Sopite syndrome

Sopite syndrome also known as mild motion sickness or mal de debarquement syndrome (sometimes referred to as disembarkment syndrome), is a constellation of symptoms including profound drowsiness, fatigue, apathy, depression, boredom, irritability, lethargy, disinclination for work, sleep disturbances, failure of initiative, desire to be left alone, and decreased participation in group activities that may persist for hours to days following exposure to the motion stimuli ¹. Yawning is a behavior marker for the onset of sopite syndrome ². Unfortunately, sopite syndrome is often missed because of its nonspecific symptoms and that the syndrome may occur independently of the vegetative symptoms ³. Symptoms are sometimes mild, which might lead to sopite syndrome being overlooked, while symptoms such as apathy and depression might lead to misdiagnosis of other conditions ³.

Motion sickness is an unpleasant condition that occurs when persons are subjected to motion or the perception of motion. Motion sickness is typically triggered by low-frequency vertical, lateral, angular, rotary motion, or virtual stimulator motion, to which an individual has not adapted ⁴. It results in the common symptoms of nausea, nonvertiginous dizziness, and malaise. It is generally considered to be of physiological origin. Nearly all individuals experience it if exposed to enough motion stimuli. With prolonged exposure to the same provocative motion, some individuals adapt and exhibit a reduction in symptoms. The course of this adaptation varies, but a few days are usually needed before a significant level of adaptation is achieved ⁵.

Patients who have previously experience motion sickness are much more likely to experience it again. Along with pregnant women, patients with previous vestibular syndromes or illness, a propensity toward nausea, and patients with a migraine headache history have increased rates of motion sickness.

Sopite syndrome causes

Motion sickness is typically triggered by low-frequency lateral and vertical motion (example: air, sea, road transportation) or by virtual simulator motion (video games, virtual simulators) ⁶. The sensory conflict and neural mismatch theory is the most widely accepted theory for explaining motion sickness ⁷. Motion sickness tends to occur when the input from the proprioceptive, vestibular and visual are mixed or in conflict. It describes the conflict that occurs between the visual, vestibular and somatosensory systems resulting from real or virtual motion. Afferents from the vestibular apparatus arrive at the vestibular nuclei of the brainstem, which also receives inputs from the visual and proprioceptive systems ⁸. Efferent projections then reach the temporoparietal cortex via the posterolateral thalamus, triggering autonomic reactions and the vomiting center. When there is a discrepancy between actual versus expected patterns of vestibular, visual, and kinesthetic inputs, it initiates the cascade of motion sickness symptoms ⁹.

Motion sickness is inducible in almost all people with a functioning vestibular apparatus and a sufficient provocative stimulus ⁹. Patients with a total loss of labyrinthine function are immune to motion sickness ¹⁰.

Individual susceptibility varies. Certain characteristics associated with motion sickness include ⁸:

• Sex – women are more susceptible than men
• Age – motion sickness begins around age 6 and peaks at age 9 – there is a subsequent decline during teen years due to habituation
• Elderly people are the least susceptible to motion sickness
• Fitness level – cross-sectional studies show increased susceptibility in persons with high levels of aerobic fitness; there have been suggestions that this is due to a more reactive autonomic system
• Medical conditions – patients with vertigo, vestibular pathology, Meniere’s disease, and migraines are at elevated risk
• Hormones – fluctuations during pregnancy and the menstrual cycle increase susceptibility.

Motion sickness differential diagnosis

Differential diagnosis of motion sickness includes migraine, pregnancy, concussion, intoxication, hangover, basilar artery occlusion, cerebral vascular accident, vestibulopathy, hypoglycemia, depression, and anxiety.

Sopite syndrome symptoms

Sopite syndrome is a constellation of symptoms including profound drowsiness, fatigue, apathy, depression, boredom, irritability, lethargy, disinclination for work, sleep disturbances, failure of initiative, desire to be left alone, and decreased participation in group activities that may persist for hours to days following exposure to the motion stimuli ¹. Yawning is a behavior marker for the onset of sopite syndrome ².

Less commonly, severe motion sickness symptoms may occur ¹¹. These include the inability to walk, incapacitation, postural instability, intractable retching, and social isolation. The failure to diagnose the early and more mild symptoms of motion sickness may delay treatment ¹².

Sopite syndrome diagnosis

Motion sickness is a clinical diagnosis made with a thorough history of a triggering situation (imposed or perceived motion) and typical symptoms and signs of motion sickness such as malaise, anorexia, nausea, yawning, sighing, increased salivation, burping, headache, blurred vision, non-vertiginous dizziness, drowsiness, spatial disorientation, difficulty concentrating, and sometimes vomiting. Generally, further workup through laboratory or radiographic testing is not necessary if a patient has a typical presentation or a previous history of motion sickness.

In a patient with an abrupt onset of motion sickness symptoms, workup for migraine headaches may be indicated, as they have shown to be closely associated. The prophylactic treatment of migraines may not only decrease headaches but can improve associated dizziness and motion sickness symptoms ¹³.

It is crucial to identify the life-threatening causes for motion sickness like basilar artery occlusion. Sometimes the initial presenting symptom for basilar artery occlusion is dizziness and motion sickness. Usually, these patients have other associated symptoms which are sudden in onset like diplopia, dysarthria, dysphagia and drop attacks. When suspecting basilar artery occlusion, it is vital to do CT angiography to rule out basilar artery occlusion. Once it is ruled out, then one can look for benign paroxysmal positional vertigo, vestibular migraine, vestibular neuritis, etc.

Sopite syndrome treatment

Behavioral and environmental modifications

Motion sickness is easier to prevent than to cure. As such, emphasis should be placed on prevention ¹⁴. Simple behavioral and environmental modification can be effective in the prevention of motion sickness. Susceptible individuals should avoid heavy meals, ingestion of caffeine, alcohol, foods high in histamine content (e.g., cheese, tuna, salami) or a large volume of liquid, before traveling ¹⁵. A stuffy atmosphere while traveling may predispose an individual to motion sickness and should be avoided. For smokers, smoking should be avoided ¹¹. Susceptible individuals should travel when well rested, stop often for rest, and stay well hydrated. The importance of adequate sleep cannot be overemphasized. Susceptible individuals should select the proper means of transportation that produce a minimal amount of motion.

Reducing head and body movement can reduce motion sickness ¹¹. In one study, passive restraint of the head and body helped to reduce visually induced motion sickness.57 Affected individuals should consider positioning themselves where there is less opportunity for head and body movement ⁵. This will reduce the visual-inertia conflict.

Attenuating or eliminating visual input may reduce visual sensory conflict and therefore may delay the onset of motion sickness or weaken the severity of the symptoms ¹⁶. Reading or watching a video screen while in a moving environment should be avoided ¹¹. Sitting in the front seat rather than the back seat may help to reduce motion sickness ¹¹. Focusing the eyes on a fixed spot such as the horizon or looking in a vehicle’s direction of travel is helpful ¹¹. Actively steering a vehicle may also help in the prevention of motion sickness ¹⁷. Sunglasses may reduce visual input and thus may be beneficial. If the above measures do not work, individuals with motion sickness may obtain relief by closing the eyes and lying supine where practical ¹⁶.

In one study, visually induced motion sickness was alleviated by the smell of rose ¹⁸. The authors of the study suggested that olfaction can modulate visually induced motion sickness and that a pleasant odor can potentially reduce visually induced motion sickness. Further studies are necessary to confirm or refute their findings.

It has been shown that controlled regular breathing can be used to suppress physiological responses associated with motion sickness ¹⁹. Presumably, controlled breathing can activate the parasympathetic nervous system and the known inhibitory reflex between respiration and vomiting can be used to suppress physiological responses associated with motion sickness ²⁰. Some authors suggest listening to pleasant music may help ²¹. In one study ²², 24 healthy subjects were exposed to nauseogenic Coriolis stimulation on a rotating turntable under three conditions: while listening to a music audiotape, focusing on controlling breathing, or without any intervention. The authors found that the mean motion exposure time in minutes tolerated before the onset of nausea was significantly longer for music (10.4 minutes) and for controlling breathing (10.7 minutes) compared with no intervention (9.2 minutes). Well-designed, large-scale, randomized, studies are necessary to evaluate the efficacy of controlled breathing and/or pleasant music in the prevention of motion sickness.

Reassurance about the temporary nature of the illness may alleviate the symptoms and every effort should be made to avoid suggesting the symptoms of motion sickness.

In situations when exposure to motion stimuli is inevitable and symptoms are incapacitating or severe enough to affect the ability of the individual to function, incremental exposure, progressive increasing the intensity of stimulation over multiple exposures, can be used to prevent motion sickness ²³. Continued exposure to motion stimuli leads to habituation. Presumably, the changes brought about by the habituation process are preserved in the central nervous system. Habituation/desensitization is an effective long-term countermeasure ²⁴. However, at least 5% of individuals with motion sickness show no signs of habituation.6 In addition, such habituation is highly specific to the particular stimulus that is adapted ²⁵. In seasickness, approximately 50% of the population may succeed in habituating ²⁶.

Pharmacologic therapy

Anti-motion sickness medications are helpful when given prophylactically. They are less effective for treatment because motion sickness may induce gastric stasis that interferes with the absorption of the medications given orally ¹¹. Anti-motion sickness medications may make the difference between an uncomfortable and an enjoyable trip. In general, medications may be considered for patients who are prone to significant motion sickness and for patients who do not respond to conservative measures ¹¹. The types of medication used should depend on the duration of exposure, the susceptibility of the individual to motion sickness and the severity of expected symptoms, the incidence and severity of adverse events, and the differences in the effectiveness of the medication ¹¹. Medications are most effective when combined with behavioral and environmental modifications ¹⁷. Drugs that are effective and most commonly used in the prophylaxis or treatment of motion sickness are anticholinergic agents and antihistamines.6 Because of the associated adverse events such as drowsiness and confusion, these medications may be used with sympathomimetics (catecholamine activators) to increase efficacy and to alleviate adverse events ²⁷.

Anticholinergics

It has been shown that scopolamine is effective in the prevention and treatment of motion sickness ²⁵. Scopolamine acts as a nonselective anticholinergic agent by inhibiting input to the vestibular nuclei and vomiting center in addition to its central anticholinergic properties ²⁵. Scopolamine is the drug of choice for individuals who wish to maintain wakefulness during travel ¹⁷.

Scopolamine is most commonly used as a 1 mg transdermal patch applied behind the ear on the mastoid on a clean, hairless area ¹¹. The patch should be applied at least 4 hours, preferably 8 hours, before exposure to motion, with effects lasting for approximately 72 hours, at which point the patch can be replaced if necessary ¹¹. Hands should be washed thoroughly both before and after touching the transdermal patch ¹⁴. An advantage of the transdermal route is that it allows therapeutic blood levels of a drug with a short half-life to be maintained over long periods. In addition, gastric stasis is common with motion sickness. Therefore, nonoral routes of administration, such as transdermal route, are advantageous ¹⁴. In general, transdermal scopolamine is well tolerated ¹¹. Performance is not usually affected for short-term use.72 Adverse events include dry mouth, dry eyes, blurred vision, mydriasis, photosensitivity, and dermatitis at the site of application ²⁷. Less common adverse events include headache, drowsiness, confusion, palpitations, tachycardia, bloating, constipation, and urinary retention.37 Restlessness, memory disturbances, hallucination, toxic psychosis, acute angle glaucoma, ipsilateral mydriasis, and cycloplegia have rarely been reported ²⁸. Transdermal scopolamine should not be used in children under 10 years old, as its safety in children in that age group has not been established and should be used with caution in the elderly ¹¹. The transdermal scopolamine should not be cut in half as this can affect the rate of release of the medication ²⁵. People who use scopolamine should not drive or engage in heavy machinery work. Scopolamine is contraindicated in patients with glaucoma or prostatic enlargement ¹¹. A randomized, double-blind, crossover study on 76 naval crew members showed that transdermal scopolamine is more effective than cinnarizine in the prevention of motion sickness and has fewer side effects than cinnarizine ²⁹.

When fast protection is needed, oral scopolamine is the most useful anti-motion sickness medicine ²⁸. Given orally, scopolamine is effective within 30 minutes for a period of 4–6 hours and is useful for short trips ²⁸. Nevertheless, it is advisable to take the medication 1 hour before traveling. The recommended oral dose for adults is 0.3–0.6 mg and that for children is 0.006 mg/kg. Drowsiness, blurred vision, and dry mouth are uncommon at these doses ¹⁵. If the recommended dose does not adequately relieve the symptoms, the dose may be doubled ¹⁷. Some authors prefer the combination of transdermal scopolamine and oral scopolamine for rapid onset of action and maintenance of the required plasma level to prevent motion sickness ³⁰.

In adults, intramuscular injection of 0.3–0.6 mg (children, 0.006 mg/kg) of scopolamine may be effective even if vomiting has developed ¹⁵. The dose can be repeated every 6–8 hours if necessary.

Scopolamine can also be administered as a nasal spray ²⁷. The preparation has an onset within 30 minutes after administration and has a higher peak plasma concentration than oral scopolamine ³¹. A randomized, double-blind, placebo-controlled, crossover study on 16 young adults showed that intranasal scopolamine to be efficacious for the treatment of motion sickness with no significant sedative or cognitive effects ³².

Antihistamines

Antihistamines also known as H1 receptor antagonists, decrease the firing of afferent nerves of the semicircular canals that are triggered by the histaminergic system in the hypothalamus ³³. Unfortunately, H1 antagonists are highly sedating. Studies have determined the less sedating second-generation antihistamines (e.g., cetirizine, fexofenadine, astemizole, loratadine) to be ineffective in treating motion sickness, likely due to mediation via peripheral versus central receptors ³⁴.

Many first-generation antihistamines have been shown to be effective in the prevention and treatment of motion sickness, including cinnarizine, promethazine, dimenhydrinate, diphenhydramine, cyclizine, and meclizine ²⁵. Their effectiveness is likely due to their antihistamine activity and, if applicable, their anticholinergic property ¹⁵. The blockage of histamine receptors in the vomiting center may alleviate symptoms, and the anticholinergic effects may contribute to the prophylactic effect ³⁵. Although the onset of action of antihistamines may be longer than that of scopolamine and they must be taken 2 hours before traveling, their prolonged action makes them suitable for use on long trips ³⁵. Adverse events include drowsiness, sedation, agitation, nervousness, delirium, tremors, constipation, dry mouth, blurred vision, and, occasionally, palpitation, fainting, hypotension, and urinary retention. As antihistamines can cause drowsiness and sedation more than scopolamine, they should not be used when decreased alertness may be harmful ¹⁷. The sedative effect may be potentiated by alcohol and some central nervous system depressants. Used alone, antihistamines rarely have severe toxic effects. For patients with vomiting and those who cannot tolerate oral medications, intramuscular administration of antihistamines may be necessary.

• Diphenhydramine– First generation antihistamine that also possesses anticholinergic properties. It is available in oral (over the counter) and injectable preparations. Sedation is common. Other common side effects include dry mouth/eyes, blurred vision, and photosensitivity. Confusion and urinary retention occur rarely.
• Cyclizine – First generation antihistamine available orally over the counter. It has shown similar efficacy to diphenhydramine, but with slightly less sedation and more direct action on the stomach in treating gastrointestinal symptoms ³⁶. It is FDA approved for adults and children over 6 years old.
• Meclizine – First-generation antihistamines are available orally over the counter. They are approved for patients 12 years and older but are highly sedating.
• Cinnarizine – A first-generation antihistamine with higher efficacy in treating motion sickness symptoms with the least amount of drowsiness. This drug is not available in the USA or Canada due to its calcium channel blocking properties but is still widely used in Mexico and Europe.
• Promethazine – First generation antihistamine with anticholinergic properties. It is prescription-only, available in oral, rectal, and intramuscular preparations. Promethazine has also been studied in space motion sickness, where intramuscular injections are commonly used. Studies suggest, however, its side effects may impair operational performance ³⁷. Combination therapy with caffeine has proven effective in counteracting some side effects of promethazine ³⁸.

Sympathomimetics

Sympathomimetics (catecholamine activators) such as ephedrine and dextroamphetamine have not been shown to be superior to scopolamine and antihistamines in the prevention or treatment of motion sickness. Rather, they are often used in combination with scopolamine and antihistamines to overcome the drowsiness and impaired performance caused by these agents ³⁹. The addition of ephedrine to either scopolamine or chlorpheniramine, however, does not increase the effectiveness of either medication against motion sickness ⁴⁰. Dextroamphetamine is more effective than ephedrine ⁴¹. Studies have shown that a combination of scopolamine and dextroamphetamine is highly effective because these two drugs combine their different anti-motion sickness properties and their respective side effects of sedation and stimulation cancel each other out ⁴¹. However, because of the potential of dextroamphetamine for drug dependence and abuse, the addition of dextroamphetamine to scopolamine is unsuitable for general use and is mainly used during space flights and for specialized military purposes ²⁵. Data on the efficacy of modafinil or caffeine in combination with scopolamine or antihistamines in the management of motion sickness are limited ⁴². Additional information is necessary before such a combination can be recommended. Generally, sympathomimetics should not be prescribed for patients who have or at risk for cardiovascular disease.

Therapies not recommended

• Dopamine antagonists such as metoclopramide have not consistently demonstrated efficacy in the treatment of motion sickness. Although metoclopramide is an effective antiemetic and promotes gastric emptying, studies have not demonstrated efficacy in the treatment of motion sickness ³⁸.
• Serotonin (5-HT3) receptor antagonists like ondansetron are potent antiemetics and inhibit gastric tachyarrhythmia but are not effective in preventing motion sickness symptoms ³⁸.

Medications for pregnant patients

Pregnant women may have increased susceptibility to motion sickness ¹¹. Medications used for morning sickness are felt to be safe for use in motion sickness, including meclizine and dimenhydrinate. These medications are listed as category B in pregnancy by the United States Food and Drug Administration ¹¹. On the other hand, promethazine and scopolamine are listed as category C in pregnancy by the United States Food and Drug Administration ¹¹.

Complementary and alternative therapy

Several studies have shown that acupressure, acupuncture, and electroacupuncture on the P6 point (located on the anterior surface of the forearm, two inches proximal to the distal wrist crease and between the middle two tendons of the inside of the forearm) are effective in the treatment of motion sickness ⁴³. These measures, which are more popular in Asia than in the west, represent another therapeutic option. Presumably, the above measures work by activation of insulin receptors and extracellular regulated protein kinases in the dorsal motor nucleus of the vagus ⁴⁴. Other investigators did not find acupressure and acustimulation useful in the treatment of motion sickness ⁴⁵. Well-designed, large-scale, randomized, studies are necessary to confirm the efficacy of these treatments in order to make formal recommendations regarding their use in the management of motion sickness. Suffice to say, adequate blinding and allocation concealment are difficult to perform.

Some authors suggest the use of ginger (rhizomes of Zingiber officinale), such as sucking on hard ginger candies, in the prevention and treatment of motion sickness ⁴⁶. The exact mechanism of action is not known. Studies have shown that ginger might exert its effect on the gastric system and on the 5-hydroxytryptamine (HT3) receptor ion-channel complex ⁴⁷. In a blind placebo-controlled study, the effects of powdered rhizomes of Zingiber officinale (940 mg in two gelatin capsules) were compared with those of dimenhydrinate (100 mg) in reducing symptoms of motion sickness caused by a motor-driven revolving chair in 36 undergraduate men and women ⁴⁶. The authors found that powdered rhizomes of Zingiber officinale were more effective than dimenhydrinate. In a double-blind study, 80 naval cadets (mean age of 17 years), unaccustomed to sailing in heavy seas, were randomized to receive 1 g of powdered ginger root (n=40) or 1 g of lactose as placebo (n=40) ⁴⁸. The cadets were monitored hourly for the next four consecutive hours for the symptoms of motion sickness and side effects. The authors noted that ginger root reduced the tendency to vomiting and cold sweating significantly better than the placebo did ⁴⁸. Fewer symptoms of nausea and vertigo were noted in the group with ginger root ingestion, but the difference did not achieve statistical significance. No side effects were reported in the two groups. It is hoped that future, well-designed, large-scale, randomized, double-blind, placebo-controlled trials will provide more information on the efficacy and safety profile of ginger root ingestion in the prevention of motion sickness.

A preliminary prospective, double-blind, placebo-controlled, crossover study (n=70) showed that 2 g of vitamin C is effective in suppressing symptoms of motion sickness, particularly in men and women below 27 years old ⁴⁹. Further studies are necessary to confirm or refute this finding.

Sopite syndrome prognosis

In general, the prognosis is good. The symptoms usually resolve in 72 hours after the cessation of the provoking stimuli. Patients with a previous history of motion sickness are more likely to experience it again in the presence of the same or similar environment.

The majority of individuals with motion sickness have mild to moderate symptoms that are self-limited. Once the triggering motion ceases, symptoms often resolve entirely within 24 hours ⁸. The minority of patients whose condition progresses to extreme nausea and vomiting may result in dehydration, electrolyte disturbances or esophageal tears.

References

1. Kaplan J, Ventura J, Bakshi A, et al. The influence of sleep deprivation and oscillating motion on sleepiness, motion sickness, and cognitive and motor performance. Auton Neurosci. 2017;202:86–96. doi: 10.1016/j.autneu.2016.08.019
2. Matsangas P, McCauley ME. Sopite syndrome: a revised definition. Aviat Space Environ Med. 2014;85(6):672-673. doi:10.3357/asem.3891.2014
3. Van Ombergen A, Lawson BD, Wuyts FL. Motion sickness and sopite syndrome associated with parabolic flights: a case report. Int J Audiol. 2016;55(3):189–194. doi: 10.3109/14992027.2015.1111526
4. Leung AK, Hon KL. Motion sickness: an overview. Drugs Context. 2019;8:2019-9-4. Published 2019 Dec 13. doi:10.7573/dic.2019-9-4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048153
5. Golding JF. Motion sickness. Handb Clin Neurol. 2016;137:371–390. doi: 10.1016/B978-0-444-63437-5.00027-3
6. Turner M, Griffin MJ, Holland I. Airsickness and aircraft motion during short-haul flights. Aviat Space Environ Med. 2000 Dec;71(12):1181-9.
7. Zhang LL, Wang JQ, Qi RR, Pan LL, Li M, Cai YL. Motion Sickness: Current Knowledge and Recent Advance. CNS Neurosci Ther. 2016 Jan;22(1):15-24.
8. Koch A, Cascorbi I, Westhofen M, Dafotakis M, Klapa S, Kuhtz-Buschbeck JP. The Neurophysiology and Treatment of Motion Sickness. Dtsch Arztebl Int. 2018 Oct 12;115(41):687-696.
9. Golding JF. Motion sickness susceptibility. Auton Neurosci. 2006 Oct 30;129(1-2):67-76.
10. Lackner JR. Motion sickness: more than nausea and vomiting. Exp Brain Res. 2014 Aug;232(8):2493-510.
11. Takov V, Tadi P. Motion Sickness. [Updated 2020 Jul 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539706
12. Shupak A, Gordon CR. Motion sickness: advances in pathogenesis, prediction, prevention, and treatment. Aviat Space Environ Med. 2006 Dec;77(12):1213-23.
13. Lee SH, Jeong SH, Kim JS, Kim HJ, Choi KD, Choi JH, Oh SY, Park JY, Kim DU, Kim BK. Effect of Prophylactic Medication on Associated Dizziness and Motion Sickness in Migraine. Otol. Neurotol. 2018 Jan;39(1):e45-e51.
14. Murdin L, Golding J, Bronstein A. Managing motion sickness. BMJ. 2011;343:d7430. doi: 10.1136/bmj.d7430
15. Leung AK. Motion sickness. In: Leung AK, editor. Common Problems in Ambulatory Pediatrics: Symptoms and Signs. New York: Nova Science Publishers, Inc; 2011. pp. 323–328.
16. Ishak S, Bubka A, Bonato F. Visual occlusion decreases motion sickness in a flight simulator. Perception. 2018;47(5):521–530. doi: 10.1177/0301006618761336
17. Brainard A, Gresham C. Prevention and treatment of motion sickness. Am Fam Physician. 2014;90(1):41–46.
18. Keshavarz B, Stelzmann D, Paillard A, et al. Visually induced motion sickness can be alleviated by pleasant odors. Exp Brain Res. 2015;233(5):1353–1364. doi: 10.1007/s00221-015-4209-9
19. Stromberg SE, Russell ME, Carlson CR. Diaphragmatic breathing and its effectiveness for the management of motion sickness. Aerosp Med Hum Perform. 2015;86(5):452–457. doi: 10.3357/AMHP.4152.2015
20. Russell ME, Hoffman B, Stromberg S, et al. Use of controlled diaphragmatic breathing for the management of motion sickness in a virtual reality environment. Appl Psychophysiol Biofeedback. 2014;39(3–4):269–277. doi: 10.1007/s10484-014-9265-6
21. Koch A, Cascorbi I, Westhofen M, et al. The neurophysiology and treatment of motion sickness. Dtsch Arztebl Int. 2018;115(41):687–696. doi: 10.3238/arztebl.2018.0687
22. Yen Pik Sang FD, Billar JP, Golding JF, et al. Behavioral methods of alleviating motion sickness: effectiveness of controlled breathing and a music audiotape. J Travel Med. 2003;10(2):108–111. doi: 10.2310/7060.2003.31768
23. Lackner JR. Motion sickness: more than nausea and vomiting. Exp Brain Res. 2014;232(8):2493–2510. doi: 10.1007/s00221-014-4008-8
24. Schutz L, Zak D, Holmes JF. Pattern of passenger injury and illness on expedition cruise ships to Antarctica. J Travel Med. 2014;21(4):228–234. doi: 10.1111/jtm.12126
25. Schmäl F. Neuronal mechanisms and the treatment of motion sickness. Pharmacology. 2013;91(3–4):229–241. doi: 10.1159/000350185
26. Tal D, Hershkovitz D, Kaminski-Graif G, et al. Vestibular evoked myogenic potentials and habituation to seasickness. Clin Neurophysiol. 2013;124(12):2445–2449. doi: 10.1016/j.clinph.2013.05.016
27. Zhang LL, Wang JQ, Qi RR, et al. Motion sickness: current knowledge and recent advance. CNS Neurosci Ther. 2016;22(1):15–24. doi: 10.1111/cns.12468
28. Spinks A, Wasiak J. Scopolamine (hyoscine) for preventing and treating motion sickness. Cochrane Database Syst Rev. 2011;6:CD002851. doi: 10.1002/14651858.CD002851.pub4
29. Gil A, Nachum Z, Tal D, et al. A comparison of cinnarizine and transdermal scopolamine for the prevention of seasickness in naval crew: a double-blind, randomized, crossover study. Clin Neuropharmacol. 2012;35(1):37–39. doi: 10.1097/WNF.0b013e31823dc125
30. Nachum Z, Shahal B, Shupak A, et al. Scopolamine bioavailability in combined oral and transdermal delivery. J Pharmacol Exp Ther. 2001;296(1):121–123.
31. Klöcker N, Hanschke W, Toussaint S, et al. Scopolamine nasal spray in motion sickness: a randomised, controlled, and crossover study for the comparison of two scopolamine nasal sprays with oral dimenhydrinate and placebo. Eur J Pharm Sci. 2001;13(2):227–232.
32. Simmons RG, Phillips JB, Lojewski RA, et al. The efficacy of low-dose intranasal scopolamine for motion sickness. Aviat Space Environ Med. 2010;81(4):405–412.
33. Schmäl F. Neuronal mechanisms and the treatment of motion sickness. Pharmacology. 2013;91(3-4):229-41.
34. Cheung BS, Heskin R, Hofer KD. Failure of cetirizine and fexofenadine to prevent motion sickness. Ann Pharmacother. 2003 Feb;37(2):173-7.
35. Leung AK, Robson WL. Motion sickness. Ann R Coll Physician Surg Can. 1992;25(4):196–198.
36. Weinstein SE, Stern RM. Comparison of marezine and dramamine in preventing symptoms of motion sickness. Aviat Space Environ Med. 1997 Oct;68(10):890-4.
37. Cowings PS, Toscano WB, DeRoshia C, Miller NE. Promethazine as a motion sickness treatment: impact on human performance and mood states. Aviat Space Environ Med. 2000 Oct;71(10):1013-22.
38. Huang M, Gao JY, Zhai ZG, Liang QL, Wang YM, Bai YQ, Luo GA. An HPLC-ESI-MS method for simultaneous determination of fourteen metabolites of promethazine and caffeine and its application to pharmacokinetic study of the combination therapy against motion sickness. J Pharm Biomed Anal. 2012 Mar 25;62:119-28.
39. Weerts AP, Pattyn N, Van de Heyning PH, et al. Evaluation of the effects of anti-motion sickness drugs on subjective sleepiness and cognitive performance of healthy males. J Psychopharmacol. 2014;28(7):655–664. doi: 10.1177/0269881113516201
40. Buckey JC, Jr, Alvarenga DL, MacKenzie TA. Chlorpheniramine and ephedrine in combination for motion sickness. J Vestib Res. 2007;17(5–6):301–311.
41. Murray JB. Psychophysiological aspects of motion sickness. Percept Mot Skills. 1997;85(3 Pt 2):1163–1167. doi: 10.2466/pms.1997.85.3f.1163
42. Zhang LL, Liu HQ, Yu XH, et al. The combination of scopolamine and psychostimulants for the prevention of severe motion sickness. CNS Neurosci Ther. 2016;22(8):715–722. doi: 10.1111/cns.12566
43. Fydanaki O, Kousoulis P, Dardiotis E, et al. Electroacupuncture could reduce motion sickness susceptibility in healthy male adults: a double-blinded study. Med Acupunct. 2017;29(6):377–382. doi: 10.1089/acu.2017.1246
44. Tian D, Mo F, Cai X, et al. Acupuncture relieves motion sickness via the IRβ-ERK1/2-dependent insulin receptor signalling pathway. Acupunct Med. 2018;36(3):153–161. doi: 10.1136/acupmed-2016-011202
45. Miller KE, Muth ER. Efficacy of acupressure and acustimulation bands for the prevention of motion sickness. Aviat Space Environ Med. 2004;75(3):227–234.
46. Mowrey DB, Clayson DE. Motion sickness, ginger, and psychophysics. Lancet. 1982;1(8273):655–657. doi: 10.1016/s0140-6736(82)92205-x
47. Abdel-Aziz H, Windeck T, Ploch M, et al. Mode of action of gingerols and shogaols on 5-HT3 receptors: binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum. Eur J Pharmacol. 2006;530(1–2):136–143.
48. Grøntved A, Brask T, Kambskard J, et al. Ginger root against seasickness. A controlled trial on the open sea. Acta Otolaryngol. 1988;105(1–2):45–49. doi: 10.3109/00016488809119444
49. Jarisch R, Weyer D, Ehlert E, et al. Impact of oral vitamin C on histamine levels and seasickness. J Vestib Res. 2014;24(4):281–288. doi: 10.3233/VES-140509