Adults from five countries chosen to be representative of Europe (Germany, France, the United Kingdom [UK], Spain and Poland) were recruited. Eligible participants were at least 18 years old, representing the primary decision maker and purchaser of health care products in their household, and had suffered from a cold within the past 12 months for which they used the therapeutic ointment VVR in combination with OTC cold medicines (i.e., paracetamol, oral multi-symptom relief products, or nasal decongestants). Persons involved in the pharmaceutical industry, in manufacturing or developing health care products, in marketing consumer, pharmaceutical or health care products, or working in market research, in an advertising agency, or for a public relations agency were excluded. Furthermore, while COVID-19 patients with severe symptoms requiring hospital treatment were excluded, those with mild symptoms who did not require hospital treatment were included. Within this publication, the population surveyed including cold and mild COVID-19 patients is summarised by the colloquial term “cold sufferers”. No questions regarding present health status were asked. The intent was to recruit at least 300 adults from each country, with a natural ratio of females to males.

Toluna Start, a global online platform that provides access to more than 40 million consumers across 70 markets, was used for this study. Participants were recruited from Toluna online panels using sample targeting techniques to ensure that the sample composition reflected the total population according to country census data. Consent was obtained from online panellists upon sign-up. All panellists were assured of confidentiality and anonymity.

Between March and April 2022, a 20-minute online quantitative questionnaire was conducted in each country in accordance with standard local market research practices. The questionnaire comprised 20 questions covering inclusion and exclusion criteria, demographics, habits, experience with using VVR concomitantly with an OTC cold remedy, and statements requiring participants to rate their agreement on a 5-point Likert scale (“strongly agree”, “agree”, “neither agree or disagree”, “disagree”, “strongly disagree”). A total of 18 such statements related to effectiveness (statements 1 - 9), sleep (statements 10 - 12), sleep + effectiveness (statements 13 - 14), speed of action (statements 15 - 16) and user satisfaction (statements 17 - 18) were surveyed in Germany, France, the United Kingdom, and Spain. In Poland, two statements (11 and 12) from the sleep panel were omitted because of differences in the locally authorised indications of VVR. To avoid bias due to closely related statements, statement order was randomised. An overview of the statements is presented in Figure 1.

Multiple quality checks were conducted throughout the process, including 1) the questionnaire phase (design and compliance with local product information of VVR in each country) to ensure that the language was consumer friendly and the logic of the questionnaire was correct, 2) the online survey link to ensure the link was functional and there were no technical errors, and 3) the data tables, to check for accuracy of survey logic, as well as applying category knowledge checks.

Demographic data from all participants who completed the questionnaire were analysed using descriptive statistics. Top 2 Box (T2B) scores, the percentages associated with the top 2 scale responses (e.g., “strongly agree” and “agree”), were calculated from the 5-point Likert scale survey questions by country and across all countries. To provide bounds on the estimates of the true T2B percentages, 95% Wilson Score confidence intervals [21] were calculated with JMP v. 16.1.

A total of 2662 participants completed the questionnaire. Of those, 1149 participants did not meet all requirements for inclusion. The test population included in the analysis consisted of 1513 respondents across Europe, 301 in Germany, 304 in France, 300 in the United Kingdom, 308 in Spain and 300 in Poland.

Basic demographics are presented in Table 1. Overall, 896 (59.2%) females and 615 (40.6%) males were included in the analysis. The most prevalent age group was 35 to 49 years, followed by the age groups 50 to 65 years, 19 to 34 years and ≥66 years. Country-specific differences regarding age group distribution were present in Germany, where most survey participants were 50 to 65 years old, and in Spain and Poland, where 19- to 34-year-olds were more prevalent than those aged 50 to 65 years.

During the past 12 months, about one-fifth of the study population reported mild COVID-19 symptoms without hospitalisation (total, 18.9%; min, 15.5% in France; max, 26.7% in Poland), while the majority of participants experienced common cold symptoms (Table 1). The participants self-evaluated the perceived intensity of their symptoms on a 6-point scale from “none” to “severe”. Overall, as shown in Table 2, symptom severity was most often experienced as “moderate to severe” or “severe” for blocked nose (n = 1081; 71%), runny nose (n = 1036; 68%), cough (n = 868; 57%); sneezing (n = 843; 56%), sore throat (n = 842; 56%), headache (n = 837; 55%), muscle pain (n = 689; 46%) and “none” or “very mild” for fever (n = 683; 45%). Across all symptoms, about one-fifth of total respondents reported “mild to moderate” or “moderate” severity.

To get more insights regarding treatment combinations, participants were asked if they used VVR together with other products. Of 1565 panellists who used VVR, 52 (3.3%) used VVR as a single treatment due to its effectiveness, the natural ingredients, pre-existing health conditions, or to limit potential drug interactions. These patients were excluded from the rest of the survey.

All cold sufferers who used treatment combinations were provided three multiple choice options when asked for the concomitantly used products: paracetamol, MSR products and nasal decongestants. Results for the total population are shown in Figure 2(a); detailed results are summarised in Table 3. A total of 1513 cold sufferers (96.7%) used VVR in combination with other cold medicines: 1148 (75.9%) with paracetamol, 969 (64.0%) with MSR products and 862 (57.0%) with nasal decongestants. Cold sufferers were also asked to indicate which product they most frequently combined with VVR (see Figure 2(b) for total population, and Table 3 for detailed results). In France, the UK and Spain, the preferred choices were paracetamol (66.1%, 52.7%, and 50.3%, respectively) and MSR products (20.1%, 32.7%, and 33.1%, respectively); in Germany and Poland, VVR was mainly combined with MSR products (38.9%, and 57.3%, respectively) followed by nasal decongestants in Germany (33.2%) and paracetamol in Poland (26.3%).

To gain more insight into treatment habits, cold sufferers were asked when, regarding daytime and days of disease, and how they administered VVR. Detailed results are presented in Table 4. VVR was mainly used in the evening across the five countries (total; n = 1347; 89.0%, see Figure 3(a); range across countries 82.3% to 93.0%) while paracetamol, MSR and nasal decongestants were predominantly used in both mornings and evenings (data not shown). In general, a lower frequency of VVR and cold medicine use occurred during the afternoon (total; n = 328; 21.7%; range 14.6% to 31.0%; data not shown for paracetamol, MSR and nasal decongestants).

As shown in Figure 3(c), most of the cold sufferers applied VVR topically (total; n = 1055; 69.7%), followed by combined topical and inhalation use (total; n = 319; 21.1%). Inhalation use alone was the least frequent mode of application (total; n = 131; 6.7%). Of note, in Poland, none of the respondents inhaled VVR vapours, which is in line with the local product information since inhalation via water bath is not authorised in this country.

Across the five countries, VVR was most commonly used on days 3 - 4 of disease (total; n = 1136; 75.1%, see Figure 3(b); range across countries 69.7% to 79.7%). Disease days 5 - 6 were associated with the lowest frequency of VVR use in all countries except France, where least frequent use was reported for the first five days of disease (15.8% on days 1 - 2 vs. 18.1% on days 5 - 6). See Table 4 for detailed results.

We also wanted to investigate the influence of VVR use on sleep quality. Therefore, cold sufferers were asked to rate their sleep during their last cold episode, when cold medication was used in combination with VVR, compared to their sleep without VVR as a treatment component. As shown in Figure 4 and Table 5, a total of 1171 respondents (77.4%) reported improved sleep when VVR was used [T2B; intercountry range 70.8% to 82.5%]. Of those, 693 participants (45.8%) reported that their sleep quality “much improved” and 478 respondents (31.6%) reported that their sleep “improved”. In all countries except France, the most frequently chosen answer was “much improved” (see Table 5).

Impact of VVR use on sleep was also surveyed by specific statements (see Figure 1) that had to be answered using a 5-point Likert scale ranging from “strongly agree” to “strongly disagree”. Results are shown in Table 6, where T2B scores and 95% Wilson Score confidence intervals are indicated.

In total, 86.4% (T2B; 95% CI, 84.4%, 88.2%) of cold sufferers agreed that VVR provided the additional benefit of a better solution for the night (statement 12). Of note, this statement was surveyed in all countries except Poland and had lower national T2B scores in Germany (84.4%) and France (84.2%). An equal

total T2B score was retrieved for statement 13 related to the topic sleep + effectiveness and regarding better sleep as a result of more effective cold symptom relief by VVR (T2B, 86.4%; 95% CI, 84.6%, 88.0%). Also, the second statement related to the sleep + effectiveness topic, i.e., statement 14 regarding better overall relief of cold symptoms when VVR was used at night, reached a T2B score of 85.8% (95% CI, 83.9%, 87.5%). On a national level, these two statements reached T2B scores > 85% in all countries except Germany.

Statement 11, claiming that VVR was used to achieve a positive impact on sleep, reached a national T2B score of 87.3% in the UK, but scores in the other countries surveyed, i.e., Germany, France, and Spain, and overall were slightly lower (total T2B, 83.9%; 95% CI, 81.8%, 85.9%). Statement 10, regarding an impact of VVR on waking up refreshed the next morning, had the lowest total T2B score of all statements surveyed (T2B, 74.8%; 95% CI, 72.5%, 76.9%) and the largest span of national T2B scores, ranging from 67.7% (95% CI, 62.2%, 72.7%) in the UK to 82.7% (95% CI, 78.0%, 86.5%) in Poland.

Apart from its impact on sleep, we wanted to learn about consumer perception regarding effectiveness, speed of action and satisfaction of VVR treatment combined with other cold remedies as part of a treatment regimen. This was surveyed by specific statements that had to be answered using a 5-point Likert scale ranging from “strongly agree” to “strongly disagree”.

All statements except for those concerning the topics of sleep and sleep + effectiveness, are summarised in Table 7. These thirteen statements reached total T2B scores ≥ 81.8%. The statements with the highest total level of agreement were statement 18 with a T2B of 88.3% (95% CI, 86.6%, 89.8%), claiming that the respondent would recommend the addition of VVR to the existing cold treatment to family or friends, followed by statement 1 (T2B, 87.9%; 95% CI, 86.2%, 89.5%), concerning the effectiveness of VVR in relieving cold symptoms as part of a regimen, and statement 4 (T2B, 87.6%; 95% CI, 85.9%, 89.2%), claiming the additional benefit of a free breathing sensation. These top three statements also reached national T2B scores > 85% in all five countries surveyed.

In total, more than 87.6% of cold sufferers (95% CI, 85.8%, 89.1%) agreed that they would use VVR again alongside other cold treatment products. National T2B scores ≥ 85.7% for this statement (statement 17) were retrieved from all countries except France (T2B, 82.9%; 95% CI, 78.3%, 86.7%). Statement 5, claiming an additional benefit of VVR for better relief was agreed by a total of 86.2% of cold sufferers (95% CI, 84.4%, 87.8%), national T2B scores ranged from 83.3% in the UK (95% CI, 78.7%, 87.1%) to 90.3% in Poland (95% CI, 86.5%, 93.2%).

Statements 2 and 3, regarding use of VVR alongside to other cold treatment products to achieve better symptom relief, and a more complete relief, respectively,

reached a total T2B of 86.1% (95% CI, 84.1%, 87.7%) and 85.7% (95% CI, 83.8%, 87.3%) and T2B scores > 85% in all countries except Germany and the UK with T2Bs of 82.1% and 80.9% for better symptom relief and 80.7% and 84.9% for more complete relief.

The remaining statements, i.e., 6 - 9, 15 and 16, including both statements on speed of action and four of nine statements regarding effectiveness, reached total T2B scores between 81.8% and 84.7%. Interestingly, in Poland, all questions surveyed except statement 9 concerning the topic of effectiveness and statement 10 concerning the topic of sleep (see Table 6 and Table 7) reached a T2B score > 85%. Although being ranked third-last overall, statement 16 regarding the additional benefit of fast onset of action or symptom relief reached a national T2B score of 91.3% (95% CI, 87.6%, 94.0%) in Poland, which is within the top five of all national T2B scores reported.

The results indicate that VVR is commonly combined with other cold medicines to treat symptoms (approx. 97%). Country-specific differences offer new insights into consumer perception on using VVR with other cold treatments: France, UK, and Spain combine VVR mainly with paracetamol. Paracetamol is one of the most used drugs for relief of pain and fever—both symptoms typically associated with a common cold [22] [23] . It is also frequently included in combination products [24] .

MSR products are particularly popular in Germany and Poland, according to our results. A survey of 1000 people conducted by the German Medicines Manufacturer’s Association in 2020 found that 77% of participants say that fixed combination products have always or most of the time helped them. When asked why they took fixed combination products, 57% of the respondents said that they had chosen a MSR preparation because they had previous good experiences with them [25] .

The questionnaire used in our study did not specify or restrict MSR to double, triple, quadruple, etc. combination medicines. MSR medicines containing up to four or more active ingredients aim to relieve the various coexisting cold symptoms simultaneously. Dual combination treatments, such as the combination of an analgesic with a decongestant, are the most common MSR medicines for common cold treatment. Triple oral antihistamine-decongestant-analgesic combinations are preferentially used at night-time since first-generation antihistamines cause drowsiness which might aid sleep [14] .

There is a bidirectional relationship between sleep and immunity [26] . Short sleep duration is associated with lower resistance to rhinovirus infection [27] . Sleep affects immune parameters and is crucial for optimal immune competence [26] . Cold symptoms are experienced as more bothersome during the night, due to lack of distractions. Laying down also allows mucus to accumulate in the throat or sinuses, leading to coughing, nasal congestion and restless nights. In addition, immune system activity and resulting inflammation (causing fever, congestion, or sore throat) have a highly circadian rhythm. The immune system is most active at night: cortisol levels are at their lowest, therefore cytokine production and the inflammation responsible for cold symptoms are less suppressed [28] .

A cold or flu negatively impacts the ability to sleep well, according to 46.1% of respondents in a global poll [29] . Inability to sleep is a major concern and an important reason for cold sufferers to medicate [7] [29] . In our study, night-time use of VVR was particularly popular, probably due to the perceived better overall relief of cold symptoms, which also improved sleep quality. This correlates well with the results of a clinical study in adult patients experiencing a common cold (n = 100), where treatment with VVR chest rub led to a perceived improvement in sleep quality [16] . Similarly, Paul (2010) found that children treated with VVR slept significantly better than those who received no treatment or petrolatum control, due to symptomatic relief of nocturnal cough and congestion [30] .

In our survey, more than two-thirds of patients rated their nasal symptom (i.e., blocked or runny nose) intensity as moderate to severe. Cough, sneezing, sore throat, and headache intensity were also experienced as moderate to severe by more than half of the participants. Although we did not examine symptom severity changes over the course of the illness, it is well known that cold symptoms usually peak within two to three days [5] , with worsening nasal congestion, onset of cough and difficulty sleeping. As symptoms become increasingly bothersome, patients may be more willing to take additional medication. This might explain why VVR was more commonly used during days 3 - 4 of cold symptoms, across all five countries. Only in Poland did participants claim to use VVR at a similar frequency from days 1 to 4 of their colds. Beliefs that using VVR in combination with other OTC medicines could speed up recovery and provide quicker relief might be responsible for the decision of Polish participants to start treatment with VVR early on (data not shown). The onset of action of therapeutic ointments is instinctively expected to be faster than oral medication [31] . A rapid clinical effect of VVR was confirmed by a clinical study in patients suffering from common colds and experiencing nasal symptoms [31] . During days 5 - 6, VVR is used less often. A possible explanation could be that symptoms gradually decreased at this stage, but further information would be needed to draw firm conclusions.

Our study showed that combining VVR with other cold treatments had the additional benefit of a free breathing sensation. Inhalation of camphor, eucalyptus or menthol vapour causes a subjective nasal decongestant effect, experienced as a cold sensation in the nose and the sensation of improved airflow. Interestingly, this does not correlate with any objective decongestant effect such as nasal airway resistance. It is believed that eucalyptus and menthol stimulate TRPM8 “cold” receptors (also called CMR1) served by the trigeminal nerve in the nose [32] [33] . Menthol, in particular, provides symptomatic relief from nasal congestion associated with rhinitis due to its specific interaction with a “cold air” receptor on trigeminal nerve endings in the nose [34] . VVR was shown to produce a sensation of nasal cooling within 12 seconds and nasal decongestion within 62 seconds [31] .

The conducted survey aimed to investigate the consumer usage of VVR in addition to other common cold medicines but without allocation to intervention.

Study limitations include the potential for recall bias given the retrospective nature of the self-reports. The population surveyed included common cold and mild COVID-19 patients. It was not ascertained whether patients had a physician diagnosis, and no attempt was made to distinguish treatment effects, if any, from those of the underlying cause.

Differences in local practices and legal constraints on the availability of OTC medicines may have influenced responses. The availability of OTC medicines varies significantly in the studied countries. Pharmacist-only, pharmacy-only, and unrestricted consumer choice represent the main modes of availability. This will have influenced some of the responses particularly in the UK (mainly unrestricted consumer choice) and Germany (mainly pharmacy-only).

This online survey sheds light on VVR usage in combination with other cold treatments from the patient’s perspective. Due to the study design, in which the role of decision-maker in the purchase of health products was crucial for inclusion, the distribution of age groups and gender is not homogeneous between countries. This, however, provided the opportunity to analyse consumer-reported outcomes in a real-world setting from the patient perspective. We therefore gained insights into patient-decision making. Symptomatic relief perceived by the individual patient is considered beneficial for wellbeing, stress reduction, and sleep quality. Future research should be conducted to confirm our results in a prospective observational study.