Nasal Inhalation of l-menthol Reduces Respiratory

Discomfort Associated with Loaded Breathing

TAKASHI NISHINO, YUGO TAGAITO, and YASUYOSHI SAKURAI
Department of Anesthesiology, School of Medicine, Chiba University

To test the hypothesis that stimulation of cold receptors in the upper airway may alleviate the sensation of respiratory discomfort, we investigated the effects of nasal inhalation of l-menthol (a specific
stimulant of cold receptors) on the respiratory sensation and ventilation during the loaded breathing
in 11 normal subjects. Subjects were asked to rate their sensation of respiratory discomfort using a visual analog scale (VAS) while breathing on a device with a flow-resistive load (180 cm H2O/L/s) or
with an elastic load (75.5 cm H2O/L). The effects of inhalation of l-menthol on ventilation and respiratory sensation were evaluated by comparing the steady-state values of ventilatory variables and VAS
scores obtained before, during, and after l-menthol inhalation. In 8 of 11 subjects inhalation of strawberry-flavored air instead of l-menthol was performed during loaded breathing. Both during the
flow-resistive loading and the elastic loading, inhalation of l-menthol caused a significant reduction
in sensation of respiratory discomfort (flow-resistive loading: 62 6 14 [mean 6 SD] VAS units before
inhalation versus 36 6 16 during inhalation, p , 0.01; elastic loading: 68 6 13 before inhalation versus 55 6 17 during inhalation, p , 0.01) without a significant change in breathing pattern and ventilation. Comparison of the effects between the flow-resistive loading and the elastic loading also revealed that the reduction in VAS score was more during the flow-resistive loading than during the
elastic loading (p , 0.01). Inhalation of strawberry-flavored air caused neither changes in VAS score
nor changes in breathing pattern and ventilation, indicating that olfaction is not a contributing factor in the relief of respiratory discomfort. We concluded that stimulation of cold receptors in the upper airway with nasal inhalation of l-menthol reduces the sensation of respiratory discomfort associated with loaded breathing. This effect is more effective during the flow-resistive loading than during
the elastic loading. Nishino T, Tagaito Y, Sakurai Y. Nasal inhalation of l-menthol reduces respiratory discomfort associated with loaded breathing.
AM J RESPIR CRIT CARE MED 1997;156:309313.

The sensation of discomfort associated with the act of breathing may be modulated by afferent information from a variety
of sources, including the upper airways, chest wall, lower airways, and lungs (1). It is a commonplace experience that patients who suffer from dyspnea can occasionally obtain subjective relief when they sit near an open window or in front of a
fan. Also, it has been reported that, in patients with chronic
obstructive pulmonary disease (COPD), breathing cold air reduces the sensation of dyspnea and improves exercise performance (2).
There is much evidence (36) to suggest the presence of a
specific type of upper airway receptors responding to inspiratory airflow both in animals and humans. These receptors, which
operate as thermoreceptors responsive to small decreases in

(Received in original form September 11, 1996 and in revised form January 22, 1997 )
Supported in part by a Grant-in-Aid from the Ministry of Health and Welfare for
the Second-term Comprehensive 10-year Strategy for Cancer Control.
Correspondence and requests for reprints should be addressed to Dr. T. Nishino,
Department of Anesthesiology, School of Medicine Chiba University, 1-8-1 Inohanacho, Chuo-ku, Chiba 260, Japan.
Am J Respir Crit Care Med Vol. 155. pp. 309313, 1997

luminal temperature of the upper airways, are now called cold

receptors (5). Cold receptors in the upper airway may be one
source of information on inspiratory flow rate and inspired
volume, and therefore, stimulation of cold receptors may
modulate the respiratory sensation.
Although breathing cold air has been shown to alter both
the pattern of breathing and the response to CO2 (7, 8), little
information is available as to the effect of stimulation of cold
receptors in the upper airway on respiratory sensation. Furthermore, a decrease in upper airway temperature not only
stimulates specific cold receptors but also inhibits mechanoreceptors in the upper airway (9), and the contribution of the
latter cannot be disregarded when evaluating the changes in
respiratory sensation during cold air inhalation.
Schwartzstein and colleagues (10) demonstrated that a flow
of cold air against the face reduces the sensation of breathlessness associated with loaded breathing in normal subjects.
However, their subjects breathed gases maintained at room
temperature without inspiring the cold air directed against the
face, and therefore, stimulation of cold receptors in the upper
airway as a cause of the respiratory relief is unlikely.
l-menthol is known as a specific stimulant of cold receptors
and the potential use of l-menthol as a tool for the respiratory
study has been suggested (11). In the present study we investi-

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gated the effect of nasal inhalation of l-menthol on changes in

perception of respiratory discomfort induced by addition of
external loads in normal subjects. We postulated that inhalation of l-menthol would reduce the sensation of respiratory
discomfort associated with loaded breathing.

METHODS
We studied 11 volunteers (10 males, 1 female) who ranged in age from
23 to 39 yr. None had clinical evidence of cardiovascular, respiratory,
neuromuscular, and rhinolaryngological disorders. All subjects were
nonsmokers. The protocol was approved by the institutional ethics
committee, and each subject gave informed consent. None was familiar with the hypothesis being tested.
Each subject was seated during the experiment and breathed
through an experimental apparatus containing a nasal mask, a twoway valve, a pneumotachograph (CP-100, Allied Health Care Product
Inc., St. Louis, MO), and a bypass circuit (Figure 1). The experimental
apparatus had a resistance of 5.5 cm H2O/L/s at a flow rate of 0.5 L/s
with or without the use of the bypass circuit. The bypass circuit had a
total respiratory space of approximately 250 ml in which 300 mg of
l-menthol crystal was deposited. The choice of this dose of l-menthol
was based on the results of several preliminary studies in which the
subjects inhaled through the bypass circuit containing different doses
of l-menthol, and the dose that produced the most comfortable cooling sensation was assessed.
In order to induce the sensation of respiratory discomfort in subjects, two different types of external loads, i.e., a flow-resistive load
and an elastic load, were added to the experimental apparatus. To apply the flow-resistive loading, an easily exchangeable flow resistor (2.5
mm in diameter and 10 cm in length) was placed in the distal inspiratory limb of the experimental apparatus. The total inspiratory resistance of the respiratory circuit with the resistor in place was 180 cm
H2O/L/s at a flow of 0.5 L/s with or without the use of the bypass circuit. To apply the elastic loading, a 12-L rigid glass bottle with a vent
valve was connected to the distal inspiratory limb of the experimental
apparatus. The vent valve was closed throughout each inspiration and

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1997

opened promptly during expiration in order to replenish the load with

fresh air and maintain the load constant from breath to breath. Closing and opening of the valve was effected by a solenoid triggered by
the flow signal of the pneumotachograph. The magnitude of the elastic load was 75.5 cm H2O/L without the use of the bypass circuit and
74.0 cm H2O/L when the bypass circuit was used.
Ventilatory airflow was measured through the pneumotachograph
while the subject was breathing only through the nose. Tidal volume
(VT) was obtained by electrical integration of the inspired flow signal.
Mask pressure was measured with a pressure transducer (Transpac
IV; Abbott Critical Care Systems, Chicago, IL). End-tidal P CO2 (PETCO2)
was monitored with an infrared CO2 analyzer (Aika MEL RAS-41;
Tokyo, Japan).
During the experiment, the subject was asked to rate continuously
the intensity of the sensation of respiratory discomfort using a visual
analog scale (VAS). The analog scale, ranging from 0 to 100, was displayed on an oscilloscope screen, and the subjects measured the VAS
score by adjusting the knob of a potentiometer, thus altering the display on the oscilloscope anywhere on the scale from 0 to 100 arbitrary
units. The numerical value of 0 was given for the sensation of not at
all unpleasant and 100 for the sensation of intolerable. Respiratory
discomfort was defined as an unpleasant urge to breathe. No further clarification or definitions were given, and the subjects were not
asked to distinguish different qualities or dimensions of the respiratory sensation. Mask pressure, Vt, PETCO2, and VAS score all were recorded on a four-channel recorder (Graphtec WR-3701; Tokyo, Japan). Before the start of the main study, a preliminary experiment was
performed to familiarize the subject with the apparatus, the protocol,
the sensation of breathing against the added loads, and the use of VAS.
The main study was conducted 10 min after the preliminary study,
and the usual protocol is described in the following paragraph.
When the subject breathed through the experimental apparatus
without the load in place and the breathing pattern was stable (unloaded breathing), the subject rated the magnitude of respiratory discomfort, and values of ventilation were calculated from measurements of 30-s periods. Then either the resistive load or the elastic load
was applied and maintained throughout inspirations continuously for at
least 11 min. This time was required to evaluate the effects of l-men-

Figure 1. Schematic illustration of the experimental apparatus.

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Brief Communication
TABLE 1
CHANGES IN BREATHING PATTERN CAUSED BY LOADING
AND INHALATION OF L-MENTHOL*

Flow-resistive load
VT, ml
f, bpm
TI, s
TE, s

VI, L/min
VT/TI, L/s
PETCO2, mm Hg
Elastic load
VT, ml
f, bpm
TI, s
TE, s

VI, L/min
VT/TI, L/s
PETCO2, mm Hg

Unloaded

Loaded (Baseline)

Test

Recovery

653 6 146
13.9 6 2.4
1.5 6 0.3
3.0 6 0.6
9.2 6 2.3
0.45 6 0.11
40.5 6 3.3

698 6 219
10.9 6 4.7
3.5 6 1.4
2.9 6 1.2
6.9 6 1.3
0.21 6 0.05
44.0 6 3.2

686 6 209
720 6 220
10.7 6 3.9 10.6 6 4.2

3.6 6 1.5
3.7 6 1.6
2.7 6 0.9
2.8 6 1.0
6.8 6 1.3
6.9 6 1.3
0.21 6 0.06 0.21 6 0.05
44.2 6 3.2 44.0 6 3.3

677 6 130
13.7 6 2.2
1.4 6 0.3
3.0 6 0.5
9.2 6 1.9
0.48 6 0.11
39.7 6 2.5

477 6 128
17.4 6 4.8
1.4 6 0.5
2.4 6 0.7
8.0 6 2.0
0.38 6 0.10
42.3 6 3.9

475 6 112 474 6 115

17.3 6 4.5 17.7 6 5.0
1.4 6 0.6
1.4 6 0.6
2.4 6 0.7
2.3 6 0.8
8.1 6 2.3
8.1 6 2.3
0.37 6 0.10 0.37 6 0.10
42.1 6 3.7 42.2 6 3.8

* Values are mean 6 SD.

p Value , 0.01, compared with the values during unloaded breathing.

thol on the sensation of respiratory discomfort under a near steady

respiratory state in the presence of added loads. After the application
of the respiratory load, when breathing pattern and VAS values had
remained nearly steady for at least 2 min, the subject started to breathe
through the bypass circuit, thus inhaling the air containing l-menthol
for 4 min, after which time the bypass circuit was closed and the inhalation of l-menthol was discontinued while the measurements of ventilatory variables and VAS score were continued for another 3 min, and
then the load was removed.
The order of application of the resistive load and the elastic load
was randomized, but each subject received two trials of both the elastic and resistive loads with an interval of 5 min between each trial. The
results obtained from two trials for one type of load on each subject
were averaged. On different days, in 8 of 11 subjects the same experiment as in the above protocol was repeated. However, in this series of
experiments a strawberry essence was deposited in the bypass circuit

so that the subjects inhaled strawberry-flavored air instead of l-menthol during loaded breathing.
The effects of inhalation of l-menthol or strawberry-flavored air
on ventilation and respiratory sensation were evaluated by comparing
the steady-state values of ventilatory variables and VAS scores obtained from measurements of at least five consecutive breaths at 1 min
before the opening of the bypass circuit (baseline period), at 3 min after the opening of the bypass circuit (test condition), and at 3 min after the closing of the bypass circuit (recovery period). Data are expressed as mean 6 SD.
Statistical analysis was performed by using two-way analysis of
variance (ANOVA) followed by Scheffes test, paired t test with Bonferroni correction, where appropriate.

RESULTS
All subjects tolerated both flow-resistive and elastic loads and
completed the experimental protocol.
Immediately after the addition of an external load, regardless of the type of loading, there were changes in VT and respiratory frequency (f) with a concomitant increase in VAS
score. These changes gradually stabilized within 2 min, and
thereafter, breathing patterns as well as VAS scores remained
nearly steady. Although there was an intersubject variability,
in general the breathing pattern with the flow-resistive load
during the steady-state was characterized by a slow breathing
with a marked prolongation of inspiratory time (TI) while the
breathing pattern with the elastic load was characterized by a
rapid, shallow breathing with a shortening of expiratory time
(TE) (Table 1).
Figure 2 shows experimental records illustrating changes in
breathing pattern and VAS score in response to inhalation of
l-menthol during the flow-resistive loading (Figure 2A) and
the elastic loading (Figure 2B). During the flow-resistive loading, shortly after the start of inhalation of l-menthol there was a
slight decrease in VT with a concomitant increase in PETCO2, but
soon these changes returned to the pre-inhalation baseline level
that remained nearly steady for the remainder of inhalation of
l-menthol. The VAS score also decreased shortly after inhala-

Figure 2. Experimental records illustrating changes in breathing pattern and VAS score in response to inhalation of l-menthol during the
flow-resistive (A) and elastic loading (B). Arrows indicate the start and end of inhalatian of l-menthol. VAS 5 visual analog scale; Pmask 5
mask pressure; VT 5 tidal volume; PETCO2 5 end-tidal PCO2.

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tion of l-menthol and reached its nadir within 60 s after the

start of inhalation of l-menthol. Thereafter, there was a slight
attenuation of the decrease in VAS score, but the VAS score
remained low throughout the period of inhalation of l-menthol. Discontinuation of inhalation of l-menthol caused a
prompt recovery of the VAS score to the baseline level.
Unlike the changes observed during the flow-resistive loading, inhalation of l-menthol during the elastic loading caused
almost no change in breathing pattern. However, the changes
in VAS score were qualitatively similar to those observed during the flow-resistive loading, and thus, the VAS score decreased immediately after the start of inhalation of l-menthol
and returned to the baseline level shortly after the discontinuation of inhalation of l-menthol. Similar changes in breathing
patterns and VAS scores in response to inhalation of l-menthol
were observed in the majority of subjects, although in 2 of 11
subjects l-menthol inhalation did not cause any change in VAS
score during the elastic loading. Table 1 summarizes changes in
breathing patterns in response to inhalation of l-menthol during
loaded breathing in 11 subjects. Both during the flow-resistive
loading and the elastic loading, the inhalation of l-menthol
caused neither changes in breathing pattern nor changes in
mean inspiratory flow rate (VT/TI).

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1997

Figure 3 shows changes in VAS scores in response to inhalation of l-menthol. Before the start of inhalation of l-menthol,
the values of the VAS score during the flow-resistive loading
and the elastic loading were 62 6 14 and 68 6 13, respectively.
There was no significant difference between the two values.
The inhalation of l-menthol caused significant decreases in
VAS scores both during the flow-resistive loading (36 6 16, p ,
0.01) and during the elastic loading (55 6 17, p , 0.01), but the
values of VAS scores during the elastic loading were significantly higher (p , 0.01) than those during the flow-resistive
loading. After the discontinuation of inhalation of l-menthol,
the values of VAS scores during the flow-resistive loading and
the elastic loading were 63 6 14 and 68 6 13, respectively.
These values were almost identical to those obtained before
the start of inhalation of l-menthol.
The results of inhalation of strawberry-flavored air are summarized in Table 2. These results show that neither breathing
patterns nor VAS scores changed in response to inhalation of
the strawberry-flavored air both during the flow-resistive loading and the elastic loading.

DISCUSSION
In this study we have demonstrated that nasal inhalation of
l-menthol can considerably reduce the sensation of respiratory
discomfort produced by addition of external respiratory loads.
Although underlying mechanisms of this reduction in the sensation of respiratory discomfort are not entirely clear, cold receptors in the upper airway seem to play an important role
since l-menthol is known as a specific stimulant of cold receptors in the upper airway (11).
There is some evidence to suggest that cooling of the upper
airway or stimulation of cold receptors in the upper airway depresses respiratory activity both in humans and animals (7, 8,
12). It has been also proposed that an increase in inspiratory
motor output or respiratory drive causes an increased sense
of effort and dyspnea (13). Thus, one mechanism by which l-menthol reduces the sensation of respiratory discomfort might be
through a reduction in respiratory drive. In fact, in our study
there was a slight decrease in ventilation with a concomitant
decrease in the sensation of respiratory discomfort immediately after the start of inhalation of l-menthol during the flowresistive loading. However, such decrease in ventilation was
transient and was never observed during the elastic loading.
Furthermore, during both the flow-resistive loading and the
elastic loading the breathing patterns and ventilation at 3 min

TABLE 2
CHANGES IN BREATHING PATTERN AND VAS SCORE IN RESPONSE
TO INHALATION OF STRAWBERRY-FLAVORED AIR*

Figure 3. Changes in VAS scores in response to inhalation of l-menthol during the loaded breathing. Both individual data ( upper
panel ) and averaged data (lower panel ) are shown. wp value ,
0.01, significantly different from the baseline values; qp , 0.01,
compared with the corresponding values of the elastic loading.

Flow-resistive load
VT, ml
f, bpm

VI, L/min
VT/TI, L/s
PETCO2, mm Hg
VAS
Elastic load
VT, ml
f, bpm

VI, L/min
VT/TI, L/s
PETCO2, mm Hg
VAS
* Values are mean 6 SD.

Baseline

Test

Recovery

713 6 208
9.5 6 3.6
6.3 6 1.4
0.20 6 0.05
46.3 6 2.1
58 6 14

709 6 192
9.6 6 3.4
6.4 6 1.4
0.20 6 0.05
46.2 6 2.5
57 6 13

698 6 185
9.5 6 3.4
6.3 6 1.4
0.20 6 0.05
46.6 6 3.1
58 6 14

493 6 119
16.4 6 3.2
8.0 6 2.1
0.38 6 0.10
42.3 6 3.9
66 6 16

498 6 107
16.0 6 2.4
8.0 6 2.0
0.37 6 0.10
42.1 6 3.7
66 6 16

503 6 104
16.1 6 2.9
8.1 6 2.0
0.37 6 0.10
42.2 6 3.8
66 6 17

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Brief Communication

after the start of inhalation of l-menthol did not differ from

those during the baseline period, despite that the improvement of respiratory discomfort continued throughout the inhalation of l-menthol. We did not measure occlusion pressure
at the steady-state, but the lack of changes in mean inspiratory
flow rate and breathing patterns suggests that there is little, if
any, change in respiratory drive during inhalation of l-menthol. Therefore, the reduction in respiratory discomfort following inhalation of l-menthol cannot be explained solely by
the reduction in respiratory drive.
Another possible mechanism by which inhalation of l-menthol reduces the respiratory discomfort might be through an
altered perception of the respiratory discomfort. Afferent information from the skin, the airway, or chest wall, which is
projected to the sensory cortex, is known to alter respiratory
sensation (10, 1418). Indeed, Schwartzstein and colleagues
(10) showed that a flow of cold air directed to the face reduces
the intensity of breathlessness associated with loaded breathing without causing a significant reduction in ventilation. They
hypothesized that the reduction in breathlessness is due to
stimulation of trigeminal nerve afferents, the information from
which may be processed in the central nervous system to alter
the perception of breathlessness. Also, it has been shown that
chest wall vibration reduces breathlessness in normal subjects
(17) and in patients with chronic lung disease (18), presumably
through stimulation of receptors in the chest wall. Thus, it is
likely that increased information from cold receptors in the upper airway may decrease the sensation of respiratory discomfort
independently of changes in ventilation and pattern of breathing. This notion is compatible with the work of Simon and coworkers (19), who showed that, in patients with COPD, stimulation of oral mucosa flow receptors reduces the intensity of
breathlessness induced by hypercapnia and an inspiratory resistive load, independently of changes in ventilation or pattern
of breathing.
The possibility exists that the observed reduction in sensation of respiratory discomfort might not depend on specific receptor mechanisms but rather on nonspecific effects of l-menthol, including distraction. In this connection, it is worthy to
note that l-menthol is not only a specific stimulant of cold receptors but also a strong olfactory stimulus. Our finding that
inhalation of strawberry-flavored air did not cause significant
changes in breathing patterns and VAS scores suggests that
the distraction associated with olfaction may not improve the
respiratory discomfort during loaded breathing. However, it is
in practice difficult to dissociate the effects of l-menthol on cold
receptors from that of olfaction (11). Therefore, we cannot exclude the possibility that the cooling sensation following l-menthol inhalation might have provided the potential distraction
from the respiratory discomfort during loaded breathing.
The difference in the relief of respiratory discomfort between the flow-resistive loading and the elastic loading may be
related to the difference in breathing patterns between the
two different types of loading. For example, the breathing patterns during flow-resistive loading are characterized by a slow
breathing, whereas those during elastic loading are characterized by a rapid, shallow breathing. Thus, it is likely that the relatively prolonged stimulation of cold receptors due to the marked
prolongation of TI during the flow-resistive loading may cause
the greater relief of respiratory discomfort than during the elastic loading.
During continued inhalation of l-menthol, in the majority
of subjects there was a slight attenuation of the reduction in
sensation of respiratory discomfort. This attenuation of relief
of respiratory discomfort is consistent with either an adaptation of cold receptors to l-menthol or central adaptation, or

both. Considering the nature of cold receptors that adapt rapidly to a constant airflow (5), it is possible that the adaptation
of cold receptors to l-menthol may in part explain the slight attenuation of relief of respiratory discomfort observed during
continued inhalation of l-menthol. The central adaptation is
another important feature of sensory mechanisms. Indeed, the
sensory magnitude of any stimulus declines following prolonged periods of stimulation for all sensory modalities, and
the respiratory sensation is not an exception (20). Thus, we
cannot deny the possibility that the attenuation of relief of respiratory discomfort during continued inhalation of l-menthol
may be due to the central adaptation mechanism.
In conclusion, our results support the hypothesis that stimulation of cold receptors in the upper airway alleviates the
sensation of respiratory discomfort.
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