OCCASIONS IN A ROTATING ENVIRONMENT USING THE "DIAL TEST" 3 1 End point. Uokiiie III t Mean pIacebo ieveI 5 Stondardned pattern of head mo> â¢ments . experimenter paced using o tape recording w An*istaniines Anthstommes Combinations Sympathommelic & Â» CNS DewesOTt * AcIon 3 ? t t sell Â» 3 ff s (Sympalhdylic) S S 2 % ill!If a i I I :S ? if ? iii I r f s i I Â« all I! ie a Is a i I I! III!!! O Qi â N H! s V I S * r Â§||r If lj :8 Mo ii~ SÂ£ Â«: FIGURE 1. âRelative effectiveness of the drugs tested against motion sickness on the SRR. Drugs are arranged in order of effectiveness of the usually recommended dose, and increased doses and combinations are plotted adjacent to the recommended dose. Drug classification is indicated by brackets.
104 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION medications are very effective against chemically induced nausea; however, in the usually recom- mended dose they produced only a slight in- crease in tolerance to motion over the placebo level with all representatives tested. When the dose was increased, these preparations reduced the tolerance to motion below the placebo level. It would appear that any drug which reduces sympathetic activity will be ineffective or will increase susceptibility to motion sickness. These results further illustrate that drugs which protect against chemically induced nausea must act by a different mechanism from those which protect against motion sickness. Any recom- mendation of a drug as a motion-sickness pre- ventative should be based on its efficacy in tests involving motion and not on its activity against other types of nausea. Trimethobenzamide, which is reported to be an effective antinausant with little, if any, auto- nomic activity, was ineffective in our studies. In fact, even a triple dose did not produce a significant variation from the placebo level of susceptibility to motion sickness. The antihistamines include a large number of effective anti-motion-sickness remedies; these have an "atropine-like effect" which is thought to be due to a central anticholenergic (para- sympatholytic) action. All drugs in this classifi- cation were effective, to some extent, in prevent- ing motion sickness. It appears that the antihistamines are quite useful during exposure to the mild types of motion. They have a longer duration of action and milder side effects than some of the other groups of anti-motion-sickness drugs. In exposure to more severe motion, the antihistamine types did not prove to be highly effective. The failure of the British investiga- tors to find these drugs to be effective may have been due to the more severe stress to which they exposed their subjects (ref. 10). The sympathomimetics represent another class of drugs found to be effective; they were first used to relieve the drowsiness caused by some of the other anti-motion-sickness drugs. The most effective representative of this class for this purpose was d-amphetamine. Tested alone in a 10-mg dose, it was found to rank in effectiveness near the middle of the antihistamine group. Ephedrine was another representative of this class of drugs and it proved to be almost as effective as cf-amphetamine in preventing motion sickness; it was effective when used in combina- tion with scopolamine and when used alone. Ephedrine was not so effective in relieving the drowsiness produced by scopolamine as was d-amphetamine. The effectiveness of both of these drugs served to illustrate that medications which activate the sympathetic division of the autonomic nervous system also afford some pro- tection against motion sickness. In searching the literature, it was found that rf-amphetamine had been tested against motion sickness prior to World War II (refs. 11 and 12) and was found to be fairly effective by some British investigators; however, due to conflicting results in other studies it was not then adopted as a motion-sickness preventative. The parasympatholytic class of anti-motion- sickness drugs is represented in this study by scopolamine. This preparation, also known as hyoscine by the British, has had extensive testing and has proven to be the most effective drug in this classification, which includes a number of synthetic preparations and atropine. The central action of scopolamine is known to be several times greater than that of atropine; therefore, it was chosen to represent this class of drugs. The antihistamines also have a central anti- cholenergic effect and are effective against motion sickness, but scopolamine has a much more pro- nounced action. Scopolamine was the single most effective drug in our series of studies, but the side effects of dry mouth and drowsiness are disturbing factors with its use. Various combinations of drugs have been tried against motion sickness, usually with little if any increase in efficacy. In the present study, cf-amphetamine was combined with scopolamine as well as with meclizine in an attempt to relieve the drowsiness produced by these drugs. When used alone, d-amphetamine was effective against motion sickness, as was previously mentioned, and combined with scopolamine, a potentiation of effectiveness was obtained; that is, the effect obtained was greater than the
DRUGS IN PREVENTION OF MOTION SICKNESS 105 sum of the effect of the two drugs when tested separately. The combination of ^-amphetamine and meclizine failed to increase effectiveness, however. The increased protection afforded by the combination of a sympathomimetic (d-amphetamine) and a parasympatholytic (scopolamine) indicates a prominent role for the autonomic nervous system in motion sickness and its prevention. As motion sickness develops, the involvement of the autonomic reactions is quite obvious. Earlier theories of motion sickness were based on autonomic activation, but the inability to demonstrate consistent changes in such areas as blood pressure, respiration, etc., which are responsive to alterations in autonomic activity, caused these theories to be discarded. However, when a subject in whom motion sickness is developing is observed in controlled experiments in the SRR, a waxing and waning of the various autonomic reactions can be seen. The face of the subject may flush, then become pale, only to return to normal color. Variations also can be seen in sweating, stomach awareness, etc., until motion sickness actually develops. In individuals who have a tolerance above the stress of the motion they are being exposed to, various reactions related to motion sickness can fre- quently be seen. This is also true of persons protected by medications. Such observations, along with the types of drugs which give pro- tection against motion sickness, would suggest the action of competing systems in the central nervous system involving both divisions of the autonomic nervous system. The signs and symptoms associated with the sympathetic division would then appear to be protective, while those associated with the parasympathetic division would contribute to the ultimate vomiting of motion sickness. Therefore, as a person is exposed to the stresses of motion, the con- flicting sensory stimuli, such as vestibular, visual, and proprioceptive, would activate both autonomic divisions. As the stress continues, either the protective sympathetic reactions would be sufficient to prevent motion sickness or the stress would override this protection and the parasympathetic-somatic reactions would result in vomiting. The results of our drug evaluation studies indicate that the effective drugs act by activat- ing the central sympathetic activity or blocking the central parasympathetic activity. In this way, the autonomic activity during exposure to motion would be shifted toward the protec- tive sympathetic reactions. Habituation to motion could be the result of conditioning these same protective mechanisms to a stronger reaction when exposed to motion. The diverse nature of the effective anti-motion-sickness drugs argues for a central action rather than a primary one on the receptors or on the effector organs through peripheral actions. The reticular activating system is known to have a marked influence on the autonomic activity; however, the presence of both stimulant and depressant drugs in the effective groups would indicate that this is not the primary site of action. It would appear, therefore, that higher systems directly involved with the autonomies are the critical ones involved in the motion sickness reaction. Motion sickness certainly involves not only the autonomic system, but rather a complex of higher systems, including the vestibular, cerebellum, somatic motor areas, hypothalamus, and possibly the reticular system. The perfect anti-motion-sickness drug has not been found, but the results of our studies appear to indicate promising pharmacological areas for future exploration. The present drugs only increase an individual's resistance and do not make him immune to motion sickness. In addition, the most effective drugs have unde- sirable side effects. Therefore, much progress is still possible in this field. The studies re- ported here demonstrate that the combination of scopolamine with (/-amphetamine is the most effective preparation now available. The superiority of this combination of drugs has been demonstrated in SRR studies as well as in acro- batic and sea studies. For exposure to milder conditions, antihistamines such as cyclizine may be sufficient and more agreeable to the patient.
106 THE ROLE OF THE VESTIBULAR ORGANS IN SPACE EXPLORATION REFERENCES 1. WOOD, C. D.; KENNEDY, R. S.; AND GRAYBIEL, A.: Review of Antimotion Sickness Drugs From 1954-1964. Aero- space Med., vol. 36, Jan. 1965, pp. 1-4. 2. WOOD, C. D.; KENNEDY, R. S.; GRAYBIEL, A.; WHERRY, R. J., JR.; AND TRUMBULL, R.: Clinical Effectiveness of Antimotion-Sickness Drugs. Computer Review of the Literature. J. Am. Med. Assoc., vol. 198, Dec. 12, 1966, pp. 1155-1158. 3. CHINN, H. I.; AND SMITH, P. K.: Motion Sickness. Pharmacol. Rev., vol. 7, Mar. 1955, pp. 33-82. 4. WOOD, C. D.; GRAYBIEL, A.; AND KENNEDY, R. S.: A Comparison of Effectiveness of Some Antimotion Sick- ness Drugs Using Recommended and Larger Than Recommended Doses as Tested in the Slow Rotation Room. Aerospace Med., vol. 37, Mar. 1966, pp. 259- 262. 5. WOOD, C. D.; GRAYBIEL, A.; MCDONOUGH, R. G.; AND KENNEDY, R. S.: Human Centrifuge Studies on the Relative Effectiveness of Some Antimotion Sickness Drugs. Aerospace Med., vol. 37, Feb. 1966, pp. 187- 190. DISCUSS KM Baldes: As Dr. Jones pointed out in his introductory remarks, this symposium is devoted to the role of the ves- tibular organs in space exploration, but I am going to take you out of orbit and bring you down to some lap-of-the- Earth problems with which the Army is concerned. As you all must know, a few years ago competition was entered into by 12 aircraft companies for the development of an advanced aerial fire-support system. This competition was won by Lockheed which developed what is known as the com- pound helicopter; this is a most unusual aircraft called the Cheyenne. Ten of these prototypes have now been accepted by the Army for testing purposes. Regarding the maneuver- ability of this aircraft, it has the following capabilities: a diving speed of 264 knots, and an ordinary speed of about 220. It has the capability of turning around 180Â° in 8 seconds at a speed of 100 knots, the radius of turn being 435 feet. That means it is exposed to more than 2 radial g; it is stressed for 3i, actually. It can hold a 90Â° bank, and roll at the rate of 60Â°/sec. It is powered by 3400-horsepower gas turbine. It is called a compound helicopter because it has wings and a pusher prop tail. The thing of interest which I think might be of concern to some of us is this: Remembering that this is a highly maneuverable aircraft, the problem concerns the gunner or the copilot who sits tandem with the pilot, but at a lower level. The gunner's seat is placed on a rotating table; this can rotate at a maximum rate of 100Â°/sec, the maximum excursion of the rotation being 210Â° from stop to stop. The maximum acceleration of the rotating table is 180Â°/sec2. Assuming equal acceleration and deceleration rates of the 6. MILLER, E. F., II: Counterrolling of the Human Eyes Produced by Head Tilt With Respect to Gravity. Acta Oto-Laryngol., vol. 54, 1962, pp. 479-501. 7. McLEOD, M. E.; AND MEEK, J. C.: A Threshold Caloric Test: Results in Normal Subjects. NSAM-834. NASA Order R-47. Naval School of Aviation Medi- cine, Pensacola, Fla., 1962. 8. GRAYBIEL, A.; CLARK, B.; AND ZAKRIELLO. J. J.: Observa- tions on Human Subjects Living in a "Slow Rotation Room" for Periods of Two Days. Arch. Neurol., vol. 3, 1960, pp. 55-73. 9. GRAYBIEL, A.; WOOD, C. D.; MILLER, E. F., II; AND CRAMER, D. B.: Diagnostic Criteria for Grading the Severity of Acute Motion Sickness. Aerospace Med., vol. 39, 1968, pp. 453-455. 10. GLASER, E. M.; AND McCANCE, R. A.: Effect of Drugs on Motion Sickness Produced by Short Exposure to Arti- ficial Waves. Lancet, vol. 1, Apr. 1959, pp. 853-856. 11. BLACKHAM, R. J.: Sea-sickness. Brit. Med. J., vol. 2, July 22, 1939, pp. 163-167. 12. HILL, J.: Benzedrine in Seasickness. Brit. Med. J., vol. 2, Dec. 4, 1937, pp. 1109-1112. seat, the time for rotation of 210Â° from stop to stop may be less than 3 seconds. When this rotation is combined with maneuverability of the aircraft, I think there will be problems of a vestibular nature. In addition, may I point out that the gunner looks forward and downward through his telescope at the target. He does not sit upright and thus aline the vertical through his head. This should bring up some very interest- ing problems in disorientation. Dr. Wood, do you have a pill or capsule you can recommend that can be bought at a drugstore for motion sickness? Wood: These, of course, have to be made up, but they have a few more side effects than the antihistamines. The antihistamines such as Marezine or Dramamine are usually effective for the usual type of motion sickness. Licking: I have been working in Dr. Wang's laboratory and with Dr. Tokumasu of the University of Tokyo. We have tested scopolamine on several units in the vestibular nuclei of several cats, and scopolamine seems to have quite a dramatic effect, decreasing the capacity of motion-sensitive units responding to a specific movement. Were your sub- jects also tested as to their thresholds for perceiving motion, pitch, yaw, plunging, etc.? Wood: No; but Dr. Miller may have done some other research in his area. He could probably answer that question because these same subjects were used in other Pensacola studies. Miller: The semicircular canal threshold of most, if not all, the subjects used by Dr. Wood was determined by measuring the smallest angular acceleration for which the direction of apparent movement of a fixed target (oculogyral
DRUGS IN PREVENTION OF MOTION SICKNESS 107 illusion) could be correctly identified. The thresholds which covered a wide range of acceleration values showed no apparent correlation with motion-sickness susceptibility. Johnson: I want to congratulate Dr. Wood for a very well-organized research program and his explanation of how these drugs act in relation to their chemistry. As he has pointed out, controversy does exist as to the relative effectiveness of such drugs. I think this is due to experi- mental design. The British, for instance, have long pre- ferred hyoscine in the Royal Navy. I must point out that I have published an article (W. H. Johnson and P. E. Ireland, "Suppression of Motion Sickness by Thiethylperazine (Torecan)," Aerospace Med., vol. 37, 1966, pp. 181-183) which disagrees with your conclusions as to the effectiveness of Torecan (a phenothiazine). We tested this compound in the Canadian Air Force on several search-and-rescue mis- sions involving low flying in turbulent areas. The airmen experienced considerable airsickness until we used this compound. Possibly you used a different dose. Wood: As shown in figure 1 of the text, we used 30 mg of thiethylperazine (Torecan) in one instance and 10 mg in another. There was very little effect with 10 mg, and with 30 mg, the effectiveness fell below the baseline. Johnson: We found Torecan effective only when using 40 mg. Schiflf: It was very interesting to see how effective Drama- mine was. Dramamine is made of two molecules, one is a molecule of Benadryl and the other part is a chlorotheophyllin. The Benadryl is highly parasympatholytic, and the chlorotheo- phyllin is a preventive against sleepiness: so it is decidedly a sympathomimetic. There is a question whether or not sweating and skin changes as occur with other parasympathetic, other cholin- ergic, phenomena, occur since all preganglionic fibers are cholinergic; some of the postganglionic fibers are adrenergic. If the level at which the acetylcholine was working was con- ceived to be acting on the preganglionic fiber, we would be able to explain all the phenomena without having to separate them into two categories. This appears to be what happens because the sympathomimetic also is antagonistic to the parasympathetic. So one is driven further toward a greater control. It is a very interesting study.