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Open Journal of Respiratory Diseases, 2017, 7, 83-101
http://www.scirp.org/journal/ojrd
ISSN Online: 2163-9418
ISSN Print: 2163-940X
DOI: 10.4236/ojrd.2017.72009 May 27, 2017
Efficacy of a Topical Aromatic Rub
(Vicks VapoRub®) on Effects on Self-Reported
and Actigraphically Assessed Aspects of
Sleep in Common Cold Patients
Nayantara Santhi1, David Ramsey2, Gill Phillipson3, David Hull3*, Victoria L. Revell4,
Derk-Jan Dijk1
1Surrey Sleep Research Centre, School of Biosciences and Medicine, Faculty of Health
and Medical Sciences, University of Surrey, Surrey, UK
2The Procter & Gamble Company, Mason Business Center, Mason Montgomery Road, Mason, OH, USA
3Procter & Gamble, Greater London Innovation Centre, Whitehall Lane, Egham, Surrey, UK
4Surrey-Clinical Research Centre, Department of Clinical and Experimental Medicine, School of Biosciences and Medicine,
Faculty of Health and Medical Sciences, University of Surrey, Surrey, UK
Abstract
Common cold sufferers frequently report sleep disruption during the sym
p-
tomatic period of infections. We examined the effects of treatment with
a
topical aromatic pharmaceutical ointment (Vicks VapoRub®), on
associated
sleep disturbances. The effects of Vicks VapoRub® versus placebo
(petrolatum
ointment) on subjective and objective measured sleep parameters were a
s-
sessed in an exploratory study of 100 common cold patients, in a
randomized,
single blind, controlled, two-arm, parallel design study. The primary
efficacy
variable was subjective sleep quality measured with the SQSQ
(Subjective
Quality of Sleep Questionnaire). Additional measures included, ease of
falling
asleep and depth of sleep (measured with a post-sleep Visual Analog
Scale),
total sleep time, sleep onset latency, activity score, percentage of sleep,
sleep
efficiency (measured with actigraphy and SQSQ) and sleep quality
index
measured with a modified Karolinska Sleep Diary (KSD). The primary en
d-
point, “How was the quality of your sleep last night?” showed a
statistically
significant difference in change from baseline in favour of VapoRub
treatment
(
p
= 0.0392) versus placebo. Positive effects of VapoRub versus placebo
were
also observed for How refreshed did you feel upon waking up? (
p
=
0.0122)
(SQSQ), “Did you get enough sleep?” (
p
= 0.0036) (KSD), “How was it to
get
up?” (
p
= 0.0120) (KSD) and “Do you feel well-rested?” (
p
= 0.0125)
(KSD).
No statistically significant changes from baseline versus placebo were
detected
in the Actiwatch endpoints. Vicks VapoRub®
when applied before retiring to
How to cite this paper:
Santhi, N., Ram-
sey
, D., Phillipson, G., Hull, D., Revell, V.L.
and
Dijk, D.-J. (2017)
Efficacy of a Topical
Aromatic Rub (Vicks VapoRub
®
) on Effects
on
Self-Reported and Actigraphically As-
sessed Aspects of Sleep in Common Cold
Patients
.
Open Journal of Respiratory Di
s-
eases
,
7
, 83-101.
https://doi.org/10.4236/ojrd.2017.72009
Received:
April 25, 2017
Accepted:
May 24, 2017
Published:
May 27, 2017
Copyright
© 2017 by authors and
Scientific
Research Publishing Inc.
This
work is licensed under the Creative
Commons
Attribution International
License
(CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access
N. Santhi et al.
84
bed can reduce subjective sleep disturbances during a common cold. The re-
sults of this exploratory study support the belief among patients that the
use
of VapoRub improves subjective sleep quality during common cold which
was
associated with more refreshing sleep.
Keywords
Upper Respiratory Tract Infection, Common Cold, VapoRub,
Sleep Disturbance, Aromatic Oils
1. Introduction
The common cold, an infection of the upper respiratory tract, is reported to be
the most common human infectious disease [1] [2]. Adults can experience two
to four episodes a year and children six to eight [2].
Common cold is generally a mild illness of the upper respiratory tract, primarily
affecting the nose, nasopharynx and paranasal sinuses and is readily self- diag-
nosed by sufferers [3]. Rhinoviruses are the most common causative agents ac-
counting for up to 50% of symptomatic infections [1]. The main symptoms of
common cold include nasal congestion, nasal discharge, sneezing, headache, sore
throat, and cough [4]. Of these, nasal congestion and cough have been reported as
the most bothersome symptoms of a cold on 6 of the first 7 days of a cold [5].
Additionally, it is well recognised that during symptomatic common cold,
sleep can be adversely affected [6]. While this effect may be considered modest
(c. 23 minutes decrease in sleep and a 5% reduction in sleep efficiency) from a
scientific perspective [7], it is generally accepted that common cold-induced
sleep disruption is clinically meaningful. Smith (2012) [6] showed correlations
between symptom scores and sleep parameters. In general sleep measures and
total symptom score were correlated, indicating that increasing symptom sever-
ity was associated with sleep disturbance. The data suggested that nasal conges-
tion severity was a significant driver of the correlation. Therefore, remedies that
can alleviate rhinitis induced disturbances of sleep without the use of sedation,
to ensure a well-rested feeling upon awakening, have an important place in
therapy.
In the UK and many other countries, Vicks VapoRub® (VVR) is indicated for
the reduction in cough frequency [8] and feeling of relief from nasal congestion
[9]. As cough and nasal congestion (regardless of aetiology) are recognised bar-
riers to restful and restorative sleep [10], [11], [12], their relief using a topical
ointment like VVR can be predicted to improve elements of sleep quality.
VVR is a pharmaceutical preparation containing a combination of levomen-
thol (2.75% w/w), eucalyptus oil (1.5% w/w), turpentine oil (5% w/w) and cam-
phor (5% w/w) as active ingredients, and thymol, cedarwood oil, and white soft
paraffin (petrolatum) as excipients. VVR is an ointment that is either applied
topically to the chest, throat, and back or added to hot water and the aromatic
N. Santhi et al.
85
vapours inhaled. When applied to the skin, the active ingredients are evaporated
by body temperature and inspired into the airways. The therapeutic effects, re-
duction in cough frequency and relief from nasal congestion, are likely due, at
least in part, to interactions of the aromatics with the largely calcium-selective
ion channel, transient receptor potential (TRP) receptors. Recent data suggest
that the transient receptor potential receptors TRPM8, TRPV1 and TRPA1 are
up-regulated in respiratory virus infected cells [13] [14]. TRPM8 mediates the
feeling of coolness associated with menthol and eucalyptus oil [15], [16] and so
is likely the main mediator of the sensation of cooling and nasal decongestion
associated with menthol and eucalyptus oil [9]. Camphor, eucalyptus oil and
menthol have been shown to interact with the TRPV1 and TRPA1 receptors [17]
[18] [19] which are implicated in the neurophysiology of cough [13] [14]. These
interactions may therefore have a role in controlling cough sensitivity.
This study compared the effects of VVR versus placebo on subjectively and
objectively assessed sleep parameters in adult common cold sufferers. Sleep pa-
rameters were measured using subjective questionnaires (Subjective Quality of
Sleep Questionnaire [SQSQ] [20], a modified Karolinska Sleep Diary [KSD] [21],
and a study-specific post-sleep questionnaire) and actigraphy, an objective
method of monitoring rest-activity patterns [22]. Several subjective question-
naires were employed because this was the first exploration of the effect of VVR
on sleep parameters so little knowledge existed of likely effect size or which ele-
ments of sleep may be affected. Actigraphy was employed as it is a validated ob-
jective albeit surrogate measure of sleep.
2. Methods
2.1. Participants
One hundred and forty-one adult participants were screened for this study and
100 were enrolled and randomized to the 2 treatment groups (Figure 1). The
mean (SD) age of those enrolled was 23 years (8.7) with a mean Body Mass In-
dex (BMI) of 23 (2.9). The population was 61% female and most participants
(71%) were Caucasian. One participant withdrew consent during the study and
their data were not included. Subjects were recruited by advertisement from the
staff and students of the University of Surrey and the greater London area. Those
participating received £120 compensation.
Randomized participants were suffering from a common cold and experienc-
ing nasal congestion, cough and disturbance to normal sleep. Key inclusion cri-
teria included suffering from a self-diagnosed common cold of no more than 36
hours duration; suffering from at least mild cough and nasal congestion due to
the common cold (scores of at least 1 on the 4-point ordinal scale); having an
average score of < 50 on the 2 responses to the question “How would you com-
pare the quality of last night’s sleep with your usual sleep without a cold?” from
the Leeds Sleep Evaluation Questionnaire (LSEQ) [23], a 100-mm Visual Analog
Scale (VAS), where Response 1 is 0 = “Less restful than usual” and 100 = “More
N. Santhi et al.
86
Figure 1. Subject disposition.
restful than usual” and Response 2 is 0 = “More periods of wakefulness than
usual” and 100 = “Fewer periods of wakefulness than usual”.
Volunteers were excluded if they had any of the following: A previously diag-
nosed sleep disorder, a current sleep disturbance or poor sleep quality unrelated
to their cold based on the Pittsburgh Sleep Quality Index (PSQI) [24] (
i.e.
, a
score of >5); a clinically significant nasal abnormality; a history of clinically re-
levant anosmia; were employed on night or rotating shift work or needed to tra-
vel across more than 2 time zones in the 14 days prior to screening or planned to
do so during the study; a history of allergy or hypersensitivity to any of the in-
gredients of VVR; a history of significant airway disease or pronounced hyper-
sensitivity of the airways/asthma or Chronic Obstructive Pulmonary Disease, a
significant history of recurrent sinusitis or currently experiencing allergic rhini-
tis, or significant history of chronic cough; a body temperature > 100.5°F
(38.1˚C); had used, within 5 half-lives, substances or medications known to af-
fect sleep; had used nasal decongestants in the past 24 hours; had a self-reported
consumption of >5 caffeinated beverages daily; used nicotine in any form; took
naps daily; used inhaled, topical, or oral nedocromil or cromolyn sodium, tricyc-
lic antidepressant medications, or monoamine oxidase inhibitors for 14 days
prior to screening; had a history of alcohol or drug abuse within the past 2 years;
N. Santhi et al.
87
were currently enrolled in another clinical trial, or had received any other inves-
tigational drug within the past 30 days; if female and of child-bearing potential
had a positive urine pregnancy test at screening or were lactating; had a history
of malignancy within the past 2 years, or had current or past history of serious,
severe, or unstable physical or psychiatric illness; or were taking medication that
the Investigator believed would interfere with the evaluation of the study, pose a
safety risk, or confound the interpretation of the study results.
2.2. Study Design
The study (EudraCT# 2013-004524-11) was a randomized, single-(Investigator)
blind, controlled, 2-arm (Vicks VapoRub® [VVR] vs. petrolatum), parallel de-
sign, single site study conducted at Surrey Clinical Research Centre, University
of Surrey, between November 2014 and May 2015.
The study was conducted in accordance with the ICH Guideline for Good
Clinical Practice, 1997; the US CFR Title 21 parts 50, 56 and 312; applicable na-
tional laws and regulations; the ethical requirements of Directive 2001/20/EC;
and the ethical principles with their origin in the Declaration of Helsinki. The
study was approved by the NRES Committee London-Brent Ethics Committee
and all participants provided written informed consent prior to any study pro-
cedures being conducted.
The study included a baseline visit (Day 0) at the study site to confirm study
eligibility and to randomly assign subjects to 1 of 2 test products (VVR or petro-
latum). Randomized subjects were sent home with the SQSQ, KSD, and post-
sleep questionnaire, along with the Actiwatch sleep monitoring equipment and
their assigned test product. Subjects were instructed to use the Actiwatch on this
first evening of Day 0, but did not apply test product. Upon waking the next
morning, subjects completed the SQSQ, KSD, and the post-sleep questionnaire.
The test period began on the evening of Day 1 when subjects applied their
randomly assigned test product as directed, immediately before going to bed.
Subjects continued using the Actiwatch overnight. Upon waking the next
morning, subjects completed the SQSQ, KSD, and post-sleep questionnaire.
These procedures were repeated on the evening of Day 2 and the following
morning. Subjects then returned to the study site on Day 3 to complete exit pro-
cedures and to return their sleep monitoring equipment, completed question-
naires, and test product containers with any remaining study test product. At
this point, the subjects exited from the study.
2.3. Test Products
7.5 grams of commercially available VVR and petrolatum base (placebo) were
packaged in identical individual 25 gram jars identifiable only by participant
number. Participants were provided with 2 identical jars of either VVR or pla-
cebo at Day 0 with the instructions to apply all of the product from the first jar
on the evening of Day 1 at bedtime, and all of the product from the second jar
on the evening Day 2 at bedtime.
N. Santhi et al.
88
2.4. Sleep Measures
The effect size of VVR on sleep was not expected to be large in absolute terms.
Further, we were most interested in the subjective perceptions of sleep quality
therefore change in the, “How was the quality of your sleep last night?” question
of the SQSQ, a validated questionnaire which has been shown to be sensitive to
effects of zolpidem, temazepam [25], gaboxadol and traffic noise [20] and slow
wave sleep disruption by acoustic stimuli [26], was chosen as the primary end-
point. The KSD questionnaire [21], [27] was modified for this study by remov-
ing the first 5 questions due to duplication of sleep measures with the SQSQ.
Actigraphy is considered a valid method to quantify sleep patterns in healthy
controls, patients with sleep disorders and their treatment response [28]. This
method was included in the study because if positive correlation with the subjec-
tive measures were observed, it would provide additional confidence in the effect
and its magnitude. The Actiwatch 4® is a gyroscopic actigraphic device worn on
the non-dominant wrist to collect objective indirect measurements of sleep and
wakefulness (
i.e.
, where movement is a surrogate for wakefulness) utilizing an
automated computer and scoring algorithm. Derived sleep measures were total
sleep time, sleep onset latency, mean activity score, percentage of sleep (per-
centage of actual sleep time between sleep onset and sleep end), sleep efficiency
(percentage of time spent asleep from “Lights out” to “Lights on”), and number
of sleep bouts. For computations of sleep and wakefulness the software algo-
rithm used the activity data recorded by the Actiwatch 4® in a series of linked
calculations, such that each data point from each epoch and those surrounding
was used to compute a total score based on these activity counts. With a default
Medium Sensitivity, for 1-minute epoch data (and pro rata for other epochs
used) a total score of 40 was designated as an “Awake” epoch. The activity scale
was set to 2000. To determine “Sleep Start”, the algorithm looked for a period of
at least 10 minutes of consecutively recorded immobile data, with no more than
1 epoch of movement within that time, following the “Bed Time”. To determine
‘Sleep End’, the algorithm looked for a 10-minute consecutive period of activity
around the “Get Up Time” and then worked back to find the last epoch of im-
mobility. To set the analysis window, the actigraphy marker-based bedtime and
get-up times were used. In instances, where subjects failed to use the markers,
their sleep-diary based bedtime and get up times were used instead.
2.5. Statistical Methods
Randomization and Stratification of Participants: All potential study participants
were given a subject number (starting at 1001 in the order in which they were
screened for the study). Eligible volunteers were stratified by average LSEQ score
on the 2 responses to the question “How would you compare the quality of last
night’s sleep with your usual sleep without a cold?” (0 - 20.8 = “Very poor”; >
20.8 - 35.4 = “Rather poor”; > 35.4 - < 50 = “Intermediate”). Participants were
then randomly assigned to test products (VVR or placebo) using a block ran-
domization. A unique randomization number (e.g., 101, 102, 103, etc) was as-
N. Santhi et al.
89
signed to each eligible participant.
Safety Analyses: All safety summarization was done on Intent-to-Treat popu-
lation (all randomized subjects).
Efficacy Analyses: All efficacy analyses were done on Per-Protocol population.
The Per-Protocol population comprised those participants who were generally
compliant with test product usage instructions (used ≥ half of the allocated dose)
and met key inclusion and exclusion criteria. The Per-Protocol assessment was
determined on blinded data prior to receiving treatment codes. In order to ob-
tain a more consistent response, the two treatment days (Day 1 and Day 2) for
each endpoint were averaged for analysis purposes and served as the response
variable for the analyses.
Comparability of treatments at baseline for demographics, baseline character-
istics, SQSQ, post-sleep questionnaire, Actiwatch, and KSD was assessed via 2-
sample t-test, Fisher’s exact test, and Cochran-Mantel-Haenszel test, as appro-
priate per the data type. Analysis of covariance (ANCOVA) was used for ana-
lyzing primary and secondary endpoints using the Mixed procedure of SAS ver-
sion 9.4 (SAS Institute, Cary, NC, USA).The primary endpoint was sleep quality
as measured by the SQSQ. Each hypothesis was tested separately using an
ANCOVA model that included relevant baseline measures as a covariate and
treatment group as independent variable (fixed factor). The following hypothe-
ses were tested separately for each endpoint:
Null Hypothesis: the change from baseline mean <
insert endpoint
> is the
same for VVR versus placebo. Alternative Hypothesis: the change from baseline
mean <
insert endpoint
> is different for VVR versus placebo.
Two of the secondary KSD measures (“Did you take any drugs before retir-
ing?” and “Did you wake up ahead of time without being able to return to
sleep?”) required nonparametric assessments as described in the protocol due to
assumptions of ANCOVA not being met. All hypotheses were tested at a
two-sided significance level of 5%. No corrections for multiplicity were con-
ducted in this exploratory investigation.
2.6. Sample Size
The sample size was determined by logistical considerations and previous ex-
perience with sleep studies.
3. Results
Demographics: Table 1 shows the demographic composition of the participants.
Participant screening and baseline characteristics: common cold symptom se-
verity, PSQI, LSEQ (abbreviated, only displayed two Leeds questions that were
part of inclusion criteria), SQSQ, KSD and Post-sleep questionnaire, did not dif-
fer between groups (Tables 1-3).
Product Dosing Compliance: Product dosing compliance was assessed by
weighing the sample jars before and after treatment. On average participants
used 23% less product than instructed on both treatment nights. There were no
N. Santhi et al.
90
Table 1. Summary of demographics and baseline characteristics (Intent-to-treat).
Parameter
Statistic/Category
VapoRub
(N = 50)
Petrolatum
(N = 50)
P
value1
Age
23.1 (9.45) 23.7 (7.99) 0.7154
Sex
0.6820
Female 32 (64%) 29 (58%)
Male 18 (36.0%) 21 (42%)
Race
0.1287
Caucasian
30 (60%)
41 (82%)
Asian Indian
8 (16%) 1 (2%)
Black
3 (6%) 3 (6%)
Other
9 (18%) 5 (10%)
Height (cm)
170.5 (9.24)
170.9 (11.47)
0.8511
Weight (kg)
69.5 (12.66) 67.7 (11.80) 0.4618
BMI
23.8 (3.25) 23.1 (2.46) 0.1915
Nasal Congestion
0.3696
Mild
25 (50%)
23 (46%)
Moderate
25 (50%) 24 (48%)
Severe
0 (0%) 3 (6%)
Cough
0.3235
Mild
38 (76.0%) 33 (66%)
Moderate
11 (22.0%) 16 (32%)
Severe
1 (2%) 1 (2%)
Runny Nose
0.7911
Not Present
3 (6%) 1 (2%)
Mild
16 (32%) 23 (46%)
Moderate
25 (50%) 19 (38%)
Severe
6 (12%) 7 (14%)
Sore Throat
0.6862
Not Present
8 (16%) 6 (12.0%)
Mild
22 (44%) 24 (48.0%)
Moderate
19 (38%) 18 (36.0%)
Severe
1 (2%) 2 (4.0%)
Sneezing
0.5225
Not Present
13 (26%) 12 (24%)
Mild
23 (46%) 22 (44%)
Moderate
14 (28%) 14 (28%)
Severe
0 (0%) 2 (4%)
PSQI total
2 2.8 (1.38) 2.9 (1.33) 0.8256
Leeds Quality 1: More/Less Restful
3 29.5 (15.68) 27.8 (12.35) 0.5646
Leeds Quality 2: Fewer/More Periods Of Wakefulness
4 34.2 (14.00) 32.9 (15.71) 0.6685
Values are means (SD) or n(%) of subjects. 1P-values were calculated with 2 sample t-test for conti-
nuous variables, Fisher's exact test for non-ordered categorical variables, and Coch-
ran-Mantel-Haenszel test for ordered categorical variables. Continuous data that violated normality
were also analyzed nonparametrically with the Wilcoxon Rank Sum Test with similar conclusions of
no statistically significant difference (
p
> 0.05). 2Pittsburgh Sleep Quality Index. Leeds sleep evalua-
tion questionnaire question: “How would you compare the quality of last night’s sleep with your
usual sleep without a cold?” 3A 100-mm Visual Analog Scale (VAS), where response is 0 = “Less
restful than usual” and 100 = “More restful than usual”. 4A 100-mm Visual Analog Scale (VAS),
where response is 0 = “More periods of wakefulness than usual” and 100 = “Fewer periods of wake-
fulness than usual”.
N. Santhi et al.
91
Table 2. Summary of subjective quality of sleep questionnaire, post-sleep questionnaire,
and actiwatch for baseline (per-protocol).
Parameter/Category
VapoRub
(N = 46)
Petrolatum
(N = 47)
P
value1
Subjective Quality of Sleep Questionnaire
Wake Up Refreshed3 36.5 (15.59) 31.2 (20.00) 0.1575
Sleep Quality2 60.8 (17.49) 65.1 (19.98) 0.2750
Sleep Onset Latency (min) 25.1 (18.08) 26.4 (19.31) 0.7518
Number of Awakenings 2.5 (2.11) 2.9 (2.03) 0.4154
Total Sleep Time (min) 463.1 (57.76) 466.9 (46.96) 0.7337
Wake After Sleep Onset (min) 19.1 (23.61) 18.8 (20.99) 0.9447
Sleep Efficiency 89.5 (7.05) 89.7 (5.92) 0.8527
Post-sleep Questionnaire
How Easy Falling Asleep3 41.7 (17.01) 42.0 (23.85) 0.9472
How Deep Was Sleep2 57.5 (19.15) 57.1 (23.14) 0.9291
Actiwatch
Total Sleep Time (min) 403.7 (65.97) 394.0 (40.77) 0.3939
Sleep Onset Latency (min) 18.7 (28.70) 18.7 (25.47) 0.9992
Mean Activity Score 21.9 (10.26) 21.3 (9.43) 0.7652
Percentage of Sleep 83.4 (5.62) 83.1 (5.84) 0.8070
Sleep Efficiency 79.9 (7.05) 79.2 (7.00) 0.6226
Number of Sleep Bouts 32.9 (8.54) 32.1 (8.79) 0.6637
Wake After Sleep Onset (min) 80.1 (28.14) 81.0 (32.64) 0.8829
Values are means (SD). 1P-values were calculated with 2-sample t-test. Continuous data that violated nor-
mality were also analyzed nonparametrically with the Wilcoxon Rank Sum Test with similar conclusions of
no statistically significant difference (
p
> 0.05). 2VAS with lower numbers better. 3VAS with higher num-
bers better.
between-group differences—both groups used between 5.7 and 5.8 grams versus
the supplied single-dose amount of 7.5 grams. The Per-Protocol analyses ex-
cluded seven participants for the nights they used less than half the allocated
dose (3 VVR and 4 placebo participants).
Table 4 shows the data from statistical testing of between group differences in
the various subjective scales used.
Subjective Quality of Sleep Questionnaire Endpoints: Statistical testing of the
between group differences showed that the primary endpoint of Sleep Quality in
the SQSQ showed a statistically significant difference in change from baseline in
favour of VVR treatment compared to placebo (Table 4, Figure 2;
p
= 0.0392).
This was also found for the “Wake up refreshed” SQSQ endpoint (Table 4, Fig-
ure 2;
p
= 0.0122). None of the other SQSQ endpoints showed statistically sig-
nificant between group differences (Table 4, Figure 2). Examination of the mo-
nadic changes from baseline were consistent with the between group findings:
89% of participants who used VVR reported an improved quality of sleep vs
N. Santhi et al.
92
Table 3. Summary of Karolinska sleep diary for baseline (Per-Protocol).
Parameter/Category
VapoRub
(N = 46)
Petrolatum
(N = 47)
P
value1
How well did you sleep
0.2227
1-VERY POORLY 0 (0%) 4 (8.5%)
2-RATHER POORLY 17 (37.0%) 20 (42.6%)
3-INTERMEDIATE 23 (50.0%) 16 (34.0%)
4-RATHER WELL 5 (10.9%) 6 (12.8%)
5-VERY WELL 1 (2.2%) 1 (2.1%)
Difficulties falling asleep
0.5029
1-GREAT DIFFICULTIES 1 (2.2%) 4 (8.5%)
2 13 (28.3%) 12 (25.5%)
3-RATHER 13 (28.3%) 15 (31.9%)
4 14 (30.4%) 10 (21.3%)
5-NOT AT ALL 5 (10.9%) 6 (12.8%)
Have a restless sleep
0.7131
1-VERY 4 (8.7%) 6 (12.8%)
2 14 (30.4%) 12 (25.5%)
3-A LITTLE 15 (32.6%) 19 (40.4%)
4 10 (21.7%) 6 (12.8%)
5-NOT AT ALL 3 (6.5%) 4 (8.5%)
How deep was your sleep
0.9959
1-VERY LIGHT 3 (6.5%) 0 (0%)
2-RATHER LIGHT 4 (8.7%) 15 (31.9%)
3-INTERMEDIATE 28 (60.9%) 18 (38.3%)
4-RATHER DEEP 10 (21.7%) 11 (23.4%)
5-VERY DEEP 1 (2.2%) 3 (6.4%)
How much did you dream
0.3483
1-MUCH 0 (0%) 1 (2.1%)
2 4 (8.7%) 5 (10.6%)
3-A LITTLE 10 (21.7%) 10 (21.3%)
4 4 (8.7%) 8 (17.0%)
5-NOT AT ALL 28 (60.9%) 23 (48.9%)
Did you get enough sleep
0.7085
1-NO FAR TOO LITTLE 0 (0%) 0 (0%)
2-NO TOO LITTLE 8 (17.4%) 11 (23.4%)
3-NOT QUITE 16 (34.8%) 18 (38.3%)
4-YES ALMOST 19 (41.3%) 11 (23.4%)
5-YES DEFINITELY 3 (6.5%) 7 (14.9%)
N. Santhi et al.
93
Continued
How was it to get up
0.4289
1-VERY DIFFICULT 0 (0%) 4 (8.5%)
2-RATHER DIFFICULT 20 (43.5%) 18 (38.3%)
3-INTERMEDIATE 18 (39.1%) 17 (36.2%)
4-RATHER EASY 6 (13.0%) 7 (14.9%)
5-VERY EASY 2 (4.3%) 1 (2.1%)
Do you feel well rested 0.3988
1-NOT AT ALL 4 (8.7%) 7 (14.9%)
2 20 (43.5%) 24 (51.1%)
3-RATHER 16 (34.8%) 10 (21.3%)
4 6 (13.0%) 4 (8.5%)
5-FULLY 0 (0%) 2 (4.3%)
What caused your final awakening 0.8701
1-OTHER 3 (6.5%) 2 (4.3%)
2-NEED BATHROOM 2 (4.3%) 1 (2.1%)
3-NOISE 1 (2.2%) 2 (4.3%)
4-ALARM CLOCK 30 (65.2%) 29 (61.7%)
5-NOTHING PARTICULAR 10 (21.7%) 13 (27.7%)
Take any drugs before retiring
5-NO 46 (100%) 47 (100%)
Occurrences that might have affected sleep 0.5698
1-NO 36 (78.3%) 34 (72.3%)
2-STRESS 2 (4.3%) 0 (0%)
3-WORRIES 2 (4.3%) 3 (6.4%)
4-DISEASE, PAIN 1 (2.2%) 2 (4.3%)
5-HARD PHYSICAL WORK 2 (4.3%) 2 (4.3%)
6-NOISE 3 (6.5%) 3 (6.4%)
7-OTHER 0 (0%) 3 (6.4%)
Wake up ahead of time not able to return to sleep 0.8571
2 2 (4.3%) 2 (4.3%)
3-SOMEWHAT EARLY 5 (10.9%) 7 (14.9%)
4 5 (10.9%) 3 (6.4%)
5-NO 34 (73.9%) 35 (74.5%)
N = number of subjects within specified treatment. n(%) = number and percentage of subjects within speci-
fied parameter, treatment, and category. 1P-values were calculated with Fisher’s exact test and Coch-
ran-Mantel-Haenszel test, as appropriate per the data type.
N. Santhi et al.
94
Table 4. Analysis of covariance of subjective sleep questionnaires and diaries (Per-Protocol).
Change From Baseline
Endpoint
Count
Adjusted Mean (SE)
Adjusted Mean (SE)
Treatment Difference
VapoRub
Petrolatum
VapoRub
Petrolatum
VapoRub
Petrolatum
Adjusted Mean (SE)
P
-value
Subjective Quality of Sleep Questionnaire
Sleep Quality1 46 47 41.4 (2.68) 49.3 (2.65) −21.6 (2.68)
−
13.7 (2.65)
−7.9 (3.78) 0.0392
Wake Up Refreshed2 46 47 53.5 (2.33) 45.0 (2.30) 19.6 (2.33) 11.2 (2.30) 8.4 (3.29) 0.0122
Sleep Onset Latency (min) 46 47 21.8 (2.22) 22.6 (2.20) −4.0 (2.22) −3.2 (2.20) −0.8 (3.13) 0.7929
Number of Awakenings 46 47 1.3 (0.17) 1.7 (0.17) −1.3 (0.17) −1.0 (0.17) −0.3 (0.25) 0.2048
Total Sleep Time (min) 46 47 471.2 (5.91)
472.3 (5.84)
6.2 (5.91) 7.3 (5.84) −1.1 (8.31) 0.8988
Wake After Sleep Onset (min) 46 47 10.0 (1.49) 12.1 (1.48) −9.0 (1.49) −6.9 (1.48) −2.1 (2.10) 0.3271
Sleep Efficiency 46 47 92.3 (0.77) 91.7 (0.76) 2.7 (0.77) 2.1 (0.76) 0.6 (1.08) 0.5505
Karolinska Sleep Diary
How well did you sleep 46 47 3.5 (0.11) 3.3 (0.11) 0.9 (0.11) 0.7 (0.11) 0.2 (0.16) 0.2272
Difficulties falling asleep 46 47 3.6 (0.12) 3.4 (0.12) 0.5 (0.12) 0.3 (0.12) 0.2 (0.17) 0.2732
Have a restless sleep 46 47 3.6 (0.12) 3.4 (0.12) 0.8 (0.12) 0.6 (0.12) 0.2 (0.17) 0.2843
How deep was your sleep 46 47 3.7 (0.09) 3.5 (0.09) 0.6 (0.09) 0.5 (0.09) 0.1 (0.13) 0.3444
How much did you dream 46 47 3.9 (0.13) 3.8 (0.13) −0.2 (0.13) −0.3 (0.13) 0.1 (0.18) 0.6127
Did you get enough sleep 46 47 3.9 (0.11) 3.4 (0.11) 0.6 (0.11) 0.1 (0.11) 0.5 (0.16) 0.0036
How was it to get up 46 47 3.5 (0.11) 3.1 (0.11) 0.8 (0.11) 0.4 (0.11) 0.4 (0.15) 0.0120
Do you feel well rested 46 47 3.4 (0.11) 3.0 (0.11) 0.9 (0.11) 0.5 (0.11) 0.4 (0.16) 0.0125
What caused your final awakening 46 47 4.1 (0.10) 4.1 (0.09) 0.1 (0.10) 0.1 (0.09) 0.0 (0.13) 0.8840
Occurrences that might
have affected Sleep 46 47 1.7 (0.19) 2.0 (0.19) −0.2 (0.19) 0.0 (0.19) −0.2 (0.26) 0.4165
Sleep Quality Index 46 47 3.9 (0.08) 3.7 (0.08) 0.6 (0.08) 0.5 (0.08) 0.1 (0.11) 0.3124
Post−sleep Questionnaire
How Easy Falling Asleep2 45 46 52.1 (2.59) 50.5 (2.56) 10.3 (2.59) 8.6 (2.56) 1.6 (3.64) 0.6564
How Deep Was Sleep1 46 47 38.1 (2.21) 44.0 (2.18) −19.2 (2.21)
−
13.3 (2.18)
−5.9 (3.11) 0.0606
1. 0 - 100 VAS scale where lower values are better (negative treatment difference better); 2. 0 - 100 VAS scale where higher values are better (positive treat-
ment difference better).
baseline, and 91% who used VVR reported an improved “wake up refreshed”
score vs baseline. In examining the consistency of response of the primary end-
point (sleep quality as measured by SQSQ), subgroup analyses by demographics
and baseline characteristics were assessed. The results for all subgroups analysed
favoured VVR compared to placebo, indicating consistency of response. Statis-
tical significance of VVR vs. placebo for sleep quality was observed in the sub-
group of subjects with moderate-to severe cough at baseline (
p
= 0.0294), runny
nose not present/mild at baseline (
p
= 0.0492) and PSQI ≥ 3 (
p
= 0.0486) (Data
not shown).
N. Santhi et al.
95
(a)
(b)
Figure 2. (a) Plot of mean differences and 95% Confidence Intervals for each of the Sub-
jective Quality of Sleep Questionnaire (SQSQ) questions comparing answers provided
“on awakening” with baseline; (b) Primary. Histogram showing the statistical analysis of
results from the SQSQ question identified
a piori
as Primary Objective comparing an-
swers provided “on awakening” with baseline. Visual Analogue Scale–“How was the qual-
ity of your sleep last night?” 0 = “Very Good” and 100 = “Very Bad”. Between group dif-
ference statistically significant at
p
< 0.0392. (b) Secondary. Histogram showing the sta-
tistical analysis of results from the SQSQ question identified
a piori
as “First Secondary
Objective”, comparing answers provided “on awakening” with baseline. Visual Analogue
Scale–“How refreshed did you feel upon waking up?” 0 = “Very Good” and 100 = “Very
Bad”. Between group difference statistically significant at
p
< 0.0122.
Karolinska Sleep Diary Endpoints: Statistical testing of the KSD endpoints
showed significant between group differences for “Did you get enough sleep?” (
p
= 0.0036), “How was it to get up?” (
p
= 0.0120) and “Do you feel well-rested?” (
p
= 0.0125) favouring VVR compared to placebo (Table 4, Figure 3). While none
of the other KSD or Post-sleep Questionnaire endpoints reached statistical sig-
nificance, VVR treatment showed a numerical improvement in the KSD results
(Table 4 & Figure 3). The two secondary KSD measures (“Did you take any
N. Santhi et al.
96
Figure 3. Plot of mean differences and 95% Confidence Intervals for each of the Karo-
linska Sleep Diary (KSD) questions comparing answers provided “on awakening” with
baseline.
drugs before retiring?” and “Did you wake up ahead of time without being able
to return to sleep?”) analyzed by nonparametric measures did not show signifi-
cant treatment differences (data not shown). A trend in favour of VVR com-
pared to placebo (
p
= 0.0606), was observed in change from baseline for the
“How deep was sleep?” endpoint in the Post-sleep Questionnaire but no differ-
ence in ease of falling asleep (Table 4).
Actigraphy Endpoints: There were no statistically significant changes from
baseline treatment differences in the Actiwatch endpoints. There was, however, a
trend in favour of VVR compared to placebo for change from baseline in Sleep
Onset Latency (Table 5, Figure 4; treatment difference 11.5 minutes and
p
=
0.0538).
Safety
Both treatments were well-tolerated during this study. There were no deaths, se-
rious or other significant Adverse Events (AEs). Eight participants reported 10
AEs; 5 on placebo and 3 on VVR and all resolved without any action being taken
to ameliorate the AE.
4. Discussion
The results from this exploratory study show for the first time that application of
Vicks VapoRub® before retiring to bed has a positive effect on perceived sleep
quality for adults suffering from symptoms of common cold. The primary end-
point subjective finding supports the long-held association described by com-
mon cold patients of VVR use and improved sleep. It cannot be determined
from these data alone whether this is a result of symptom relief facilitating sleep
(as has been suggested for cough relief [29]) or a direct effect on sleep. However,
the active ingredients in VVR are not known to have a sedative effect. This sug-
gests that a patient-perceived sleep quality benefit in patients with a cold would
be due to a different mechanism, likely symptom relief. Indeed, the subgroup of
patients with moderate-to-severe cough at baseline reported improvement for
sleep quality vs placebo (
p
= 0.0294).
N. Santhi et al.
97
Table 5. Analysis of covariance of Actiwatch (Per-Protocol).
Change From Baseline
Endpoint
Count
Adjusted Mean (SE)
Adjusted Mean (SE)
Treatment Difference
VapoRub
Petrolatum
VapoRub
Petrolatum
VapoRub
Petrolatum
Adjusted Mean (SE)
P
-value
Total Sleep Time (min)
46 47 394.9 (7.44) 381.8 (7.36) −3.9 (7.44) −17.1 (7.36)
13.2 (10.48) 0.2124
Sleep Onset Latency (min)
46 47 18.8 (4.18) 30.3 (4.14) 0.1 (4.18) 11.6 (4.14) −11.5 (5.88) 0.0538
Mean Activity Score
46 47 21.4 (1.49) 23.7 (1.48) −0.2 (1.49) 2.1 (1.48) −2.3 (2.10) 0.2820
Percentage of Sleep
46 47 83.6 (0.78) 82.7 (0.77) 0.4 (0.78) −0.6 (0.77) 1.0 (1.10) 0.3837
Sleep Efficiency
46 47 79.6 (1.16) 76.9 (1.15) 0.0 (1.16) −2.6 (1.15) 2.7 (1.64) 0.1050
Number of Sleep Bouts
46 47 30.1 (0.91) 29.8 (0.90) −2.3 (0.91) −2.7 (0.90) 0.3 (1.28) 0.8077
Wake After Sleep Onset (min)
46 47 76.5 (3.82) 80.1 (3.78) −4.0 (3.82) −0.5 (3.78) −3.5 (5.38) 0.5122
Figure 4. Plot of mean differences and 95% Confidence Intervals for each of the Acti-
watch endpoints comparing answers provided on awakening with those at baseline.
It was hypothesised that VVR would affect sleep as a result of its known de-
congestion and antitussive effects rather than as a sleep aid. Consequently, while
for completeness both subjective and objective assessments of sleep were em-
ployed, it was predicted that subjective endpoints were most likely to be affected.
Change in the SQSQ sleep quality was chosen as the primary objective as it of-
fered a global retrospective assessment of the perceived sleep experience. The
KSD was also included as a source of secondary endpoints to permit a more
granular description of the subjective elements of sleep affected. As nasal de-
congestion and cough relief are the licensed indications of VVR in the UK, they
were not measured in this study wherein the focus was sleep-related effects.
The difference in perceived sleep quality assessed by the SQSQ was statistically
significant (
p
= 0.0392). To place this change in perspective it is noted that the
observed response to VVR compared to placebo for the SQSQ was 7.9 units,
which is comparable to the positive effects of gaboxadol on subjective sleep qual-
ity in a traffic noise model of sleep disruption [20] and approximately half the
size of the effect of zolpidem and temazapam on sleep in middle-aged people
[25]. Supporting this is the finding that responses to the “How refreshed did you
feel upon waking?” SQSQ endpoint were also significant (
p
= 0.0122). On aver-
N. Santhi et al.
98
age subjects had 58% better sleep quality vs. placebo and 75% better wake up re-
freshed vs. placebo. The effect sizes for questions [30] would be considered a
moderate effect (0.44 and 0.54 respectively). Taken together these findings sug-
gest that VVR had a clinically relevant effect on the perception of sleep quality.
We speculate that as subjective sleep assessments are necessarily retrospective,
the fact that the VVR aroma would still be noticeable in the morning may have
augmented the perception of improved sleep quality.
The SQSQ also includes a series of more specific time and duration related
questions. Changes in these parameters did not reach statistical significance,
consistent with the objective actigraphy results except for sleep onset latency
which objectively favoured VVR with subjects falling asleep approximately 11.5
minutes faster than placebo (
p
= 0.0538). Arguably, questions around for exam-
ple, time to get to sleep, number of awakenings, duration of awakenings, etc. re-
quire an awareness of sleep and sleep disruption that may be difficult to measure
in patients with an illness such as the common cold relative to other conditions;
further studies would be useful. It seems reasonable to expect greater effects if
subjects had more severe symptoms and/or more severe sleep disturbance at
baseline.
There were also positive findings for some of the secondary endpoints as-
sessed by the KSD. Participants provided positive (for VVR) between group re-
sponses for, “Did you get enough sleep?” (
p
= 0.0036), “How was it to get up?”
(
p
= 0.0120) and “Do you feel well-rested?” (
p
= 0.0125). The effect size for the
significant KSD questions (0.62, 0.53, and 0.53 respectively) would be considered
moderate effects [30]. These parameters may be considered to be elements of the
overall findings of improved sleep quality and the feelings of having had re-
freshing sleep. They are consistent with improvements in an improved overall
sleep experience. The remaining KSD parameters including, “How did you
sleep?” and sleep quality index, did not show a statistical significant effect.
The objective effects on sleep were assessed using arm motion during rest as a
surrogate measure for wakefulness. The Actiwatch instrument has been vali-
dated for the assessment of a variety of sleep parameters [28] [31]. We believe
this study is the first use of actigraphy in the investigation of the mild sleep dis-
turbance associated with common cold. The Actiwatch and subjective data were
broadly consistent. In this study of sleep disturbance associated with common
cold, no significant between-group differences were detected in the objective da-
ta-only “Sleep Onset Latency” approached statistical significance (
p
= 0.0538).
Several limitations of this study merit discussion. An obvious limitation is that
it was not double-blind. As the Informed Consent information made clear that
participants would be treated either with an aromatic or non-aromatic product,
those allocated VVR would have been aware that they had received active prod-
uct as soon as they sensed the aroma. The difficulty in designing double-blind
studies with VVR is a recognized design limitation [32]. It is difficult to blind a
study wherein the aroma of the product is so widely recognized and represents
the pharmacological effect. Investigators were blinded as no medication was
N. Santhi et al.
99
opened at the study site thus preserving the single blind.
Finally, while these data indicate a positive effect of VVR on sleep quality they
cannot distinguish between VVR treatment improving sleep quality solely as a
result of reducing the symptoms, exerting a direct sleep effect or a combination
of both. Further work is recommended wherein the direct sleep quality benefit in
persons with sleep disturbance and no infectious disease is examined.
5. Conclusion
Common cold sufferers using Vicks VapoRub® (applied before retiring to bed)
experienced significant differences in self-reported sleep quality compared to
control. This supports that treatment with this product can be a valuable com-
ponent in the armamentarium of safe and effective common cold therapies due
to the patient perceived improvement in sleep quality, a widespread patient be-
lief measured in this study.
Financial and Competing Interests
This work was sponsored in full by Procter & Gamble. At the time of conducting
the study and preparing this manuscript, DH, GP and DR were full-time em-
ployees of The Procter & Gamble Company and may have stock and/or stock
options in the company. VR, NS and DJD did not receive any financial payments
or other inducement apart from their usual university salary, for conducting this
study.
DH and DR were responsible for statistical analysis (DR) interpretation of
study results (DH, DR) and publication drafting (DH). VR, NS and DJD were
responsible for study execution. GP advised on design and was responsible for
product supply and management. All attributed authors participated in the de-
velopment and review of this manuscript.
Acknowledgements
The authors gratefully acknowledge the assistance of J. Brum, G. Kappler and P.
Thomas of Procter & Gamble in study design and for excellence in protocol de-
velopment and study management. Also acknowledged is the expert advice of
Ian Barton (Procter & Gamble) during study design.
Thanks also to the Clinical Research and Medical teams at the Surrey Clinical
Research Centre.
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