1. https://www.dizziness-and-balance.com/disorders/central/motion.

htm

Motion Sickness
Timothy C. Hain, MD Chicago Dizziness and Hearing. Page last
modified: June 22, 2017

Motion sickness is the nausea, disorientation and fatigue that can be induced by
head motion. The first sign is usually pallor (a pale appearance). Yawning,
restlessness and a cold sweat forming on the upper lip or forehead often follow.
As symptoms build, an upset stomach, fatigue or drowsiness may occur. The
final stages are characterized by nausea and vomiting.

Motion sickness is a general term. It can be subdivided into sickness due to

visual stimulation, due to vestibular stimulation, and occasionally, forms occur
associated with somatosensory stimulation (e.g. treadmill sickness), or head-on-
neck motion (e.g. cervical vertigo). By far the most common subgroup are pure
visual sensitivity -- usually called "visual dependence". In visual dependence,
people become sick due to visual motion (such as going to a movie).
History of motion sickness.

Motion sickness has been around as long as there has been people and motion. It
was well known to the Greeks and Romans(Huppert et al, 2016). Around 300
AD the Chinese described "Cart-influence" and "Ship-influence" (Brandt et al,
2016). Admiral Nelson, the British naval hero who first went to sea at the age of
12, was a chronic sufferer.
Who gets motion sickness ?

Motion sickness is common and normal. Nearly anyone can be made motion
sick by an appropriate stimulus, except for individuals with no vestibular system
(William James). According to Benson, nearly 100% of (human) occupants of
life rafts will vomit in rough seas. 60% of student aircrew members suffer from
air sickness at some time during their training. For vertical motion (heave),
oscillation at a frequency of about 0.2 hz is the most provocative. Motion at 1
Hz is less than 1/10th as provocative. About 7% of seagoing passengers report
vomiting during a journey (Lawther and Griffin, 1988). In a large study done in
India, the prevalence of motion sickness was about 28%, and females were more
susceptible (27%) were more susceptible than males (16.8%). However this
statistic is obviously dependent on how you define motion-sickness as nearly
anyone can be made sick by motion, if it is vigorous enough. Individuals with
more active occupations are less susceptible (Sharma, 1997). In medical
transport personnel, 46% of personnel reported nausea and 65%, the Sopite
syndrome (sleepiness caused by motion). (Wright, 1995)

Horses, cows, monkeys, chimpanzees, birds and sheep have been reported in
scientific publications to show motion sickness. Rats, unfortunately I suppose,
do not vomit so cannot serve as experimental subjects.

Women are more sensitive to motion than men, by a ratio of about 5:3, although
this may be related to reporting differences rather than true physiological
differences( Cheung, B. and K. Hofer , 2002). Women are more sensitive to
motion around the times of their menstrual cycle (Glunfeld and Gresty, 1996).
This may be due to interactions between migraine and motion sickness.

Children are said to be almost immune to motion sickness up to the age of 2. As

children grow older, the severity of motion sickness increases up to roughly the
age of 15 (Takahasi et al, 1994). In our dizziness practice, we have noticed
women of childbearing age become more prone to motion sickness as their
migraine tendency increases. There are two spikes of migraine in women of
childbearing age -- one at 35, and another around menopause.

Recently, a genetic study of motion sickness was published in an "open access"

type journal (Hromatka, 2015). They looked at 80,494 samples from a
commercial personal genetics company, 23andme. They reported that there are
35 loci in their human genome sample, largely European ancestry, were
associated with a greater propensity to develop motion sickness. Many of these
locations were near genes involved in balance, eye, ear, and brain development.
There was also an association between migraine, post operative nausea and
vomiting (PONV), vertigo, and motion sickness. Both migraine and PONV
shared genetic associations with motion sickness. One might think that a
"fishing expedition" study like this, lacking any a-priori assumptions, could
produce results due to chance alone. We hope that other similar studies emerge
that can be compared with this one.
There are certain illness that eliminate motion sickness. These include bilateral
loss of inner ear function (e.g. William James, the American Pragmatist
philospher), and lesions of the cerebellar nodulus (Bard). As these illnesses are
even worse than motion sickness, and there has been no attempt to use this
observation clinically.

What Causes Motion Sickness ?

In order for the body to determine where it is at all times, the brain combines
visual information, touch information, inner ear information, and internal
expectations. Under most circumstances, the senses and expectations agree.
When they disagree, there is conflict, and motion sickness can occur.

For example, consider the situation when one is reading in the back seat of a
car. Your eyes, fixed on the page, say that you are still. However, as the car
goes over bumps and accelerates/decelerates, your ears disagree. This is why
motion sickness in this situation is common. The driver has an advantage, as
they have a better internal model of motion, and as well, their eyes are generally
fixed on the outside world.

Another situation where motion sickness is common is in outer space. There,

the otoliths no longer register the effect of gravity (which is no longer there),
but continue to signal linear acceleration. It is presently thought that the very
common space motion sickness is due to a loss of the usual otolith signal
associated with head movement away from the gravitational axis. When the
head is pitched, the brain misses the otolithic signal saying that pitch has
occured, but continues to receive the canal signal. A partial vestibular loss (for a
subset of otolithic input) is associated with strong motion sickness.

Acquired susceptibility to motion sickness is rare.

 People with migraine are apt to get motion sick. As migraine peaks in women
at the age of 35 and 50, these are times where motion sickness may be
acquired in adults.
 Persons with rare, central nervous system disorders of the part of the brain that
processes signals from the inner ear may also be unusually susceptible to
motion sickness. Generally speaking, these are lesions of the cerebellum roof
nuclei.
 Persons with inner ear disturbance, especially a recent one, may be intolerant to
activity in general.
  Certain individuals who are constitutionally susceptible to motion sickness,
mainly women in mid-life, can develop sea sickness on ships, and a prolonged
land sickness, when they get off the ship. This rare disorder is called "mal de
debarquement", which is French for "bad getting off the ship". Persons with
unusually good vestibular function may be more susceptible to motion sickness
than others (Gordon et al, 1996).
 Persons who have changes in their visual function - -new glasses, laser eye
surgery, progressive lenses, bifocals or trifocals, progressive contacts,
mismatches between the size of images in one or the other ear, ocular
misalignment, may develop more sensitivity to visual stimuli. Persons who are
exposed to unusual visual environments, such as traders with 9 different
monitors, or air traffic controllers, may develop symptoms related to extreme
amounts of visual stimulation.

Migraine is a definite risk factor for motion sickness, with roughly a 5 fold
greater incidence than non-migraineurs, and a roughly 50% prevalence (Marcus
et al, 2005). See table below. Female gender and youth is also a risk factor. In
women, days 9-15 of the menstrual cycle appear to have a higher incidence of
nausea (Grunfeld and Gresty, 1999; Ramsay, 1994) but not all agree (Cheung,
B., R. Heskin, et al. 2001). Medications that prevent migraine may also prevent
motion sickness (see below).

Table: Patients with Migraine having Motion Sickness

Percent of migraine patients with motion Comment Authors

sickness

49% Children Bille (1962)

45% Children (60) Barabas et al (1983)

50.7% Unselected Kayan and Hood (1984)

50% Marcus et al, 2005

The space-military industrial complex has developed a theory of motion

sickness that depends on asymmetry in otoconial mass (Scherer et al, 1997).
Perhaps this mechanism is applicable in outer space, but it seems to us to have
very little relevance to "down to earth". The more logical military explanation
is the previously mentioned mechanism where the otoliths no longer provide
gravity information.

Motion sickness is sometimes associated with prolonged vestibular responses

(Hoffer et al. 2003), implying that these individuals simply appreciate motion
more than others. On the other hand, motion sickness immunity is generally
found in persons with absent vestibular responses (William James; Cheung et al.
1991). There is also less motion sickness in patients with vestibular loss
(Paillard et al, 2013).

Age is probably not a large factor in motion sickness (Cheung and Money,
1992) although children below the age of 2 are said to be immune. They happily
vomit. In our medical practice, the only substantial age effect seems to be in
women who are experiencing migraines.
Testing for motion sickness

One way of testing for motion sickness is to ask people to fill out a
questionnaire. There are many of these. Somewhat of an industry standard is the
"MSSQ", or motion sickness susceptibility questionaire originally developed by
Reason and Brand, and later shortened by Golding (1998, 2006) to become the
"MSSQ-S" (for short). The "simulator sickness questionare" can be used to
quantify how dizzy people get after motion. (Kennedy et al, 1992).

Another way to test for motion sickness is to move the subject being
investigated about in a stimulating way and find out how long it takes for them
to become sick. Certain activities, such as moving the head up and down while
rotating, or "pitch while rotating", are very stimulating, and one can use the
latency to vomit as a measure of motion sickness susceptibilty. As an example,
Calkins et al (1987) reported on the "Coriolis sickness sensitivity index", the
"staircase velocity movement test", and the "parabolic flight static chair test".

A third, very indirect, way is to determine how strong vestibular responses are,
and to make the inference that people with no sensation will have no motion
sickness. This idea probably originally derived from the observations of the
pragmatist philosopher, William James, who was also interested in deafness,
that persons without a vestibular system generally do not become motion sick.
For example, Fowler et al (2014) reported that VEMPs were higher in young
adults with motion sickness. Dai et al (2003) reported that aVOR time constants
are inversely related to motion sickness. We have just not noticed this ourselves
in our dizzy population.

By way of a summary, we don't think that in general the method of assaying for
motion sickness is a sensitive method of assaying for motion sickness
susceptibilty. We think that practically, it is best to use some sort of
standardized motion input and some sort of standardized output that correlates
with nausea -- method 2.
Treatment of Motion sickness:

There are three strategies to treat motion sickness:

 Behavioral (avoidance, mental activities)

 Medication (conventional, alternative)
 Exercise (habituation)

When all three strategies are used, it is extremely uncommon to find a person
who does not get substantially better.

There are also some unproven procedures that we will discuss under the
"experimental" heading.

Behavioral Strategies for Motion Sickness

 In the car: sit in the front seat or drive.

 Aboard a ship: stay toward the middle and look at the horizon. Avoid ship
travel if possible. Stay out of small tight places where you can't see the horizon.
 On the airplane: ask for a window seat. The front of the plane may be
preferable, as it is usually less noisy. Some people find that sitting in the middle
 is the best location as it provides one with a better appreciation of the aircraft's
tilt. Don't sit near the bulkhead as this gives you no visual help to figure out
how much you are really tilted.
 For cars: It may be helpful to mentally rehearse a trip route as familiarity and
anticipation is sometimes helpful.
 Face leeward (so if you vomit, it gets blown away from the ship, not into it).
 Eat bland foods -- crackers and bread, or bananas, rice, applesauce and toast.

One can often avoid motion sickness by anticipating the motion. Drivers have
much less motion sickness than passengers, because they are controlling the
motion, and know when they are turning, starting and stopping. Drivers on
familiar routes are less prone to getting motion sick than drivers in new
territory.

Medication for Motion Sickness

From a systems perspective, medication might change vestibular

input (ordinarily always reduce), or reduce the consequences of
motion stimulation. In other words, they might suppress input,
or suppress central reactions to the input.

Most medications for motion sickness need to be taken at least 30 minutes

before exposure to the activity that can cause the problem. Persons with
glaucoma or prostate problems should not take most of these medications unless
so advised by their doctor.

We so far have rarely encountered an individual who could not avoid motion
sickness by pretreating with klonopin and ondansetron. That being said, here are
more details.

 Antihistamines
o Meclizine (Antivert, Bonine). In the antihistamine family. Can cause drowsiness. Like
other most other medications, it is best to take these before motion
stimulation. Meclizine does not work for all types of motion -- for
example, coriolis stimulation (Dornhoffer et al, 2004).
o Dimenhydrinate (Dramamine). Similar to meclizine. Liquid forms are available for
children 2 years of age or more.
o Cyclizine is similar to meclizine. It is suitable for children 6 years of age or older as well
as adults. It is most useful in situations involving short trips (e.g. automobile).
 Haldol, Thorazine -- these anti-psychotic drugs have dopamine blocking activity which is useful
for blocking nausea as well as stimulating stomach motion which helps clear food from the
 These drugs probably work on the central motion sickness
digestive tract.
machinery rather than the vestibular system.
 Calcium channel blockers. Shupak et al. (1994) reported cinnarizine - a mixed
antihistamine/calcium channel blocker, to be very effective in preventing sea
sickness, when used in a 50 mg dose. As this medication is not available in the
US, we have little experience with it. Flunarizine is a similar medication to
cinnarizine (Lee et al, 1986), but it has more dopamine blocking effect. As
calcium channels appear to be important in the vestibular periphery, and
these drugs are very sloppy, their action may simply be vestibular
suppression. In the US, combination of verapamil and meclizine would be
likely to create a similar effect.
 Promethazine. This drug is one of the most effective available for motion sickness (Dornhoffer et
al, 2004). One dose lasts up to 8 hours. Like the other drugs, it can cause drowsiness. It is not
appropriate for cognitive workers.
 Diazepam (valium) and related "benzodiazepine" medications such as lorazepam
and klonazepam. While these drugs are not traditionally used for motion sickness, some people
find them very useful in small amounts, typically taken about 30 minutes prior to motion
exposure. These medications are very helpful for a related condition, MDD. We have rarely
encountered people who could not prevent motion sickness by taking a
klonazepam 30 minutes prior to the exposure. On the other hand, one of
these, lorazepam, did not help prevent motion sickness from coriolois
stimulation (Dornhoffer et al, 2004). These medications are sedating and
addictive. They probably work by suppressing central vestibular
responses. Unless one is addicted and has developed tolerance, only small
amounts of benzodiazepine medications are compatable with normal
cognitive function.
 Scopolamine patches -- these patches are sometimes very helpful. They are a time release form of
an anticholinergic medication, scopolamine. Scopolamine is also available in pill format (usually
given for irritable bowel). Scopolamine was found the most useful medication for prevention of
motion sickness induced by cross-coriolis stimulation (Dornhoffer et al, 2004). Whether or not
this is true for other types of motion stimulation is not known. Scopolamine contains both
the D and L isomers of hyoscine. Scopolamine (hyoscine) is close, but not
exactly the same as L-hyocyanime (the active ingrediant in Levsin).
Scopolamine may have more central activity while Levsin (a GI medication)
less. In other words, Levsin is not equivalent to scopolamine -- it is a close
relative however. Scopace is an oral version. Anticholinergics that do not
penetrate the blood-brain barrier, such as robinul, would seem to be poor
choices, as they have no target.
 Ondansetron and other serotonin-family anti nausea drugs -- these are powerful anti-nausea
medications. They do not prevent motion sickness but they may prevent vomiting. They work
 very well, with almost no side effects at all. In general, they are an excellent
choice for nausea.
 Other medications.
o Migraine medications: Verapamil (a calcium channel blocker), venlafaxine (an
antidepressant, in this context used as a migraine prevention medication). We favor
verapamil as it is also useful in cyclic vomiting. Triptans have been
reported as mildly helpful in preventing motion sickness in persons with
migraine (Furman et al, 2011). We have not encountered any reports
concerning the longer acting triptans such as frovatriptan or
naratriptan, which would seem to be logical picks.
o Seizure medications phenytoin and carbamazepine (sodium channel blockers).
Phenytoin (Knox et al, 1994) would seem to us to be a very bad choice
due to it's difficulty in dosing. Carbamazepine also would seem to us to
be a bad choice due to significant risk of side effects. We are not sure
about safer agents such as oxcarbamazine. We are dubious about this
group but have occasionally had good results.
o Non-benzodiazepine anxiety medications. Buspirone (Buspar). There are also some
atypical antipsychotics such as abilify and respirdol. We have never had
any success with this group, but they might be useful in rare situations
where everything else has failed.
o Alternative medications Betahistine (Serc). This medication is sometimes very
effective. (e.g. Matsnev and Sigaleva, 2007). Our experience is a good
effect in about 30%.
 Medications that don't work for motion sickness:
o antihistamines such as fexofenadine and cetirizine that do not get into
the brain (Cheung, B. S., R. Heskin, et al.; 2003). It also seems very
unlikely that anticholinergics that don't get into the brain (such as
Robinul) work either.

Medications for nausea and vomiting

Treatment of motion sickness differs from treatment of nausea and vomiting. A

discussion of the treatment of vomiting can be found here.
Exercises for motion sickness. Habituation

It is reasonable to assume that habituation (repeated motion exposure) makes

one less motion sensitive. (Cheung, B. and K. Hofer, 2005). In fact, the military
uses a "habituation" protocol to overcome motion sickness. This requires
expensive equipment (a rotating chair). Habituation should be "batched" --
meaning done every day. There are a number of drugs which probably reduce
habituation.

A somewhat similar approach was reported by Dai et al recently (2011), in a

civilian apparatus. It again involved a rotatory chair as well as a simultaneously
rotating optokinetic surround. In our practice in Chicago, we have abandoned
the effort implement this protocol with our own equipment, but we have set up a
similar protocol, also copied from work of Dai, using an optokinetic stimulus
and the pseudocoriolis effect.

Habituation can be obtained through sports activities or physical therapy

procedures. These procedures generally involve use of visual-vestibular
mismatches, called "times 2" and "times 0" viewing. Stimulators with "disco
balls" are often used too. We are unsure if these procedures are effective.

A home exercise method has been proposed to overcome motion sickness -- the
"Puma" method. These exercises were developed by a flight surgeon (Sam
Puma), to assist pilots with motion sickness in overcoming their sensitivity to
motion. They are very stimulating exercises, that may be useful to extremely
motivated people, who are not able to use more conventional methods of
management of motion sickness such as medications. The Puma method appears
to us to be a habituation protocol -- repeated exposure to the things that make
one ill. This may well work -- if you can tolerate the process. We are cautiously
hopeful about this method -- although it seems to us to be likely to cause a lot of
nausea itself. When we sometimes suggest this to our patients in our dizziness
practice, we suggest that they use ondasetron to avoid nausea. It is rare that
someone with motion sensitivity is able to tolerate these exercises.

Activities that promote formation of "internal models" of motion may also be

useful for motion sickness prevention. We do not know of any formal protocols
that use this idea.

We recently have proposed a protocol for visual dependence that may be useful
in treatment of motion sickness (Chang and Hain, 2007). See the page on visual
dependence for more detail.
Alternative medications

 There are numerous "alternative" remedies for motion sickness. The most
popular are Ginger derivatives, such as ginger tea, powdered ginger capsules,
and even raw ginger between the teeth. We have not seen much success in our
patients. Holtman et al(1989) reported no effect on vestibular responses by
ginger, and suggested that Ginger's main effect is on the stomach, to prevent
vomiting.
 Acupuncture and acupressure has been reported useful for motion sickness. It
appears to be a little better than placebo.

Experimental treatments --

 Experimentally, motion-sickness can be eliminated in dogs by surgically

removing part of the brain (the nodulus, according to Tyler and Bard, 1949).
 In theory, vestibular ablation with streptomycin or gentamicin should
eliminate motion sickness (at the price of developing bilateral vestibular
loss). This method seems to us to be unreasonably damaging.
 Passing electrical current into the scalp was suggested by Arshad and others to
be a "therapy for motion sickness" (2015). There are many practical issues
with this technique. It appears to be a curiosity.
 Treatment of vertical heterophoria is also sometimes useful in visual motion
sickness (Jackson and Bedell, 2012).
 2 https://wwwnc.cdc.gov/travel/yellowbook/2018/the-pre-travel-
consultation/motion-sickness

31 may 2017

Motion Sickness
Stefanie K. Erskine

RISK FOR TRAVELERS

Motion sickness is the term attributed to physiologic responses to motion by sea, car, train, air, and
virtual reality immersion. Given sufficient stimulus all people with functional vestibular systems can
develop motion sickness. However, people vary in their susceptibility. Risk factors include the
following:

 Age—children aged 2–12 years are especially susceptible, but infants and toddlers are generally
immune. Adults older than 50 years are less susceptible to motion sickness.
 Sex—women are more likely to have motion sickness, especially when pregnant, menstruating,
or on hormones.
 Race/ethnicity—Asians may be more susceptible to motion sickness than Europeans.
 Migraines—people who get migraine headaches are more prone to motion sickness, especially
during a migraine.
 Medication—some prescriptions can worsen the nausea of motion sickness.

CLINICAL PRESENTATION
Travelers suffering from motion sickness commonly exhibit some or all of the following symptoms:

 Nausea
 Vomiting/retching
 Sweating
 Cold sweats
 Excessive salivation
 Apathy
 Hyperventilation
 Increased sensitivity to odors
 Loss of appetite
 Headache
 Drowsiness
 Warm sensation
 General discomfort
PREVENTION
Nonpharmacologic interventions to prevent or treat motion sickness include the following:

 Being aware of and avoiding situations that tend to trigger symptoms.

 Optimizing position to reduce motion or motion perception—for example, driving a vehicle
instead of riding in it, sitting in the front seat of a car or bus, sitting over the wing of an aircraft,
holding the head firmly against the back of the seat, and choosing a window seat on flights and
trains.
 Reducing sensory input—lying prone, shutting eyes, sleeping, or looking at the horizon.
 Maintaining hydration by drinking water, eating small meals frequently, and limiting alcoholic and
caffeinated beverages.
 Avoiding smoking—even short-term cessation reduces susceptibility to motion sickness.
 Adding distractions—controlling breathing, listening to music, or using aromatherapy scents
such as mint or lavender. Flavored lozenges may also help.
 Using acupressure or magnets is advocated by some to prevent or treat nausea, although
scientific data on efficacy of these interventions for preventing motion sickness are lacking.
 Gradually exposing oneself to continuous or repeated motion sickness triggers. Most people, in
time, notice a reduction in motion sickness symptoms.

TREATMENT
Nonpharmacologic treatments for preventing and treating motion sickness can be effective with few
adverse side effects (see Prevention above). However, these measures can be time-consuming and
unpleasant for travelers. Many patients will prefer medication.

Before deciding which medications to prescribe, consider factors such as individual susceptibility
and type, magnitude, and duration of potential stimuli. Medications to treat motion sickness are most
effective when taken before exposure.

A primary side effect of most efficacious medications used for motion sickness is drowsiness, along
with other drug-specific side effects. Some medications may interfere with or delay acclimation to the
offending movement. Because gastric stasis can occur with motion sickness, parenteral delivery may
be advantageous.

Antihistamines are the most frequently used and widely available medications for motion sickness;
non-sedating ones appear to be less effective. Antihistamines commonly used for motion sickness
include cinnarizine (not currently available in the United States), cyclizine, dimenhydrinate,
meclizine, and promethazine (oral and suppository). Other common medications used to treat
motion sickness are anticholinergics such as scopolamine (hyoscine, oral, intranasal, and
transdermal), antidopaminergic drugs (such as prochlorperazine), metoclopramide,
sympathomimetics, and benzodiazepines. Clinical trials have not shown that ondansetron, a drug
commonly used as an antiemetic in cancer patients, is effective in the prevention of nausea
associated with motion sickness.

When recommending any of these medications to travelers, providers should make sure that
patients understand the risks and benefits, possible undesirable side effects, and potential drug
interactions. Travelers may consider trying the medication before travel to see what effect it has on
them.

Medications in Children
For children aged 2–12 years, dimenhydrinate (Dramamine), 1–1.5 mg/kg per dose, or
diphenhydramine (Benadryl), 0.5–1 mg/kg per dose up to 25 mg, can be given 1 hour before travel
and every 6 hours during the trip. Because some children have paradoxical agitation with these
medicines, a test dose should be given at home before departure.

Antihistamines are not approved by the Food and Drug Administration to treat motion sickness in
children. Caregivers should be reminded to always ask a physician, pharmacist, or other clinician if
they have any questions about how to use or dose antihistamines in children before they administer
the medication. Oversedation of young children with antihistamines can be life-threatening.

Scopolamine can cause dangerous adverse effects in children and should not be used;
prochlorperazine and metoclopramide should be used with caution in children.

Medications in Pregnancy
Drugs with the most safety data regarding the treatment of the nausea of pregnancy are the logical
first choice. Alphabetical scoring of the safety of medications in pregnancy may not be helpful, and
clinicians should review the actual safety data or call the patient’s obstetric provider for suggestions.
Web-based information may be found at the websites www.Motherisk.org and www.Reprotox.org.
 1. http://www.aafp.org/afp/2014/0701/p41.html

Prevention and Treatment of Motion

Sickness
ANDREW BRAINARD, MD, MPH, and CHIP GRESHAM, MD, Middlemore Hospital, Auckland, New
Zealand
Am Fam Physician. 2014 Jul 1;90(1):41-46.

Motion sickness is a common syndrome that occurs upon exposure to certain types of
motion. It is thought to be caused by conflict between the vestibular, visual, and other
proprioceptive systems. Although nausea is the hallmark symptom, it is often preceded by
stomach awareness, malaise, drowsiness, and irritability. Early self-diagnosis should be
emphasized, and patients should be counseled about behavioral and pharmacologic
strategies to prevent motion sickness before traveling. Patients should learn to identify
situations that will lead to motion sickness and minimize the amount of unpleasant motion
they are exposed to by avoiding difficult conditions while traveling or by positioning
themselves in the most stable part of the vehicle. Slow, intermittent exposure to the motion
can reduce symptoms. Other behavioral strategies include watching the true visual horizon,
steering the vehicle, tilting their head into turns, or lying down with their eyes closed.
Patients should also attempt to reduce other sources of physical, mental, and emotional
discomfort. Scopolamine is a first-line medication for prevention of motion sickness and
should be administered transdermally several hours before the anticipated motion exposure.
First-generation antihistamines, although sedating, are also effective. Nonsedating
antihistamines, ondansetron, and ginger root are not effective in the prevention and
treatment of motion sickness.

Motion sickness is a syndrome that occurs when a patient is exposed to certain types of motion and
usually resolves soon after its cessation. It is a common response to motion stimuli during travel.
Although nausea is a hallmark symptom, the syndrome includes symptoms ranging from vague
malaise to completely incapacitating illness. These symptoms, which can affect the patient's
recreation, employment, and personal safety, can occur within minutes of experiencing motion and
can last for several hours after its cessation.

Enlarge Print
SORT: KEY RECOMMENDATIONS FOR PRACTICE
EVIDENCE
CLINICAL RECOMMENDATION RATING REFERENCES

To prevent and reduce symptoms of motion sickness, C 2–5

passengers should look forward at a fixed point on the
horizon and avoid close visual tasks.

To prevent and reduce symptoms of motion sickness in C 6–8

vehicles, passengers should actively steer, tilt their head
into turns, recline, stabilize their head and body, or rest with
their eyes closed.

Scopolamine should be a first-line medication for A 1, 2, 14, 15, 20, 21, 24

preventing motion sickness in persons who wish to
maintain wakefulness during travel.

First-generation antihistamines are effective for preventing B 1, 2, 16, 17, 19–21, 26

motion sickness, but often have sedative and other side
effects.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented

evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For
information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

Nearly all persons will have symptoms in response to severe motion stimuli, and a history of motion
sickness best predicts future symptoms.1 Females, children two to 15 years of age, and persons with
conditions associated with nausea (e.g., early pregnancy, migraines, vestibular syndromes) report
increased susceptibility.

Etiology
The pathogenesis of motion sickness is not clearly understood, but it is thought to be related to
conflict between the vestibular, visual, and other proprioceptive systems.2 Rotary, vertical, and low-
frequency motions produce more symptoms than linear, horizontal, and high-frequency motions.1

Clinical Presentation
Although nausea may be the first recognized symptom of motion sickness, it is almost always
preceded by other subtle symptoms such as stomach awareness (i.e., a sensation of fullness in the
epigastrium), malaise, drowsiness, and irritability. Failure to attribute early symptoms to motion
sickness may lead to delays in diagnosis and treatment. Although mild symptoms are common,
severely debilitating symptoms are rare2 (Table 11,2).

Enlarge Print
Table 1.

Signs and Symptoms of Motion Sickness

SEVERITY SIGNS SYMPTOMS

Mild Belching Stomach awareness

Yawning Malaise

Facial and perioral pallor Headache

Heartburn Irritability

Hypersalivation Drowsiness

Urinary frequency Fatigue

Moderate Cold diaphoresis Nausea

Flushing Nonvertiginous dizziness

Increased body warmth Apathy

Hyperventilation Depression

Vomiting Disinterest in social activities

Disinclination for work

Decreased cognitive performance

Exaggerated sense of motion

Increased postural sway

 SEVERITY SIGNS SYMPTOMS

Severe Inability to walk Social isolation

Incapacitation

Loss of postural stability

Persistent retching

NOTE: Signs and symptoms are listed in decreasing order of prevalence.

Information from references 1 and 2.

Behavioral Interventions
Prevention of motion sickness is more effective than treating symptoms after they have occurred.
Therefore, patients should learn to identify situations that may lead to motion sickness and be able
to initiate behavioral strategies to prevent or minimize symptoms1,2 (Table 21–13).

Enlarge Print
Table 2.

Behavioral Strategies to Prevent or Minimize Symptoms of Motion Sickness

GENERAL PRINCIPLE TACTICS

Minimize vestibular motion Avoid particularly noxious types of motions

Complex (multiple and off-axis) motions are worse

than simple (one-axis) motions

Low-frequency motions are worse than high-

frequency motions

Rotary motion is worse than linear motion

Vertical motions are worse than horizontal

motions

Avoid travel in difficult conditions and locations

Avoid air travel in storms and turbulent conditions

Avoid terrain with many turns, accelerations, and

ups and downs
GENERAL PRINCIPLE TACTICS

Avoid travel on water in storms and large waves

Avoid travel through fog, clouds, and other

conditions with poor visibility

Choose location within the vehicle that minimizes

motion

Airplanes: over the wing

Automobiles: driver's or front passenger seat,

facing forward3,4

Boats: facing toward the waves, away from the

rocking bow, near the surface of the water2

Buses: near the front, at the lowest level, facing

forward3

Trains: at the lowest level, facing forward

Habituate to motion Gradually increase amount of motion stimuli

Start travel in calm conditions and slowly increase

the amount of motion exposure

If symptomatic, attempt to reduce, but not

eliminate, motion stimuli

Synchronize the visual system with View the true visual horizon2–5
the motion
Avoid close work (e.g., reading, looking at
computer screens, photography)

Avoid spaces where the horizon cannot be seen

Focus on a distant point on the horizon

GENERAL PRINCIPLE TACTICS

Look toward the motion or direction of travel

Maintain a wide view of the horizon

If unable to view the true visual horizon

Close eyes and hold head still

Wear sunglasses

Actively synchronize the body with the Perform active movements if possible
motion
Actively tilt head into turns6

Pilot the vehicle or connect with steering device7

Stand with legs bent, and anticipate the motion by

moving entire body

Actively swim if in water

Walk around the vehicle if possiblePerform active

movements if possible

If unable to perform active movements

Brace body and head to avoid additional motion 8

Lay supine or recline head to 30 degrees

GENERAL PRINCIPLE TACTICS

Reduce other sources of physical, Treat and prevent gastritis2

mental, and emotional discomfort
Avoid alcoholic drinks

Eat before traveling, and avoid an empty stomach

Eat light, soft, bland, low-fat, and low-acid food

Stay or get comfortable2

Attempt to sleep

Avoid dehydration, hunger, and fatigue

Stay dry

Avoid or reduce other unpleasant stimuli

Assure adequate ventilation

Avoid discussing motion sickness

Avoid noxious stimuli (e.g., exhaust fumes, smell

of emesis)

Avoid unpleasant thoughts9

Listen to music10

Maintain a positive attitude11,12

Use cognitive behavior therapy2

Practice mindful breathing13

 GENERAL PRINCIPLE TACTICS

Information from references 1 through 13.

MINIMIZE VESTIBULAR MOTION
Patients should be advised to avoid traveling in difficult weather conditions. If they must travel, they
should sit in the part of the vehicle with the least amount of rotational and vertical motion.2 This is
usually the lowest level in trains and buses, close to water level and in the center of boats, and over
the wing on airplanes.

HABITUATE TO MOTION
With continuous exposure to motion, symptoms of motion sickness will usually subside in one to two
days. Alternatively, slow, intermittent habituation to motion is an effective strategy to reduce
symptoms.1 For example, spending the first night aboard a boat in the marina, followed by a day
acclimating in the harbor, is preferable to going straight into the open ocean.

SYNCHRONIZE THE VISUAL SYSTEM WITH THE MOTION

A small study found that focusing on the true horizon (skyline) minimized symptoms of motion
sickness.5 A survey of 3,256 bus passengers suggested that forward vision was helpful in reducing
symptoms.3 Another study indicated that forward vision in a car can reduce symptoms.4

ACTIVELY SYNCHRONIZE THE BODY WITH THE MOTION

Actively steering the vehicle is an accepted strategy for reducing symptoms of motion sickness,
although evidence is limited.7 Additionally, a small study of automobile passengers found that
actively tilting the head into turns was effective in preventing symptoms.6 A survey of 260 cruise ship
passengers supported the common advice to recline and passively stabilize themselves if they are
unable to initiate active movements.8

REDUCE OTHER SOURCES OF PHYSICAL, MENTAL, AND EMOTIONAL

DISCOMFORT
Frequent consumption of light, soft, bland, low-fat, and low-acid food can minimize symptoms of
motion sickness.2 Treating gastritis is useful,2 as is avoiding nausea-inducing stimuli (e.g., alcohol,
noxious odors). Discussing symptoms with others can exacerbate the condition. Passengers should
be well rested, well hydrated, well fed, and comfortable before beginning travel. Small studies have
shown that cognitive behavior therapy, mindful breathing, and listening to music may also reduce
symptoms of motion sickness.9,10,13
Medications
Medications are most effective when taken prophylactically before traveling, or as soon as possible
after the onset of symptoms2 (Table 31,2,14–23). Medications are most effective when combined with
behavioral strategies. To familiarize themselves with common side effects, patients should first take
medications in a comfortable environment before using them for motion sickness during travel.

Enlarge Print
Table 3.

Medications for Motion Sickness

EFFECTIVENESS
FOR
MEDICATION PREVENTION DOSAGE COMMENTS SIDE EFFECTS*

Anticholinergic

Scopolamine14–16 Transdermal: Transdermal: one First-line Common:

most effective patch applied to medication for dry eyes,
mastoid at least four prevention; dry mouth,
hours before travel, transdermal sensitivity
then every 72 hours as formulation to bright
needed available by light
prescription;
oral Less
formulation not common:
available in the blurred
United States; vision,
causes more dizziness,
dry eyes and headache,
dry mouth than sedation
antihistamines, Uncommon:
but less acute angle
sedation; may glaucoma,
double dose or confusion,
combine with contact
antihistamines, dermatitis,
or combine monocular
oral and pupillary
transdermal dilation
formulations urinary
(increased risk retention
of side
effects); use
with caution in
older patients;
not
recommended
for children
younger than
10 years
 EFFECTIVENESS
FOR
MEDICATION PREVENTION DOSAGE COMMENTS SIDE EFFECTS*

Oral: Oral: 0.4 to 0.6 mg one

moderately hour before travel, then
effective every eight hours as
needed

Antihistamines (first-generation, listed from least to most sedating)

Cinnarizine15 Moderately Adults and Available over Class

effective children older the counter in effects
than 12 years: Mexico and
30 mg two Europe; not Very
hours before available in the common:
travel, then 15 United States sedation
mg every or Canada; Common:
eight hours as has calcium dry eyes,
needed channel– dry mouth
blocking
Children five properties Less
to 12 years of common:
age: 15 mg blurred
two hours vision,
before travel, sensitivity
then 7.5 to 15 to bright
mg every light
eight hours as
needed Uncommon:
confusion,
urinary
retention
:

Cyclizine Least effective Adults and Available over

(Marezine)17 children older the counter
than 12 years:
50 mg one
hour before
travel, then
every four to
six hours as
needed
(maximum:
200 mg per
day)

Children six to
11 years of
age: 25 mg
 EFFECTIVENESS
FOR
MEDICATION PREVENTION DOSAGE COMMENTS SIDE EFFECTS*

one hour
before travel,
then every six
to eight hours
as needed
(maximum: 75
mg per day)

Dimenhydrinate16,18 Least effective Adults and Available over

children older the counter
than 12 years:
50 to 100 mg
every four to
six hours
(maximum:
400 mg per
day)

Children six to
12 years of
age: 25 to 50
mg every six
to eight hours
as needed
(maximum:
150 mg per
day)

Diphenhydramine Least effective Adults and Oral

children older formulations
than 12 years: available over
25 to 50 mg the counter;
every four to solution for
six hours intramuscular
(maximum: administration
300 mg per available by
day) prescription

Children six to
12 years of
age: 12.5 to
25 mg every
four to six
hours as
needed
(maximum:
150 mg per
day)
 EFFECTIVENESS
FOR
MEDICATION PREVENTION DOSAGE COMMENTS SIDE EFFECTS*

Promethazine16,19 Moderately Adults: 25 mg Prescription

effective 30 to 60 only; also
minutes available as
before travel, rectal
then every 12 suppositories
hours as and as
needed solution for
intramuscular
Children: 12.5 injection
to 25 mg
twice daily as
needed

Meclizine Least effective Adults and Available over

(Antivert)16,18 children 12 the counter
years and
older: 25 to 50
mg one hour
before travel,
then every 24
hours as
needed

Children
younger than
12 years: not
recommended

*—Most side effects are dose-related.

Information from references 1, 2, and 14 through 23.

SCOPOLAMINE
Scopolamine, an anticholinergic, is a first-line option for preventing motion sickness in persons who
wish to maintain wakefulness during travel.2,20,24 A Cochrane review of 14 randomized controlled trials
(RCTs) showed that scopolamine is effective for the prevention of motion sickness.14 A more recent
RCT of 76 naval crew members showed that transdermal scopolamine is more effective and has
fewer side effects than the antihistamine cinnarizine (not available in the United States).15 If the
recommended dose of scopolamine does not adequately relieve symptoms, the dose may be
doubled. Adding a second patch of transdermal scopolamine was well tolerated in a small RCT of 20
sailors.25

ANTIHISTAMINES
First-generation antihistamines have been used to treat motion sickness since the 1940s.1 They are
generally recommended for patients who can tolerate their sedative effects.2,20 Cyclizine (Marezine),
dimenhydrinate, promethazine, and meclizine (Antivert) demonstrated effectiveness in small RCTs
of varying quality.16–19 Nonsedating antihistamines are not effective in preventing or treating motion
sickness.26

OTHER MEDICATIONS
Benzodiazepines are occasionally administered for severe symptoms of motion sickness and have
been proven effective in a single small study.27 The serotonin agonist rizatriptan (Maxalt) reduced
motion sickness symptoms in a single RCT of 25 patients with recurrent migraines.28 The serotonin
antagonist ondansetron (Zofran) is ineffective for the prevention and treatment of motion
sickness.29,30

COMPLEMENTARY AND ALTERNATIVE THERAPIES

Although ginger root is often reported to prevent motion sickness, it had no statistically significant
effects in an RCT of 80 naval cadets.31 A single RCT of pregnant women showed that stimulation of
the P6 acupressure point on the anterior wrist increased their tolerance of motion stimuli.32Controlled
trials of behavioral, pharmacologic, or alternative therapies for motion sickness have demonstrated
strong placebo effects. Therefore, treatments are likely to be most effective if the patient believes
that they will work.
 4.http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD012715/full

Antihistamines for motion

sickness
 Protocol
 Intervention

Authors
 Nadine Karrim,
1.
 Nombulelo Magula,
1.
 Yougan Saman
1.
o
 First published: 7 July 2017
 Editorial Group: Cochrane ENT Group

Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness of antihistamines in the prevention and treatment of motion sickness
in adults and children.

Background
Description of the condition
Definition
Motion sickness is a syndrome that occurs as a result of
passive body movement in response to actual motion, or the
illusion of motion when exposed to virtual and moving
visual environments. It generally occurs as a physiological
response in a healthy person with an intact vestibular system;
however, the presentation may be modulated by various
pathologies (Bertolini 2016; Murdin 2015).
Presentation
The presentation can include nausea, vomiting, loss of
appetite, gastric awareness, increased sensitivity to odours,
headaches (including migraines), dizziness, sweating, pallor,
sensations of bodily warmth, increased salivation,
bradycardia, arterial hypotension, general malaise, repetitive
yawning and sopite syndrome (Bertolini 2016; Golding
2015). Space motion sickness differs from general motion
sickness and is characterised by sudden projectile vomiting
within minutes of weightlessness (Thornton 2013).
Symptoms produced by motion sickness may be severe
enough to have a negative impact on cognition and
performance (Matsangas 2014).
Epidemiology
Historically, motion sickness was first described in seafarers
(Hippocrates). A recent study undertaken on expedition
ships to Antarctica has shown that motion sickness was the
most common reason for consultation, with 150 out of a total
of 680 physician consultations for prophylaxis followed by
an additional 142 visits (27%, 4.2 per 1000 person-days) for
treatment (Schutz 2014).
Car sickness can affect most people with varying degrees of
severity, under the right circumstances (Wada 2015), and is
worse in passengers than drivers (Dong 2011). In one study
it occurred in 25.9% of experienced rally co-drivers, while
reading and while seated as rear-seat passengers (Perrin
2013). It may also prove a significant factor in the use of
autonomous cars (Diels 2016), and on tilting trains, but can
be influenced by compensation strategies (Förstberg 1998).
Space motion sickness affects 50% of astronauts within the
first 24 to 72 hours of weightlessness (Thornton 2013).
Virtual reality has been shown to induce motion sickness
(Nishiike 2013), and an incidence of up to 56% has been
demonstrated with the use of video games (Stoffregen
2008). Amongst cinema patrons, 54.8% experienced motion
sickness after viewing a 3D movie compared to 14.1% after
viewing a 2D movie (Solimini 2013).
Motion sickness is rare in children under the age of two, but
increases through childhood with a peak incidence at age
nine, followed by a progressive decline through adolescence
and adulthood (Henriques 2014). There is a slight
preponderance in females (Henriques 2014; Paillard
2013; Perrin 2013).
Ménière’s disease and vestibular migraines are associated
with increased motion sensitivity (Sharon 2014). A similar
association between patients with vestibular migraines and
those with migraines without vestibular symptoms has been
shown (Murdin 2015). Benign paroxysmal positional
vertigo and vestibular neuritis show no association with
motion sickness (Golding 2015). Bilateral vestibular failure
has a protective effect against the susceptibility to motion
sickness, although this is not seen with unilateral vestibular
failure (Murdin 2015).
Aetiology/pathophysiology
The sensory conflict or mismatch theory suggests that
conflict arises between one's visual, proprioceptive and
vestibular systems when the actual motion experienced
differs from the anticipated motion (Reason 1978). Oman
1990 suggested that the difference between all the true
sensory input and all the expected sensory information
results in the conflict vector. The larger this vector, the
greater the likelihood and severity of motion sickness. Bles
1998 further postulated that only vertical input is responsible
for motion sickness, suggesting an alternate theory known as
the subjective vertical conflict theory, while Holly
1996expanded this to include all translations. Another
hypothesis suggests a link between motion sickness and the
time constant of velocity storage (Cohen 2003).
A genetic predisposition showed concordance of 70% in
childhood and 50% in adulthood in monozygotic and
dizygotic twins (Reavley 2006).
Diagnosis
The Reason and Brand Motion Sickness Susceptibility
Questionnaire remains the most widely used tool to assess
susceptibility to motion sickness (Golding 1998). Once
symptoms have been established, Graybiel’s diagnostic
criteria may be used to grade the severity of motion sickness
(Graybiel 1968). There is no laboratory test that is
pathognomonic of motion sickness. Electrogastrography
(Cevette 2014), vestibular evoked myogenic potentials (Tal
2013), vestibulo-ocular reflexes (Tanguy 2008), caloric
testing (Sharon 2014), computerised dynamic posturography
(Tal 2010), neurochemical markers (ACTH, epinephrine,
norepinephrine) (Kohl 1985), and measurements of
autonomic activity (Cowings 1986) have all been used to
evaluate and study motion sickness.
Management
Habituation is an effective countermeasure to motion
sickness (Cowings 2000). It is influenced by the intensity
and frequency of exposure to the stimulus, and it is
potentiated by controlled breathing (Yen Pik Sang 2005).
While playing video games, passive restraint (Chang 2013)
and being in control reduce the onset of motion sickness.
Reducing passive head movements and postural instability
by viewing the horizon and widening one's stance have been
shown to be protective (Stoffregen 2013), although the same
is not true for artificial horizons (Tal 2012). Optokinetic
training reduced sea sickness in 71.4% of participants
compared to 12% in the control group (Ressiot 2013).
Stroboscopic illumination may also be protective against
motion sickness, possibly by reducing retinal slip (Webb
2013). Other methods such as galvanic vestibular stimulation
in synchrony with the visual field (Cevette 2014),
acupuncture, acupressure, transcutaneous electrical nerve
stimulation (Chu 2012), ginger (Lien 2003), and music
(Keshavarz 2014) have all been used to control motion
sickness.
Pharmacological therapy for the management of motion
sickness primarily involves the use of anticholinergics and
antihistamines (Murdin 2011). Scopolamine is the most
commonly used anticholinergic, and is effective compared to
placebo in the prevention of motion sickness; however, there
are insufficient data regarding its treatment of established
symptoms. The side effects include dry mouth, blurred
vision, dilated pupils and bradycardia (Spinks 2011). Other
pharmacological agents include antiemetics (Muth 2007),
neuroleptics such as phenytoin (Woodard 1993), µ-opiate
receptor agonists (Otto 2006), sympathomimetics (Weerts
2014a), and various combinations of all of these drugs.
Current approaches to countering space motion sickness
include the combination of pre-training in an altered gravity
environment in combination with the use of promethazine
(Karmali 2016).
Future measures to control the incidence of motion sickness
may involve engineering the expected stimulus to be less
provocative.
Description of the intervention
Antihistamines have been used in the management of motion
sickness for decades (Brand 1967), alone or in combination
with other interventions (Weerts 2014a). H1-antihistamines
are available as over-the-counter preparations, as well as by
prescription (Simons 2004). For the control of motion
sickness, routes of administration and dosages vary
depending on the specific drug used (Zajonc 2006).
H1-antihistamines may be classified according to their
functional class (generation), or by their sedative effect.
First-generation H1-antihistamines are generally sedating,
while second and third-generation antihistamines are non-
sedating. This may be due to the fat soluble nature of first-
generation antihistamines, which allows them to cross the
blood–brain barrier, while second and third-generation
antihistamines do not. In addition, first-generation
antihistamines exhibit anticholinergic properties (Mahdy
2014). Wood 1970 suggested this as the reason for their
protective effect against motion sickness. Typically, after a
single oral dose of an H1-antihistamine, the onset of action is
between two to three hours for first-generation
antihistamines, and one to two hours for second-generation
antihistamines. The duration of action may be up to 24 hours
(Simons 2004).
Side effects that limit the use of H1-antihistamines in certain
professions (such as astronauts) include drowsiness, fatigue,
dizziness and impairment of cognitive function, memory and
psychomotor performance (Weerts 2014b). Other reported
adverse effects include dystonia, dyskinesia, agitation,
confusion, hallucinations and cardiac toxicity. Additionally,
first-generation antihistamines may produce side effects
related to their anticholinergic activity, such as blurred
vision, dry mouth, dilated pupils and urinary retention.
Second-generation H1-antihistamines have been relatively
free of adverse effects. However, two early second-
generation antihistamines, astemizole and terfenadine, have
been withdrawn due to cardiac toxicity (Simons 2004).
Antihistamines have been compared to scopolamine (Gil
2012; Pingree 1994); however, the comparative
effectiveness in the management of motion sickness was
found to be inconclusive in a Cochrane review (Spinks
2011).
How the intervention might work
Acetylcholine (ACh) is a vestibular neurotransmitter and has
been identified in all vestibular nuclei. Histamine may be a
vestibular neurotransmitter or neuromodulator, acting on
histamine receptors (H1-H3 are expressed in the vestibular
system), but this remains unclear (Soto 2010). First-
generation antihistamines are ACh and H1 receptor
antagonists, thus inhibiting their effects on the vestibular
system. Second-generation antihistamines do not possess any
anticholinergic properties but inhibit histaminergic activity
only (Mahdy 2014). Cheung 2003 concluded that second-
generation agents are not effective in the management of
motion sickness and suggested that the anticholinergic and
sedative effects of first-generation agents may be the reason
for their apparent success.
Why it is important to do this review
When motion sickness was first described by Hippocrates in
400 BC, land and sea travel were the main sources of passive
motion. Now, for the general population, this includes motor
vehicles, trains, buses, cruise liners and other smaller vessels,
and passenger aircraft. Additionally, in this age of rapid
technological advancement, new sources of motion sickness
inducing stimuli have emerged, including virtual reality, 3D
visual effects, 4D experiences, video games, driverless cars
and commercial space flight. Apart from the daily life and
recreational aspects, occupational exposure to motion
sickness inducing stimuli has increased over time. This
includes but is not limited to paramedics in helicopters and
ambulances, military personnel on naval vessels and in the
air force, pilots, seafarers, and astronauts during space flight
and training.
While habituation is effective and has no side effects, it lacks
immediacy. Antihistamines have been the most commonly
used pharmacological therapy (Weerts 2014b), however
studies reveal conflicting results regarding their efficacy in
the management of motion sickness (Buckey 2004; Cheung
2003). This review aims to potentially resolve this conflict
and to facilitate advancement of future research in the field
of motion sickness.
Objectives
To assess the effectiveness of antihistamines in the
prevention and treatment of motion sickness in adults and
children.
Methods
Criteria for considering studies for this review
Types of studies
We will include all published and unpublished randomised
controlled trials (RCTs), including cluster-randomised trials.
We will exclude cross-over studies. There will be no time or
language limitations on included studies.
Types of participants
Participants will include susceptible adults and children (the
age limit to define children will be 18 years and under), of
any gender and ethnicity, who have no vestibular, visual or
neurological co-morbidities.
We will include:
 susceptible participants in whom motion sickness is induced under natural
conditions such as air, sea and land transportation.

Susceptibility will be defined as:

 previous experience of motion sickness; and/or

 motion sickness susceptibility based on the result of any validated scale.

We will include studies in which motion sickness is induced

under experimental conditions but we will analyse data from
these studies separately.
Types of interventions
The main intervention will be all antihistamines regardless
of:
 class (first or second-generation);

 route of administration; or

 dosage.

Comparison interventions will include:

 no treatment;

 placebo;
  any other pharmacological interventions (for example: scopolamine, phenytoin,
ondansetron, metoclopramide); and

 any non-pharmacological interventions (for example: acupuncture, transcutaneous

electrical nerve stimulation, habituation techniques).

The main comparison will be:

 antihistamine versus no treatment or placebo.
Other possible comparison pairs include:
 antihistamine versus scopolamine;
 antihistamine versus antiemetics;
 antihistamine versus neuroleptics;
 antihistamine versus µ-opiate receptor agonists;
 antihistamine versus sympathomimetics;
 antihistamine versus acupuncture;
 antihistamine versus acupressure;
 antihistamine versus autogenic feedback training exercises;
 antihistamine versus transcutaneous electrical nerve stimulation.
Concurrent use of other medication will be acceptable if used
equally in each group.
Types of outcome measures
We will analyse the following outcomes in the review, but
we will not use them as a basis for including or excluding
studies.
Primary outcomes
 Proportion of susceptible participants who did not experience any motion sickness
symptoms (based on subjective reporting of nausea and/or vomiting or the use of
a validated scale).

 Proportion of susceptible participants who experienced a reduction or resolution

of existing motion sickness symptoms (based on subjective reporting of nausea
and/or vomiting or the use of a validated scale).

Secondary outcomes
 Physiological measures: heart rate, core temperature and electrogastrography.
  Adverse effects (type, duration and severity): sedation, impaired cognitive
function, blurred vision.

We will evaluate outcomes after administration of the

antihistamine as short-term (less than or equal to 24 hours)
and long-term (over 24 hours).
Search methods for identification of studies
The Cochrane ENT Information Specialist will conduct
systematic searches for randomised controlled trials and
controlled clinical trials. There will be no language,
publication year or publication status restrictions. We may
contact original authors for clarification and further data if
trial reports are unclear and we will arrange translations of
papers where necessary.
Electronic searches
Published, unpublished and ongoing studies will be
identified by searching the following databases from their
inception:
 the Cochrane Register of Studies ENT Trials Register (search to date);

 Cochrane Register of Studies Online (search to date);

 Ovid MEDLINE (1946 to date):

 Ovid MEDLINE (In-Process & Other Non-Indexed Citations);

 PubMed (as a top up to searches in Ovid MEDLINE);

 Ovid EMBASE (1974 to date);

 EBSCO CINAHL (1982 to date);

 Ovid CAB abstracts (1910 to date);

 LILACS (search to date);

  KoreaMed (search to date);

 IndMed (search to date);

 PakMediNet (search to date);

 Web of Knowledge, Web of Science (1945 to date);

 ClinicalTrials.gov, www.clinicaltrials.gov (search via the Cochrane Register of

Studies to date);
 World Health Organization (WHO) International Clinical Trials Registry Platform
(ICTRP) (search to date);

 ISRCTN, www.isrctn.com (search to date);

 Google Scholar (search to date);

 Google (search to date).

The subject strategies for databases will be modelled on the

search strategy designed for CENTRAL (Appendix 1).
Where appropriate, these will be combined with subject
strategy adaptations of the highly sensitive search strategy
designed by Cochrane for identifying randomised controlled
trials and controlled clinical trials (as described in theCochrane
Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b.
(Higgins 2011)).
Searching other resources
We will scan the reference lists of identified publications for
additional trials and contact trial authors if necessary. In
addition, the Information Specialist will search Ovid
MEDLINE, theCochrane Library and Google to retrieve existing
systematic reviews relevant to this systematic review, so that
we can scan their reference lists for additional trials.
Data collection and analysis
Selection of studies
Two review authors (NK and YS) will independently sift
through the initial search results and identify studies that
appear to meet our inclusion criteria. We will then obtain
full-text articles for the studies on this preliminary list. We
will independently examine these studies and select those
that meet our inclusion criteria. If there are any
discrepancies, we will resolve this by reviewing the original
study. We will consult the third review author (NM) where
necessary.
Data extraction and management
Two review authors (NK and YS) will independently extract
data using standardised forms. If there are any missing or
incomplete data, we will contact the study author. If there are
any discrepancies, we will consult the third review author
(NM).
We will extract the following:
 Study design features (double-/single-/non-blinded; cluster/parallel-group)

 Setting

 Sample size

 Participant (baseline) characteristics (age, gender, susceptibility to motion

sickness and how this was assessed, co-morbidities)

 Inclusion criteria

 Exclusion criteria

 Method of induction of motion sickness

  Duration of motion

 Type of antihistamine used (name, class, route, dosage)

 Comparison intervention

 Outcomes

 Funding sources

 Study author declarations of interest

See Appendix 2.
Assessment of risk of bias in included studies
NK and YS will independently assess the risk of bias of the
included studies. This will be determined using Cochrane's
tool for assessing the risk of bias as outlined in the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins 2011).
We will consider the following domains and assign a
judgement based on the following criteria:
Random sequence generation
 Low risk: Study authors describe a random component in the sequence generation
process such as referring to a random number table, using a computerised random
number generation, coin tossing, shuffling cards or envelopes, throwing dice or
drawing of lots.

 High risk: Study authors describe a non-random component in the sequence

generation process (such as allocation based on geographic location, hospital
number, date of birth).

 Unclear risk: Study authors have not specified the sequence generation process.

Concealment of allocation prior to assignment

 Low risk: Participants and/or investigators could not foresee drug allocation due
to concealed allocation (such as the use of central allocation, or sequentially
numbered, opaque envelopes or drug containers).

 High risk: Participants and/or investigators could foresee drug allocation due to an
inadequate concealment process.
  Unclear risk: Insufficient information is given on the allocation concealment
process.

Blinding of provider, participant and outcome assessor

 Low risk: Blinding of treatment provider, participant or outcome assessor
undertaken.

 High risk: Blinding not undertaken.

 Unclear risk: Study does not state whether blinding was undertaken or not.

Incomplete outcome data

 Low risk: No incomplete outcome information, or the reason for incomplete
outcome data is unrelated to the study's outcomes (for example: a participant
dropped out of the study due to relocating to a new geographic location).

 High risk: Incompleteness of outcome data is related to the study's outcomes (for
example: a participant dropped out of the study due to severe nausea).

 Unclear risk: Reason for missing data unspecified.

Selective outcome reporting

 Low risk: The study protocol is available and all of the study's pre-specified
outcomes have been reported in the pre-specified manner.

 High risk: Not all the primary outcomes have been reported, or one or more of the
primary outcomes were reported using methods of analysis that were not pre-
specified, or one or more of the primary outcomes were not pre-specified, or one
or more of the primary outcomes were reported incompletely.

 Unclear risk: Insufficient information available to assign a judgement.

Other bias
 Low risk: Study appears free of other sources of bias.

 High risk: Other source of bias noted by review authors.

We will classify studies that have been categorised as high

risk on the basis of random sequence generation and/or
concealment of allocation of treatment and/or incomplete
outcome data as having a high overall risk of bias. We will
not consider studies that have been categorised as high risk
in one or more of the other domains to have a high overall
risk of bias.
We will include a description of the risk of bias of our
included studies in our Discussion.
Measures of treatment effect
For dichotomous data, we will calculate individual and
pooled statistics as risk ratios (RR) with 95% confidence
intervals (95% CI). We will assess continuous data (for
example, heart rate) using the mean difference (MD) for
outcomes measured on the same scale and/or the
standardised mean difference (SMD) for outcomes measured
on different scales. We will use a change from baseline for
this analysis. We will complete an intention-to-treat analysis,
assuming that the relevant data are available in the included
studies.
Unit of analysis issues
For multi-arm studies, we will establish which comparisons
are relevant to this review and include data from the
respective arms. We will not include cross-over studies.
Dealing with missing data
If we identify missing data, we will attempt to contact the
trial author by email. If we are unable to contact the author
and/or if the author is unable to provide the relevant
information, we will assume the missing data to be 'missing
at random' and we will conduct the data analysis using only
the available data.
Assessment of heterogeneity
We will assess clinical, methodological and statistical
heterogeneity. We will measure statistical heterogeneity
using the Chi² test and the I² statistic. For the latter,
according to the Cochrane Handbook for Systematic Reviews of
Interventions (Higgins 2011), a value of > 50% suggests
substantial heterogeneity.
Assessment of reporting biases
We will address publication bias (between-study reporting
bias) by searching for published, unpublished and ongoing
trials in the specified trial databases. We will ensure data
from all the available outcomes across all papers are
recorded, taking care not to duplicate results. Where
potentially eligible but unpublished trials are identified, we
will contact the authors to acquire the full study results
and/or to find out the reasons why these results have not
been published. For ongoing trials, we will include results
available until the date of publication of this review. We will
address language bias by including studies in any language
and we will obtain an English translation where possible. We
will address outcome (within-study) reporting bias by
ensuring results are presented as indicated in the protocol,
which will have been published beforehand. We will assess
between-study reporting bias as outlined in the Cochrane Handbook
for Systematic Reviews of Interventions (Higgins 2011).
Data synthesis
If data are comparable, we will combine data to give a
summary measure of effect using the methods set out
in Measures of treatment effect. If data are missing, we will
use the available data to perform a meta-analysis using
Review Manger 5.3 (RevMan 2014), in the absence of
significant clinical or statistical heterogeneity. We will test
for heterogeneity using the I2 statistic and we will assume
significant heterogeneity if the I2 is greater than 50% (i.e.
more than 50% of the variability in outcome between trials
could not be explained by sampling variation) (Higgins
2011). We will use a fixed-effect model in the absence of
statistical heterogeneity and a random-effects model if
heterogeneity is present. For key outcomes presented in the
'Summary of findings' table, we will also convey the pooled
results as absolute numbers (as number needed to treat).
Subgroup analysis and investigation of heterogeneity
If there are sufficient studies available we will conduct the
following subgroup analyses in RevMan, using the formal
test for subgroup differences (RevMan 2014):
 age (adults versus children); and

 motion sickness that has been induced under experimental conditions versus
natural conditions (such as air, sea and land transportation).

Adults and children may report symptoms differently and

antihistamines may have differing effects on each group (for
example, children may be more susceptible to the side effects
of antihistamines). The subjective experience of motion
sickness symptoms may differ when motion sickness is
induced under experimental conditions compared to naturally
occurring conditions.
Therefore these subgroups have been selected as variability
in these conditions may affect the outcome.
Sensitivity analysis
Two review authors (NK and YS) will independently
conduct a sensitivity analysis by identifying studies with a
high risk of bias using the Cochrane 'Risk of bias' tool and
excluding these studies from the analysis.
GRADE and 'Summary of findings' table
We will use the GRADE approach to rate the overall quality
of evidence. The quality of evidence reflects the extent to
which we are confident that an estimate of effect is correct
and we will apply this in the interpretation of results. There
are four possible ratings: high, moderate, low and very low.
A rating of high quality of evidence implies that we are
confident in our estimate of effect and that further research is
very unlikely to change our confidence in the estimate of
effect. A rating of very low quality implies that any estimate
of effect obtained is very uncertain.
The GRADE approach rates evidence from RCTs that do not
have serious limitations as high quality. However, several
factors can lead to the downgrading of the evidence to
moderate, low or very low. The degree of downgrading is
determined by the seriousness of these factors:
 study limitations (risk of bias);
  inconsistency;

 indirectness of evidence;

 imprecision; and

 publication bias.

We will include a 'Summary of findings' table for the

comparison antihistamine versus placebo (Appendix 3),
constructed according to the recommendations described in
Chapter 11 of the Cochrane Handbook for Systematic Reviews of
Interventions (Higgins 2011).
The 'Summary of findings' table will include the following
primary outcomes:
 proportion of susceptible participants who did not experience any motion sickness
symptoms; and

 proportion of susceptible participants who experienced a reduction or resolution

of existing motion sickness symptoms.

It will also include the following secondary outcomes:

 physiological measures; and

 adverse effects.

Acknowledgements
This project was supported by the National Institute for
Health Research, via Cochrane Infrastructure, Cochrane
Programme Grant or Cochrane Incentive funding to
Cochrane ENT. The views and opinions expressed therein
are those of the authors and do not necessarily reflect those
of the Systematic Reviews Programme, NIHR, NHS or the
Department of Health.
We would also like to acknowledge Samantha Faulkner for
assisting with the search strategy and Jenny Bellorini for
copy editing and reviewing the protocol.