Anti-motion Sickness Drugs Research Articles

Galvanic vestibular stimulation as a novel treatment for seasickness

Motion sickness is the cause of major physical discomfort and impaired performance in many susceptible individuals. Some habituate to sea conditions, whereas others remain chronically susceptible, requiring lifelong pharmaceutical treatment. The present study sets out to investigate whether galvanic vestibular stimulation (GVS) coupled with rotatory chair stimulation could mimic sea conditions and alleviate motion sickness symptoms in individuals deemed chronically susceptible. Thirty seasickness susceptible subjects, after at least six months of regular sailing, were enrolled in a prospective, single-blind, randomised controlled study. The treatment group underwent GVS coupled with inverse phase rotatory chair impulse in sinusoidal harmonic acceleration protocol. The control group underwent a sham procedure. All subjects performed repeated velocity step tests to determine the vestibular time constant (Tc) and completed a seasickness questionnaire. The GVS rotatory chair procedure decreased the prevalence of severe seasickness. The number of motion sickness clinic visits and anti-motion sickness drug consumption were reduced in the treatment group three-month post intervention as compared to control. In addition, there was significant reduction of Tc in the treatment group. GVS coupled with rotatory chair impulse could decrease motion sickness severity, induce neurophysiological learning processes and promote habituation to seasickness in chronic susceptible subjects. This is a novel and promising non-pharmacological method to treat motion sickness susceptible individuals. Furthermore, the investigation demonstrated that adaptation to sea conditions may take place even after years of susceptibility to seasickness. This study was retrospectively registered on August 10th 2021 and assigned the identifier number NCT05004818.

Phencynonate S-isomer as a eutomer is a novel central anticholinergic drug for anti-motion sickness

To compare and evaluate the differences of stereoselective activity, the binding affinity, metabolism, transport and molecular docking of phencynonate isomers to muscarinic acetylcholine receptor (mAChR) were investigated in this study. The rotation stimulation and locomotor experiments were used to evaluate anti-motion sickness effects. The competitive affinity with [3H]-QNB and molecular docking were used for studying the interactions between the two isomers and mAChR. The stereoselective mechanism of isomers was investigated by incubation with rat liver microsomes, a protein binding assay and membrane permeability assay across a Caco-2 cell monolayer using a chiral column HPLC method. The results indicated that S-isomer was more effective against motion sickness and had not anxiogenic action at therapeutic doses. S-isomer has the higher affinity and activity for mAChR in cerebral cortex and acted as a competitive mAChR antagonist. The stereoselective elimination of S-isomer was primarily affected by CYP1B1 and 17A1 enzymes, resulting in a higher metabolic stability and slower elimination. Phencynonate S isomer, as a eutomer and central anticholinergic chiral drug, is a novel anti-motion sickness drug with higher efficacy and lower central side effect. Our data assisted the development of a novel drug and eventual use of S-isomer in clinical practice.

The Impact of Oral Promethazine on Human Whole-Body Motion Perceptual Thresholds.

Despite the widespread treatment of motion sickness symptoms using drugs and the involvement of the vestibular system in motion sickness, little is known about the effects of anti-motion sickness drugs on vestibular perception. In particular, the impact of oral promethazine, widely used for treating motion sickness, on vestibular perceptual thresholds has not previously been quantified. We examined whether promethazine (25mg) alters vestibular perceptual thresholds in a counterbalanced, double-blind, within-subject study. Thresholds were determined using a direction recognition task (left vs. right) for whole-body yaw rotation, y-translation (interaural), and roll tilt passive, self-motions. Roll tilt thresholds were 31% higher after ingestion of promethazine (P=0.005). There were no statistically significant changes in yaw rotation and y-translation thresholds. This worsening of precision could have functional implications, e.g., during driving, bicycling, and piloting tasks. Differing results from some past studies of promethazine on the vestibulo-ocular reflex emphasize the need to study motion perception in addition to motor responses.

Vestibular evoked myogenic potentials and motion sickness medications.

Seasickness is a widespread problem among naval crew, and has a major impact on their performance at sea. The three pharmacological agents most commonly employed in the treatment of seasickness are dimenhydrinate, cinnarizine, and scopolamine. At present, the effectiveness of anti-seasickness drugs is tested by a process of "trial and error", while sailing and exposed to sea conditions. A physiological test to evaluate the action of a drug might save crew members long periods of suffering, as well as simplifying the procedure of selecting the appropriate treatment for each individual. The cervical vestibular evoked myogenic potentials (cVEMP) test has come to be recognized as a reliable procedure for the objective evaluation of saccular function. It was the hypothesis of the present study that cVEMP otolith responses may be affected by anti-motion sickness drugs, which might thus make cVEMP a useful clinical neurophysiological tool for the assessment of drug absorption and efficacy. Thirty male sailors who regularly took medication for the treatment of seasickness participated in the study. Participants underwent the cVEMP test pre- and 1h post-drug administration. A statistically significant decrease in p13 latency was found after administration of scopolamine compared with baseline (14.46ms vs. 15.09ms, p=0.0049), with significant prolongation of the binaural average inter-latency in this group. No differences were found in the dimenhydrinate and cinnarizine study groups. This study demonstrated that scopolamine absorption can be verified by changes in cVEMP latencies. The potential of the cVEMP test for predicting action of scopolamine on the vestibular system.

Hydroxy propyl β-cyclodextrin complexation of promethazine hydrochloride for the formulation of fast dissolving sublingual film: in vitro and in vivo evaluation

Promethazine hydrochloride (PMZ-HCl) is a classical anti-motion sickness drug which has oral bioavailability (25 %) due to extensive hepatic first pass metabolism. To overcome this drawback, novel, fast dissolving sublingual film (FDSF) of drug was developed. FDSF was formulated using pullulan and propylene glycol (PG) by solvent casting method. Complete taste masking was successfully obtained with HP β-CD, aspartame and grape fruit flavour. Complex of drug was proved using Fourier transfer infrared spectroscopy, differential scanning calorimetry and X-ray diffraction studies. Optimization of concentration of pullulan and PG was done using 32 full factorial design. Batches were evaluated for the parameters like elongation, tensile strength, folding endurance and in vitro disintegration studies. In vitro dissolution indicated 100 % drug release within 7.5 min. Environmental scanning electron microscopy studies also showed uniform drug distribution and integrity of film. In vivo sublingual absorption in human indicated that 70 % of drug absorbed in 10 min. The stability studies indicated that label should state “Store at cool, dry place” at temperature 25 °C. So by formulating the taste masked FDSF of PMZ-HCl will give faster onset of action and avoid unnecessary drug intake leading to traveller friendly formulation.

Motion sickness: more than nausea and vomiting.

Motion sickness is a complex syndrome that includes many features besides nausea and vomiting. This review describes some of these factors and points out that under normal circumstances, many cases of motion sickness go unrecognized. Motion sickness can occur during exposure to physical motion, visual motion, and virtual motion, and only those without a functioning vestibular system are fully immune. The range of vulnerability in the normal population varies about 10,000 to 1. Sleep deprivation can also enhance susceptibility. Systematic studies conducted in parabolic flight have identified velocity storage of semicircular canal signals—velocity integration—as being a key factor in both space motion sickness and terrestrial motion sickness. Adaptation procedures that have been developed to increase resistance to motion sickness reduce this time constant. A fully adequate theory of motion sickness is not presently available. Limitations of two popular theories, the evolutionary and the ecological, are described. A sensory conflict theory can explain many but not all aspects of motion sickness elicitation. However, extending the theory to include conflicts related to visceral afferent feedback elicited by voluntary and passive body motion greatly expands its explanatory range. Future goals should include determining why some conflicts are provocative and others are not but instead lead to perceptual reinterpretations of ongoing body motion. The contribution of visceral afferents in relation to vestibular and cerebellar signals in evoking sickness also deserves further exploration. Substantial progress is being made in identifying the physiological mechanisms underlying the evocation of nausea, vomiting, and anxiety, and a comprehensive understanding of motion sickness may soon be attainable. Adequate anti-motion sickness drugs without adverse side effects are not yet available.

Evaluation of the effects of anti-motion sickness drugs on subjective sleepiness and cognitive performance of healthy males

This study aimed to investigate the clinical and cognitive side effects of baclofen (10 mg), meclizine (25 mg), dimenhydrinate (40 mg) plus cinnarizine (25 mg) and promethazine (25 mg) plus d-amphetamine (10 mg). The study had a double-blind, placebo controlled, repeated measures design and was conducted on healthy male volunteers. The psychomotor vigilance test, the Sternberg working memory task, the implicit memory test and the automated Operation Span (Ospan) task were performed. The Stanford, the Karolinska and the Epworth Sleepiness scale determined the degree of sleepiness. The Profile of Mood States (POMS) evaluated mood states and adverse effects were reported on a 22-item questionnaire. Letter recalls and time for solving mathematical problems, recorded during the Ospan task, were impaired by baclofen and dimenhydrinate-cinnarizine respectively, suggesting an influence of these drugs on the working memory. Significant side effects for baclofen were: sleepiness, tiredness, blurred vision, concentration problems and dizziness whereas for dimenhydrinate-cinnarizine only sleepiness and blurred vision were reported. Meclizine decreased the accuracy on the Sternberg working memory task and thus seemed to affect short-term memory. A reported side effect was increased sleepiness. Promethazine plus d-amphetamine did not affect any of the tested cognitive functions. However, many side effects such as sleepiness, dry mouth, dizziness, vertigo, confusion, insomnia and tremors were reported. The results show that meclizine and dimenhydrinate combined with cinnarizine were the two drugs with the most acceptable combination of side effects.

Effect of daily linear acceleration training on the hypergravity-induced vomiting response in house musk shrew (Suncus murinus)

The effects of repeated linear acceleration training and the antimotion sickness drug, promethazine, on hypergravity-induced motion sickness were examined in musk shrew (Suncus murinus), which is known to show a vomiting response to motion stimulation. Animals were assigned into five groups: vestibular intact, untreated animals (Sham), vestibular lesioned (VL) animals, vestibular intact animals with promethazine hydrochloride administered as daily drinking water (Prom), vestibular intact animals who underwent horizontal linear accelerator motion training (Train), and vestibular intact animals treated with both promethazine hydrochloride and linear acceleration training (Prom+Train). In Sham animals, the number of vomiting episodes was 14±2 during 2 G exposure for 10min, and was accompanied by intense Fos expression in the medial vestibular nucleus (MVe), the nucleus of the solitary tract (NTS), the area postrema (AP), and the paraventricular hypothalamic nucleus (PVN). The vomiting response and Fos expression were completely abolished in VL animals, indicating that these responses are mediated via the vestibular system. Although Train and Prom animals experienced a significantly reduced number of hypergravity-induced vomiting episodes compared with Sham animals, the effect was significantly greater in Train animals than in Prom animals. Fos expression in the NTS, AP, and PVN were significantly more reduced in Train animals than in Prom animals. Higher dose of bolus injection of promethazine (50mg/kg, i.p.) completely abolished the vomiting episodes, although the animals were drowsy and sedated due to side effects. In conclusion, daily linear acceleration training and promethazine could prevent the hypergravity-induced vomiting episodes.

Various Anti-Motion Sickness Drugs and Core Body Temperature Changes

Blood flow changes and inactivity associated with motion sickness appear to exacerbate the rate of core temperature decrease during subsequent body cooling. We investigated the effects of various classes of anti-motion sickness drugs on core temperature changes. There were 12 healthy male and female subjects (20-35 yr old) who were given selected classes of anti-motion sickness drugs prior to vestibular Coriolis cross coupling induced by graded yaw rotation and periodic pitch-forward head movements in the sagittal plane. All subjects were then immersed in water at 18 degrees C for a maximum of 90 min or until their core temperature reached 35 degrees C. Double-blind randomized trials were administered, including a placebo, a non-immersion control with no drug, and six anti-motion sickness drugs: meclizine, dimenhydrinate, chlorpheniramine, promethazine + dexamphetamine, promethazine + caffeine, and scopolamine + dexamphetamine. A 7-d washout period was observed between trials. Core temperature and the severity of sickness were monitored throughout each trial. A repeated measures design was performed on the severity of sickness and core temperature changes prior to motion provocation, immediately after the motion sickness end point, and throughout the period of cold-water immersion. The most effective anti-motion sickness drugs, promethazine + dexamphetamine (with a sickness score/duration of 0.65 +/- 0.17) and scopolamine + dexamphetamine (with a sickness score/duration of 0.79 +/- 0.17), significantly attenuated the decrease in core temperature. The effect of this attenuation was lower in less effective drugs. Our results suggest that the two most effective anti-motion sickness drugs are also the most effective in attenuating the rate of core temperature decrease.

The effect of smoking nicotine tobacco versus smoking deprivation on motion sickness

BackgroundThe experienced smoker maintains adequate nicotine levels by ‘puff-by-puff self-control’ which also avoids symptomatic nauseating effects of nicotine overdose. It is postulated that there is a varying ‘dynamic threshold for nausea’ into which motion sickness susceptibility provides an objective toxin-free probe. Hypotheses were that: (i) nicotine promotes motion sickness whereas deprivation protects; and (ii) pleasurable effects of nicotine protect against motion sickness whereas adverse effects of withdrawal have the opposite effect. MethodsTwenty-six healthy habitual cigarette smokers (mean±SD) 15.3±7.6cigs/day, were exposed to a provocative cross-coupled (coriolis) motion on a turntable, with sequences of 8 head movements every 30s. This continued to the point of moderate nausea. Subjects were tested after either ad-lib normal smoking (SMOKE) or after overnight deprivation (DEPRIV), according to a repeated measures design counter-balanced for order with 1-week interval between tests. ResultsDeprivation from recent smoking was confirmed by objective measures: exhaled carbon monoxide CO was lower (P<0.001) for DEPRIV (8.5±5.6ppm) versus SMOKE (16.0±6.3ppm); resting heart rate was lower (P<0.001) for DEPRIV (67.9±8.4bpm) versus SMOKE (74.3±9.5bpm). Mean±SD sequences of head movements tolerated to achieve moderate nausea were more (P=0.014) for DEPRIV (21.3±9.9) versus SMOKE (18.3±8.5). DiscussionTolerance to motion sickness was aided by short-term smoking deprivation, supporting Hypothesis (i) but not Hypothesis (ii). The effect was was approximately equivalent to half of the effect of an anti-motion sickness drug. Temporary nicotine withdrawal peri-operatively may explain why smokers have reduced risk for postoperative nausea and vomiting (PONV).

Screen of seasickness behavior indices of simulated seasickness in rats and observation of adaptability rules

Objective:To screen for seasickness behavior parameters in rats with simulated seasickness,so as to investigate the rule of seasickness adaptation in rats.Methods:SD rats were stimulated daily by Crampton model.Urine volume (UV) and amount of fecal particle (FP) were observed during stimulation,and the spontaneous activity (SA) was also determined immediately after stimulation.Interventional experiments were performed using anti-motion sickness drugs to examine the specificity of the indices.Results:On the first day of stimulation,the FP of stimulating group increased significantly compared with the normal control group (P0.05),while SA decreased significantly (P0.01).FP and SA of stimulating group gradually recovered with the increase of stimulation period; there was a significant correlation between FP,SA with stimulation times (P0.01).FP and SA recovered to the normal levels on the 9th,7th day,respectively.The experimental group received gastric perfusion of scopolamine(0.5,1 mg/kg)and was then subjected to rotation stimulation.The indices had no significant difference between the experimental group and the normal control group.Conclusion:It is indicated that FP during stimulation and SA after stimulation can be used for effective judgment of seasickness in rats.The rats become adapted to seasickness after 9 days' continuous stimulation.

Motion sickness susceptibility

Motion sickness can be caused by a variety of motion environments (e.g., cars, boats, planes, tilting trains, funfair rides, space, virtual reality) and given a sufficiently provocative motion stimulus almost anyone with a functioning vestibular system can be made motion sick. Current hypotheses of the ‘ Why?’ of motion sickness are still under investigation, the two most important being ‘toxin detector’ and the ‘vestibular–cardiovascular reflex’. By contrast, the ‘ How?’ of motion sickness is better understood in terms of mechanisms (e.g., ‘sensory conflict’ or similar) and stimulus properties (e.g., acceleration, frequency, duration, visual–vestibular time-lag). Factors governing motion sickness susceptibility may be divided broadly into two groups: (i) those related to the stimulus (motion type and provocative property of stimulus); and (ii) those related to the individual person (habituation or sensitisation, individual differences, protective behaviours, administration of anti-motion sickness drugs). The aim of this paper is to review some of the more important factors governing motion sickness susceptibility, with an emphasis on the personal rather than physical stimulus factors.

Behavioral Methods of Alleviating Motion Sickness: Effectiveness of Controlled Breathing and a Music Audiotape

Behavioral countermeasures for motion sickness would be advantageous because of the side effects of antiemetic drugs, but few alternative treatments are available. The objective of this study was to compare the effectiveness of controlling breathing and listening to a music audiotape designed to reduce motion sickness symptoms, on increasing tolerance to motion-induced nausea. Twenty-four healthy subjects were exposed to nauseogenic Coriolis stimulation on a rotating turntable under three conditions: whilst focusing on controlling breathing; listening to a music audiotape; or without intervention (control). The three conditions were performed by each subject according to a replicated factorial design at 1-week intervals at the same time of day. Ratings of motion sickness were obtained every 30 seconds. Once a level of mild nausea was reached subjects commenced controlling breathing or listened to the music audiotape. Motion was stopped after the onset of moderate nausea. Mean (+/- SD) motion exposure time in minutes tolerated before the onset of moderate nausea was significantly longer (p <.01) for controlling breathing (10.7 +/- 5.6 min) and longer (p <.01) for music (10.4 +/- 5.6 min) compared with control (9.2 +/- 5.9 min). Both controlling breathing and the music audiotape provided significant protection against motion sickness and with similar effectiveness. These nonpharmacologic countermeasures are only half as effective as standard doses of anti-motion sickness drugs, such as oral scopolamine; however, they are easy to implement and free of side effects.

Plasma Vasopressin, an Etiologic Factor of Motion Sickness in Rat and Human?

Arginine vasopressin (AVP) is considered as an etiologic hormone in motion sickness. However, the possible role of plasma AVP in motion sickness is still controversial. A number of studies have found a gender difference in susceptibility to motion sickness in humans and experimental animals, with female subjects being more susceptible. However, the existence of a gender difference in the AVP response to motion sickness is not known. This study was designed to verify the assumption that plasma vasopressin plays a role in motion sickness.Changes in plasma vasopressin were observed after motion sickness-inducing rotatory stimuli in both sexes in human subjects and rats receiving or not antimotion sickness treatments. Plasma vasopressin levels in motion sickness rats exhibited a decrease after rotation in female, but not in male rats. The vasopressin content of the pituitary increased in both sexes. Plasma vasopressin in rats of both sexes tended to increase after a 15-day adaptive training of rotation, but pituitary vasopressin content was not affected under this condition. In contrast, in human subjects, plasma vasopressin levels increased after rotation in all males, but not in females. When antimotion sickness drugs (domperidone 10 mg + flunarizine 5 mg) were administered, plasma vasopressin levels were elevated in both females and males. It is concluded that plasma vasopressin increases after motion sickness-induced stimulation provided subjects have become trained to motion sickness. These results do not support an etiologic role of plasma vasopressin in the genesis of motion sickness.

Motion sickness in public road transport: passenger behaviour and susceptibility

The aim of this research was to identify personal and environmental factors influencing individual susceptibility to motion sickness during road transport. A questionnaire survey of 3256 coach travellers was conducted. Information on passenger characteristics, travel regularity, activity during travel, use of antimotion sickness drugs and self-reported motion sickness susceptibility were collected over 56 private hire coach journeys. Details of the travel environment (visibility, temperature and seating) were also recorded. The relationship of these variables with passenger illness and more specific symptoms of motion sickness are examined. Overall, 28.4% of passengers reported feeling ill, 12.8% reported nausea and 1.7% reported vomiting during coach travel. Travel sickness decreased with increasing passenger age and greater travel experience. Females were more likely to report feeling ill during coach travel than males by a ratio of four to three. Poor forward visibility was found to increase sickness. Passenger illness occurrence was approximately three times higher for passengers with no view of the road ahead (mean, 34.6%) compared to passengers who could see the road ahead extremely well (mean, 12.7%). No relationships were found between the occurrence of travel sickness and temperature or time of travel. Differences in the pattern of sickness responses exhibited by coach travellers suggest: (1) habituation through greater travel regularity may occur independently of reductions in travel sickness that occur with age; (2) females are more affected by poor forward visibility than males; and (3) the incidence of travel sickness could be significantly reduced by improving the external visibility afforded to passengers.

Perspectives of electrogastrography and motion sickness

Electrogastrography (EGG) is a noninvasive measurement of stomach activity using surface electrodes positioned over the abdominal surface. For over 10 years, EGG has been used as an objective measure of epigastric symptoms and nausea experienced in visually induced sickness provoked by circularvection. It was reported that during sickness, there is a shift in the dominant basal electrical activity. The 3 cycles per minute activity decrease and the 4–9 cycles per minute activity increase. This technique has also been used to evaluate the efficacy of antimotion sickness drugs and to monitor sickness induced by other provocative stimuli such as Coriolis cross-coupling, parabolic flight manoeuvres and microgravity. It has been further postulated that peripheral changes in gastric myoelectrical activity in response to visually induced sickness are detected centrally and lead to the generation of motion sickness. However, other studies using either identical or equally effective motion stimuli failed to support the positive correlation of changes in gastric activity with the incidence and severity of motion sickness. The interpretation of spectral analysis on EGG during motion sickness must be taken with great caution. The inherent variability of the EGG and intersubject variability makes it difficult to consider EGG a reliable and robust indicator of motion sickness. Its relation to motion sickness and the underlying mechanism remains unclear. The true diagnostic value of EGG in motion sickness has yet to be determined. Crown Copyright © 1999. Published by Elsevier Science Inc.

Prophylactic effect of serotonin uptake inhibitors against motion sickness in Suncus murinus

The prophylactic effect of serotonin uptake inhibitors, imipramine and fluoxetine, against motion sickness was investigated in Suncus murinus. Imipramine (s.c.) and fluoxetine (i.p.) inhibited motion-induced emesis dose dependently with ID 50 values of 1.7 and 26 mg/kg, respectively. The results suggest that increasing the concentration of serotonin in the synaptic cleft can prevent motion-induced emesis and that serotonin uptake inhibitors are effective as anti-motion sickness drugs.

Effects of erythromycin on gastric emptying during motion sickness and after antimotion sickness drugs.

Clinical Pharmacology & Therapeutics (1996) 59, 195–195; doi: 10.1038/sj.clpt.1996.279

Pharmaceutical properties of freeze-dried formulations of egg albumin, several drugs and olive oil.

The freeze-dried ternary formulations of meclizine (MZ, an anti-motion sickness drug), prednisolone (PRED, an anti-inflammatory drug) and norfloxacin (NFLX, an anti-microbial drug) which are poorly water-soluble and are low bioavailability drugs, were prepared using egg albumin and olive oil. The powder X-ray diffractions, the dissolution rate and the bioavailabilities in vivo of these formulations were studied in comparison with each drug alone. By forming ternary formulations of these drugs, the dissolution rates of the drugs from the formulations were significantly improved compared with each drug alone. The results of their powder X-ray diffraction measurements showed that these drugs in the ternary formulations presented in an amorphous form, indicating increased dissolution rates. On the other hand, the plasma concentrations of these drugs increased significantly after oral administration in formulations to rats, except for the NFLX formulation, and the areas under the concentration-time curves (AUC) of the ternary formulations of MZ, PRED and NFLX were 2.1, 1.6 and 1.3 times those of the drugs alone, respectively. From these results, it was proven that formulations consisting of egg albumin, olive oil and poorly water-soluble drugs were useful preparations for improving the drug's disadvantageous pharmaceutical properties.

An investigation into nausea and other side-effects of head-coupled immersive virtual reality

This paper is written from a human factors perspective and discusses research into some of the side-effects of head-coupled immersive virtual reality. The paper provides a broad overview of the history of virtual reality and highlights some of the important current human factors issues. Reasons why side-effects of virtual reality technology may be expected are then discussed with particular reference to the literature on motion sickness and simulator sickness. A study is described which set out to document the frequency of occurrence and severity of side-effects of immersion in virtual reality. One hundred and fifty subjects took part in this study and were immersed in a virtual environment for 20 minutes. Sixty-one percent of the subjects were documented as reporting symptoms at some point during the 20 minute immersion period and a 10 minute post-immersion period. Five percent of the subjects had to withdraw from the study due to the severity of their symptoms. This finding led to further research that attempted to reduce the side-effects observed. Studies investigating the use of adaptation and the anti-motion sickness drug hyoscine hydrobromide are described. Both of these methods of reducing the side-effects of virtual reality proved successful with the hyoscine proving to be a very rapid method of symptom reduction.