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Open Journal of Molecular and Integrative Physiology, 2013, 3, 21-26 OJMIP
http://dx.doi.org/10.4236/ojmip.2013.31004 Published Online February 2013 (http://www.scirp.org/journal/ojmip/)
Analysis of pathomechanisms involved in side effects of
menthol treatment in respiratory diseases
Silvia Gavliakova1, Tomas Buday1, V. Manjunath Shetthalli2, Jana Plevkova1*
1Department of Pathophysiology, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia
2Royal Gwent Hospital, Newport, UK
Email: *jplevkova@gmail.com, plevkova@jfmed.uniba.sk
Received 25 September 2012; revised 3 November 2012; accepted 20 November 2012
ABSTRACT
Menthol is frequently used in over the counter medi-
cations for common colds and coughs. It was formerly
considered to be under the class of herbal medicine,
but identification of menthol receptor (TRPM8)
moved it from the class of herbal medicine to the mo-
lecular pharmacology. It has been documented that
menthol reduces dyspnoea and nasal obstruction via
stimulation of nasal cold or flow receptors. It has also
antitussive and antiirritative effect. Menthol can also
induce adverse reactions such as airway irritation,
dyspnoea, chest tightness and potentially respiratory
failure, mainly in children. The mechanisms respon-
sible for adverse reactions of menthol are not known
completely. The adverse reactions of menthol could
be due to its effects on TRPA1 channel, relevant to
airway irritation. Higher concentrations of menthol
stimulate TRPA1 channel causing airway irritation.
It also increases mucus production and at the same
time reduces cilliary activity leading to mucus stagna-
tion. As the adverse effects were reported mainly at
the night it is supposed that suppressed cough reflex
during sleep potentiated by menthol induced cough
suppression might be responsible for lack of airway
mucus clearing and obliteration of small airways.
Adverse effects could also be due to consequences of
reflexes induced by the menthol action on trigeminal
afferents, like apnoea or bronchoconstriction. Men-
thol is effective in relieving respiratory symptoms,
but cough and cold medications should be used with
caution. Recommendations are low concentrations of
menthol used locally (intranasal) and not combined
with camphor or cineole, as they may have additive
effects and should be avoided in children under 2
years. Further data are necessary to completely elu-
cidate potential risks of over the counter menthol
medication in children but based on the meta analy-
sis of documented case reports, menthol can be used
safely if its contraindications for use are followed as
with any other over the counter medications.
Keywords: Menthol; TRPM8; Airways; Treatment
1. INTRODUCTION
Recycling of respiratory viruses in the community,
seasonal factors, social factors (collective facilities—
schools, kindergartens) as well as the fact that the
respiratory system is open to environmental influences
lead to a high incidence of respiratory diseases in popu-
lation. Many of these diseases are self limiting viral
infections or common colds and they do not require any
specific treatment. However symptomatic relief may be
necessary in such infections. The most commonly used
drugs for symptomatic relief of common colds are nasal
decongestants and cough medications as nasal conges-
tion, runny nose and cough are the most limiting symp-
toms [1].
Over the last couple of years there has been a great
deal of attention focused on the potential risk of cough
and cold medication in infants and young children,
despite the fact that these medicines are widely used with
little evidence about their effectiveness [2].
Many of these symptomatic drugs contain essential
aromatic volatile substances with a characteristic smell
such as camphor, thymol, cineol, but the most common
of them is menthol. Identification of the molecular me-
chanism of the menthol effects (TRPM8 receptor), suc-
cessfully moved the substance from the class of herbal
medicine into the field of molecular pharmacology.
Extensive study of menthol action and other TRPM8
agonists could have interesting clinical applications [3].
2. MENTHOL AND ITS USE
Menthol is an aromatic substance, a component of pep-
permint extract and it has a characteristic flavor and
smell. Menthol is cyclic terpene alcohol, which has three
asymmetrically situated carbon atoms in the cyclohexane
*Corresponding author.
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S. Gavliakova et al. / Open Journal of Molecular and Integrative Physiology 3 (2013) 21-26
22
ring and the chemical structure allows the existence of
four pairs of optical isomers. L-menthol is the isomer
that has the strongest biological activity. It has typical
peppermint smell and causes cooling sensation when ap-
plied topically to the skin or mucous membranes [4,5].
Cooling effects of menthol are not caused by its rapid
evaporation from the surface as it was previously as-
sumed, but rather through the effect of menthol on ther-
mosensitive nerve endings via TRPM8 channel, as the
receptor for menthol and mild cold are identical [6].
TRPM8 is a non-selective cation channel belonging to
the group of melastine TRP channel super family.
TRPM8 was successfully cloned from dorsal root ganglia
neurons of rats, mice and humans and its expression is
not limited only to the primary sensory neurons, but it is
expressed by other cell types, such as respiratory or
genitourinary epithelium [6,7].
This receptor is sensitive to menthol, eucalyptol, lin-
alol, geraniol, icilin and other substances with cooling
effect. Electrophysiological studies have shown that this
channel is highly permeable to Ca2 + and its activation in
turn leads to increased intracellular Ca2 + due to influx
from the extracellular environment as well as release of
calcium from intracellular reserves as well [8].
Application of menthol at low concentrations causes
pleasant cooling, analgesic and antiirritant effect. Higher
concentrations of menthol can cause irritation, but this
mechanism does not depend only on concentration [9,10].
Sensations of burning and irritation after the application
of menthol can be explained by a dual mechanism of
agonism of menthol, which at higher concentrations
activates TRPA1 along with TRPM8 channel. TRPA1 is
abundantly expressed in nociceptors [11].
Symptom Relief by Menthol
One of the most common indications for the use of
menthol and menthol-containing medicines are the upper
respiratory tract diseases regardless of etiology (viral,
bacterial), because the symptomatology of these diseases
is very similar. They are nasal congestion, impaired
breathing through the nose, feeling of airway irritation,
sneezing, increased secretion from the nose and cough.
For that reason, majority of such medicines are for local
intranasal use in form of the nasal drops, sprays or oral
use—pastilles, candies and finally ointments that are
applied in a thin layer on the front and back of the chest
wall.
Application of menthol in combined products, or even
alone considerably limits the feeling of nasal congestion.
Although menthol/placebo inhalation does not affect
objectively measured nasal resistance, it significantly
increases subjective perception of nasal patency, which
was evaluated by visual analogue scale. So the applica-
tion of menthol reduces subjective discomfort caused by
the presence of this symptom [12,13]. Nerve endings
sensitive to menthol were previously known as cold/flow
receptors, because their activation occurs due to airflow
in upper airways. Each “new” breath of fresh air, colder
than the temperature of the mucosal surface activates
them, so does the menthol. Information from these re-
ceptors is in turn interpreted by brain as “a feeling of
improved airflow in the airways” [3].
Intensity of nasal symptoms is also reduced after nerve
stimulation on the palate—for example, administration of
pastilles or candy containing menthol markedly enhances
the feeling of breathing through the nose, but rhino-
manometric parameters remain unchanged [14]. These
oro-nasal interactions are mediated through palatal
nerves and menthol fumes evaporated to the nasopharynx
and nasal cavity during expiration [15]. Menthol in the
symptomatic treatment of cough is mainly used in the
case of acute cough. Antitussive effect of menthol was
shown in experimental studies as well as in the adult
volunteers, after inhalation of menthol vapors to the
lower airways [16,17]. Houghton and Beardmore also
documented antitussive effect of menthol vapors in
children [18]. However, antitussive activity of menthol is
probably mediated through afferent nerves in the upper
airways, which abundantly express TRPM8 channels
[19]. TRPM8 expression in afferent nerves in animal
airways has shown that afferent nerves in the lower
respiratory tract express TRPM8 channels significantly
less in number than those in the upper respiratory tract,
especially trigeminal endings in the nose [20,21].
In addition, antitussive activity of menthol could be
enhanced by other mechanisms. Menthol is known to
reduce the feeling of irritation and respiratory discomfort.
This finding was documented in the study, where 1% l-
menthol was used as part of premedication before fibro-
bronchoscopic examination [22]. Menthol is also known
to modulate mucociliary transport. Substances modu-
lating mucociliary transport suppress cough by reducing
the feeling of irritation of airways, liquefying mucus and
facilitate its mobilization in the airways. The other me-
chanism is that sucking pastilles or sweets containing
menthol increases production of saliva and stimulate
swallowing. Swallowing is a vagal reflex process that su-
ppresses cough [23].
There are also studies that document the administra-
tion of menthol (0.01 to 1 mM) and other TRPM8 ago-
nist icilin (100 µM) inhibits smooth muscle contraction
of airways in vitro and the effect on smooth muscle is
probably mediated through inhibition of Ca2+ entry into
cells, as was shown by fura 2 fluorescence procedures.
These findings suggest potential use of menthol in
reducing symptoms of respiratory illness caused by
bronchoconstriction [24].
Based on the available data as mentioned above, there
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S. Gavliakova et al. / Open Journal of Molecular and Integrative Physiology 3 (2013) 21-26 23
is pharmacological, clinical and laboratory evidence of
its use is alleviation of respiratory symptoms both in
children and adult population [25].
3. ADVERSE EFFECTS OF MENTHOL
CONTAINING COUGH AND COLD
MEDICINES
Although the administration of menthol containing me-
dicines is considered relatively safe and is used quite
often, it can lead to serious adverse reactions. Such mani-
festations may occur in hypersensitive adults. Young
children may also experience toxicity of menthol which
is underestimated in clinical practice.
It is fully not known about the broad range of cough
and cold medicines as their composition is not always
exactly defined and we do not know effects of all drug
components in detail. There are case reports documen-
ting serious or even life-threatening situations caused by
application of cough and cold medications containing
menthol. Meta analysis of literature and available case
histories suggest that it is not the menthol itself, but the
inappropriate use of medicines ignoring the recom-
mendations on product labels could be causing the ad-
verse incidents.
3.1. Disregulation of Breathing Induced by
Application of Menthol
It is known, that the control of breathing and airway
defensive reflexes in newborns and infants matures pro-
gressively with the development of central nervous
system. Some works indicate that these mechanisms are
not fully functional before reaching the age of 24 months
[26]. It is further known that the application of strong
chemical stimuli and cold to the nasal cavity and face
stimulates the nerve endings of the trigeminal nerve.
Relevant stimuli could be chemical, thermal or mecha-
nical. In response to the application of mentioned stimuli
such as cold and chemical irritants to the area of baby’s
nose and face, there is activation of reflex reactions with
deceleration of respiratory rate or even respiratory arrest
(apnoea) followed by the cardiovascular component of
the response in the form of bradycardia and hypertension
with blood redistribution—Kratschmer apnoeic reflex
[27]. In addition, laryngospasm may occur. These reac-
tions are part of a complex system of airway defensive
and protective reflex mechanisms, whose main function
is to prevent inhalation of potential hazards deeper into
the respiratory tract.
In few cases, all children younger than 1 year, menthol
applied to the nostrils caused reflex apnoea. Clinical
signs were laryngospasm, spasm of the glottis, instant
collapse, dypnoea, unconsciousness, cyanosis and hyper-
extensive extremities [28]. This mechanism—activation
of reflex apnoea, was probably responsible for the situa-
tion documented in case reports, where young children
were given nasal drops containing menthol. In this par-
ticular situation the drops had been stored in refrigerator
and activation of trigeminal afferents was not only
triggered by the chemical composition of the drops but
also by low temperature of it. There have also been
documented cases in which parents applied menthol-
containing chest lining VapoRub just below the nose in
an eighteen months old child and the child immediately
went cyanotic and stopped breathing. Parents responded
to the situation by turning the child upside down and
after a few strokes to back the child coughed out mucus
and then breathing went back to normal [29]. In this case
that VapoRub was used in the child younger than 2 years
(contraindicated according to the product label) and it
was not applied on the chest wall, but directly to the
proximity of trigeminal nerve endings near the nostrils.
It is documented in experimental works that cold and
menthol application directly to the nasal mucosa leads to
drop in respiratory rate in experimental animals [30,31]
and application of menthol crystals below the nose of a
newborn considerably inhibits his/her respiratory rate
[26]. Based on this knowledge we can conclude that is
not just the pharmacology of menthol inducing apnoea in
small children, but the way it is administered contri-
buting to it. Caution should always be taken when app-
lying nose drops or sprays to small children considering
possible reflex interactions and immaturity of breathing
regulation mechanisms in infants.
Searching for adverse effects of menthol nasal drops
also revealed case reports of death of infants who had
been treated with certain cough—cold products, but these
were ones containing decongestant Pseudoephedrine,
which was given in large dose [32], so this result could
not be ascribed to the menthol or other natural products.
3.2. Nasobronchial Reflex
Clinical experiences document that menthol containing
cough and cold medication triggered wheezing or bron-
choconstriction. Exact mechanism of menthol induced
airway narrowing causing wheezing is not known. Appli-
cation of menthol and its superagonist icilin in experi-
mental conditions inhibits bronchial smooth muscle con-
traction and hence the direct effect of inhaled menthol
vapors with the development of bronchoconstriction is
unlikely [24].
If we consider the most common application of men-
thol in the form of nose drops or sprays—the bron-
choconstriction could occur in terms of reflex response
called nasobronchial reflex. This increased resistance of
lower airways caused by bronchoconstriction is by irrita-
tion of the trigeminal afferent nerve endings and it is a
trigemino—vagal reflex mechanism [33]. Although the
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S. Gavliakova et al. / Open Journal of Molecular and Integrative Physiology 3 (2013) 21-26
24
opinions of nasobronchial reflex are often being dis-
cussed, the differences of opinion still do exist [34-36].
Some authors have reported bronchoconstriction after
irritation of nasal trigeminal afferents, some authors re-
ported bronchodilation and in some cases, the lower
airway resistance remained unchanged.
Extensive review by Baraniuk and Merck [33] about
nasal reflexes and their implications share that nasobron-
chial reflex is a component of diving (apnoeic) reflex
whose efferent components include bronchoconstriction
along with apnoea and laryngeal spasm. Nasobronchial
reflex is frequently under debate and it may be elicited
by stimulation of trigeminal nasal afferents by mechani-
cal, thermal or chemical stimuli—therefore application
of menthol—which is both chemical and thermal cha-
nnels agonist, might be responsible for such reactions.
3.3. Modulation of Mucociliary Transport
As it has been shown in animal models, menthol
inhalation leads to increased production of mucus in the
airways, which can be beneficial if the airways contain
thick and viscid mucus that is difficult to cough up.
Increased mucus production and change of its biophy-
sical qualities may not always be beneficial, because
menthol simultaneously inhibits the activity of cilia in
the airways, which can lead to stagnation of the mucus in
small airways [2]. Cough reflex plays important role in
the mucus elimination from the airways, but in case of
menthol treatment, cough is usually inhibited due to its
antitussive action. Application of ointments and rubs
containing menthol on the chest in the night times when
the baby does not move can deteriorate the situation
further. It is known that during sleep the sense of airway
irritation does not occur, cough is inhibited due to sleep
and the child may wake up in a paroxysm of cough, dys-
pnoe, wheezing which may eventually lead to respiratory
failure. Mucus plugs obliterate small airways, leading to
alveolar hypoventilation, ventilation-perfusion misma-
tching with impaired oxygenation and ventilation leading
to respiratory failure.
3.4. Other Problems Related to Menthol
“Toxicity”
Application of menthol on the chest can cause irritation
of the skin of the chest, which manifests as redness of the
skin with presence of blisters. These effects are probably
due to the influence of menthol on TRPA1 channels of
skin somatosensitive nociceptors.
Bioavailability and toxicity of menthol and other
components present in VapoRubs and ointments after
dermal absorbtion is minimal with relatively low syste-
mic exposure to these compounds, even when an unrea-
listically large number of patches are applied onto the
skin for unusually long time [37]. Based on the literature
retrieved via MEDLINE and our review of calls to the
PIC there have been cases of accidental poisonings with
essential oils in children. There have been documented
cases of menthol, euclyptol and camphor poisoning in
small children after unintentional ingestion of drops, oils,
or eating VapoRubs by infants [38].
The main symptoms of poisoning were epigastric pain,
nausea, vomiting, dizziness, muscle weakness, miosis,
tachycardia, and breathing difficulties. Therefore it is
important to be cautious and use common sense when
children are surrounded by products containing the
mentioned substances.
4. CONCLUSION
From the literature review, it is evident that use of
menthol and menthol-containing cough and cold medica-
tions is very common in the symptomatic treatment of
common respiratory diseases. There has been increasing
pharmacological evidence for their use in relief of
respiratory symptoms in recent days. The adverse reac-
tions have occurred mostly in cases when the route and
mode of administration was breached or when it was
used in age range when it was not supposed to be used
(children less than 2 years). Accidental poisonings can
happen as with any other mediations and caution should
be used while these medications are in proximity of
children. Overall it can be concluded that over the
counter menthol and menthol containing components can
be safely used for symptomatic relief in common respira-
tory illness in children and adults guided by manufac-
turer guidance and product labels on route and mode of
administration and avoiding their use in very young
children less than 2 years of age.
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