Topical Anesthesia and Olfactory Capability: A Pilot Study

ABSTRACT

Introduction

Topical anesthesia (TA) of the nasal fossa has been shown to be sufficient for patient comfort during nasal endoscopy. However, investigators need to know how soon after the administration of TA they can accurately evaluate olfactory capability. Thus, the main aim of this study was to assess, in healthy volunteers (HV), when the effects of TA wear off to accurately measure olfactory capability after its administration.

Methods

A prospective, single‐center, pilot study was conducted to evaluate the duration of the effect of TA on olfactory capability, using the UPSIT. Thirty healthy volunteers were recruited and analyzed. Following baseline testing (UPSIT), TA was administered intranasally (lidocaine + oxymetazoline). Then, participants underwent three additional UPSIT evaluations at distinct time points: immediately post‐application (T0), 10 min (T + 10), and 30 min post‐application (T + 30). The primary outcome was the change in UPSIT score from baseline to each subsequent time point. Paired t‐tests were applied to compare within‐subject score differences across time points. Significance was defined as p < 0.05, and the R software was used.

Results

For the 30 HV included, the mean UPSIT at T0 was 32.8 ± 3.1. At T1, the mean UPSIT (29.6 ± 4.0) was significantly lower than at T0 (3.13 ± 3.7‐point, p < 0.0001). At T2, the mean UPSIT was 31.7 ± 4.2, without any significant difference from T0 (−1.03 ± 3.5‐point, p = 0.350). At T3, the mean UPSIT was 31.7 ± 3.1, without any significant difference compared to T0 (−1.07 ± 2.6‐point, p = 0.067). Regarding subgroup analysis between healthy volunteers with or without ITH, their own perception of smell and UPSIT were significantly different.

Conclusion

Immediately after receiving 4 sprays per nostril, the mean UPSIT—with testing begun directly after the spray was administered—was significantly lower than baseline, dropping under the threshold for normal olfactory function. It was fully recovered by ten min.

Level of Evidence

3.

1. Introduction

Olfactory dysfunction (OD) affects nearly 2.7 million patients in the USA [1, 2] and severely impairs quality of life [3]. In a Cox model, the association between lower University of Pennsylvania Smell Identification Test (UPSIT) score and mortality persisted after controlling for confounding factors such as age, gender, and smoking habits (Hazard Ratio = 1.05, 95% CI 1.03–1.07, p < 0.001) [3]. Many etiologies exist for OD, including sinonasal disease, post‐infectious, post‐traumatic, aging, or associated with a neurological disorder (neurodegenerative diseases or neurotransmitter diseases), as well as many others [4]. However, no matter the putative etiology, the underlying pathology is usually thought to be damage to the olfactory cortex, bulb, nerves, or basal or supporting cells of the olfactory epithelium [5]. Indeed, there often is a conductive dysfunction associated with both a sensorineural dysfunction and/or a central dysfunction [6]. During the recent pandemic, several pathophysiological hypotheses have been proposed to explain post‐viral OD and the diversity of its manifestations [4]: a transient inflammatory edema of the nasal mucosa [7], along with the release of proteases leading to damage to olfactory neuronal receptors [8]; a prolonged inflammatory state of the olfactory epithelium with overexpression of interleukins causing irreversible damage [9]; a viral tropism for the supporting cells of the olfactory epithelium [10, 11, 12]; a direct viral invasion of olfactory neuronal receptors [11]; and/or a central inflammatory neural involvement [13]. Standardized assessments include tests like the Sniffin’ Sticks Test (SST) [14, 15], or the UPSIT [16, 17].

There is no completely curative treatment currently available [18]. Indeed, topical corticosteroids have a rather limited effect [19], even if it seems to be more effective in nasal irrigation; olfactory training has proven to be effective in postinfectious OD [20, 21, 22, 23, 24], high dose regimen in omega 3 after skull base surgery [25], but these treatments are not enough to help everyone [24, 25, 26, 27, 28, 29]. Several potential future treatment options are currently being developed for OD, as well as new and improved testing options, but there is currently a dearth of data to indicate how soon after anesthetizing the olfactory cleft (OC) we could assess patient's olfactory capability.

During nasal endoscopy or gentle manipulation of the OC, topical anesthesia (TA) has been shown to be sufficient for patient comfort [30, 31]. While leading experimental studies on how to treat persistent OD, investigators need to know how soon after the administration of TA they can accurately evaluate olfactory capability.

Thus, the main aim of this study was to assess, in healthy volunteers (HV), when the effects of TA wear off to accurately measure olfactory capability after its administration. To answer this, a prospective single‐center study including adult HV (≥ 18 years of age) was conducted between May and July 2024. A rigid endoscopy was performed to assess the nasal airway (evaluate for any septal deviation and/or inferior turbinate hypertrophy (ITH)) as well as to ensure the absence of structural obstruction of the OC such as very severe septal deviation or nasal polyps. The UPSIT was used to assess olfactory capability at four time points during the same visit.

2. Methods

2.1. Study Design and Ethics

This prospective, single‐center pilot study was conducted at the Stanford Sinus Center between May and July 2024. The objective was to evaluate the duration of the effect of TA on olfactory capability, using the UPSIT. This study was reviewed and approved by the Stanford University Institutional Review Board (IRB Protocol #73562). All procedures were conducted in accordance with the Declaration of Helsinki and institutional policies. Participants received a $20 stipend for participation. Medical oversight was ensured by the presence of trained ENT specialists throughout the duration of testing. The protocol specified that no investigational devices or drugs were involved beyond routine, clinically accepted TA.

2.2. Population

Thirty healthy volunteers were recruited and analyzed. Inclusion criteria consisted of the absence of olfactory complaints and the ability to read and understand English. Exclusion criteria included any history of olfactory dysfunction, structural nasal abnormalities, recent upper respiratory infections, or any known sinonasal disease. Pregnant individuals and minors (< 18 years) were also excluded. Participants were recruited via flyers distributed throughout the surrounding communities. After expressing interest, individuals underwent a standardized screening process that included informed consent, review of inclusion/exclusion criteria, and a baseline olfactory assessment. Written informed consent was obtained from all participants in compliance with the Stanford University IRB protocol #73562.

2.3. Baseline Assessment

At the study visit, each participant first completed a baseline UPSIT to determine initial olfactory function. The UPSIT is a validated 40‐item, forced‐choice identification test using scented booklets. Participants were blindfolded and asked to identify odors by choosing from four possible responses per item. A baseline nasal endoscopy was also performed by a trained otolaryngologist to confirm the absence of anatomical obstructions such as severe septal deviation or nasal polyps, which could potentially interfere with olfactory function. All data were recorded in REDCap using coded identifiers to protect participant confidentiality. Only study team members had access to the code key, which was stored securely in a separate location. No audio or video recordings were made during the study. Demographic data and olfactory scores were compiled into a centralized database for statistical analysis.

2.4. Intervention: Topical Anesthesia Administration and Olfactory Testing

Following baseline testing, TA was administered intranasally using a combination of 1% lidocaine hydrochloride and 0.05% oxymetazoline. The application consisted of four total sprays per nostril: two sprays were administered to each nostril generally, followed by two additional sprays specifically targeted toward the olfactory cleft using rigid endoscopic guidance. This combination of anesthetic and vasoconstrictor mirrors routine clinical practice for intranasal procedures and was not the subject of investigation itself. The safety and tolerability of this topical mixture are well‐established in otolaryngologic care. Following TA administration, participants underwent three additional UPSIT evaluations at distinct time points: immediately post‐application (T0), 10 min post‐application (T + 10), and 30 min post‐application (T + 30). All testing procedures were carried out in a quiet clinical room under the supervision of trained staff. Each UPSIT was scored by summing the number of correctly identified odors, with the maximum possible score being 40. A score above 32 is considered within the normal range for healthy individuals.

2.5. Outcome Measures and Statistical Analysis

The primary outcome was the change in UPSIT score from baseline to each subsequent time point. Secondary analyses included subgroup comparisons based on findings from the nasal endoscopy, particularly focusing on the presence of inferior turbinate hypertrophy (ITH). Descriptive statistics were used to report mean UPSIT scores and standard deviations at each time point. Paired t‐tests were applied to compare within‐subject score differences across time points. Significance was defined as p < 0.05, and the R software was used.

2.6. Study Duration and Timeline

The entire study procedure, from consent to final UPSIT, was completed in a single visit lasting approximately 90 min. Each participant underwent four UPSIT evaluations and one endoscopic examination during this visit. The overall recruitment and data collection period was planned over 6 months, with the potential to extend up to 24 months to meet enrollment goals.

3. Results

For the 30 HV included (demographics and characteristics in Table 1), the mean UPSIT at T0 was 32.8 ± 3.1. At T1, the mean UPSIT (29.6 ± 4.0) was significantly lower than at T0 (−3.13 ± 3.7‐point, p < 0.0001). At T2, the mean UPSIT was 31.7 ± 4.2, without any significant difference from T0 (−1.03 ± 3.5‐point, p = 0.350). At T3, the mean UPSIT was 31.7 ± 3.1 without any significant difference compared to T0 (−1.07 ± 2.6‐point, p = 0.067; Figure 1).

TABLE 1.

Baseline characteristics of the 30 healthy volunteers.

Characteristics	Healthy volunteers (n = 30)
Age at visit, years, mean (SD)	34.2 (±10.3)
Female, n (%)	22 (73.3%)
Race/ethnicity, n (%)
USA	22 (73.3%)
South America	2 (6.7%)
Asia	3 (10.0%)
Europe	3 (10.0%)
Prior nasal surgery, n (%)
Yes	3 (10.0%)
No	27 (90.0%)
Prior olfactometry, n (%)
Yes	4 (13.3%)
No	26 (86.7%)
Own perception of smell capabilities (Likert scale a ), mean (SD)	7.5 (±1.7)
Rigid nasal endoscopy, n (%)
Deviated septum (DS)	11 (36.7%)
Inferior turbinate hypertrophy (ITH)	1 (3.3%)
DS + ITH	5 (16.7%)
Without DS or ITH	12 (43.3%)
Baseline UPSIT (/40), n (%)	32.8 (±3.1)

Note: Volunteers were asked at inclusion how they evaluate their own sense of smell on a scale from 0 to 10, 0 being poor and 10 being an excellent sense of smell.

^a 10‐point Likert scale was used to assess the healthy volunteers' own perception of smell capabilities.

FIGURE 1.

Change in UPSIT among all healthy volunteers and according to the presence or absence of ITH at baseline, 0, 10, and 30 min after a topical anesthesia. Subgroup analysis between HV with and without ITH (comparable in terms of demographics) showed that the mean UPSIT at T0 was significantly lower in HV with ITH than those without (29.6 ± 2.3 vs. 33.5 ± 2.7, respectively, p = 0.007). The change in UPSIT, in a positive direction, between T0 and T3 was significantly higher in the HV with ITH compared to those without (difference T3‐T0 = 1.0 ± 1.4 vs. −1.6 ± 2.6, respectively, p = 0.019; Figure 1). The UPSIT is a validated olfactory score based on 40 items; the score ranges from 0 to 40 and a score greater than 32 is considered normal olfactory function. ITH, inferior turbinate hypertrophy; UPSIT, University of Pennsylvania Smell Test.

Regarding subgroup analysis between healthy volunteers with or without ITH, both groups were similar in demographics. Their own perception of smell and UPSIT was significantly different. Details are shown in Table 2.

TABLE 2.

Baseline characteristics between groups based on the presence of inferior turbinate hypertrophy.

Characteristics	No ITH	ITH	p
Age at visit, years, mean (SD)	34.3 (±10.3)	33.6 (11.4)	0.705
Female, n (%)	18 (75.0%)	4 (66.7)	0.645
Race/ethnicity, n (%)			> 0.999
USA	22 (73.3%)	5 (83.3%)
South America	2 (6.7%)	0 (0.0%)
Asia	3 (10.0%)	1 (16.7%)
Europe	3 (10.0%)	0 (0.0%)
Prior nasal surgery, n (%)			> 0.999
Yes	3 (12.5%)	0 (0.0%)
No	21 (87.5%)	6 (100.0%)
Prior olfactometry, n (%)			> 0.999
Yes	3 (12.5%)	1 (16.7%)
No	21 (87.5%)	5 (83.3%)
Own perception of smell capabilities (Likert scale a ), mean (SD)	7.2 (±1.6)	8.83 (1.5)	0.029 b
Baseline UPSIT (/40), n (%)	33.5 (±3.1)	29.7 (±2.34)	0.007 b
UPSIT at 0 min (/40), n (%)	29.9 (±4.2)	28.5 (±3.2)	0.515
UPSIT at 10 min (/40), n (%)	32.2 (±4.3)	29.8 (±3.4)	0.130
UPSIT at 30 min (/40), n (%)	32.0 (±3.3)	30.7 (±2.7)	0.190
Difference UPSIT 30 min in comparison to Baseline, mean (SD)	−1.6 (±2.6)	1.00 (±1.4)	0.019 b

Note: Volunteers were asked at inclusion how they evaluate their own sense of smell on a scale from 0 to 10, 0 being poor and 10 being an excellent sense of smell.

^a A 10‐point Likert scale was used to assess the healthy volunteers' own perception of smell capabilities.

^b Indicates statistical significance, p < 0.05 in univariate comparison using the Fisher test and Wilcoxon test.

4. Discussion

Immediately after receiving 4 sprays per nostril, the mean UPSIT—with testing begun directly after the spray was administered—was significantly lower than baseline, dropping under the threshold for normal olfactory function. A few seconds after TA, the patient is thus fully anesthetized as olfactory capability is decreased, suggesting OC manipulation or olfactory device placement is possible in this timeframe.

At 10 min post‐anesthesia, a complete recovery of olfactory capability was observed, enabling assessment at this time point in future intervention studies. Such results should be viewed in the context of previously published studies looking at more delayed time points [32, 33]. Hari et al. used a 4% lidocaine nasal spray in 6 HV and found that the olfactory function is not completely abolished at 15 min if you increase the stimulus dose and that olfactory capability returns to normal at 30 min [32]. In a randomized double‐blind controlled trial including 72 HV, Jung YG et al. did not show any difference between baseline and 15 min after TA [33]. Altogether, prior findings show that TA combining vasoconstrictor and lidocaine no longer affects olfactory capability 15 min after the spray, with our current study bringing that time down even further to 10 min.

At T1, the mean UPSIT dropped by 3.13 points in comparison to T0. The Minimal Clinically Important Difference (MCID) of the UPSIT was recently validated in patients with postinfectious, sinonasal, and procedure‐associated olfactory loss by Mahadev et al. in 2024 with an anchor‐based approach [34]. Half the baseline UPSIT standard deviation (SD) was 3.75, and half the delta UPSIT SD was 2.9. Thus, in olfactory loss, as mentioned above, authors defined an MCID of 4 as clinically meaningful. However, with 295 patients included, authors used three studies, including subjects with postinfectious OD, one with sinonasal disease, and one with subjects undergoing transsphenoidal surgery [34]. This suggests the clinical significance of only a 3‐point drop in UPSIT score is actually reliable, as it exceeds the mean delta UPSIT SD.

Subgroup analysis between HV with and without ITH (comparable in terms of demographics) showed that the mean UPSIT at T0 was significantly lower in HV with ITH than in those without. Also, the change in UPSIT, in a positive direction, between T0 and T3 was significantly higher in the HV with ITH compared to those without. One hypothesis is the vasoconstrictive effect of TA. Indeed, olfactory capability depends on nasal patency and the proper functioning of the olfactory epithelium [17, 35]. Systematic reviews on nasal surgery usually report some olfactory improvement after septoplasty or inferior turbinoplasty [36, 37] which could be explained by an increase in the olfactory cleft airflow [38].

Volunteers from the department were timed twice while performing an UPSIT for the first time and the second time. To perform psychophysical testing requires a cooperative subject who can understand and follow instructions, as well as communicate choices to the investigator [15, 39]. When performing multiple rapid tests, participants need to remain highly focused. One of the advantages of the UPSIT is the relative autonomy in which the patient can perform the test, decreasing the stress that could be induced by the research investigator monitoring the smell test. It took participants 15–18 min to complete the UPSIT for the first time; however, this time dropped down to 5–6 min on the second passage, enabling investigators to assess the same patient multiple times in a rather limited period and thus, to capture small temporal changes [17, 34]. Habituation is a filter that optimizes the processing of information by our brain in all sensory modalities. It results in an unconscious reduced responsiveness to continuous or repetitive stimulation [40]. Among all the characteristics explaining odor habituation, only one relates to the intrinsic properties of the odor perceived, which is the intensity of the stimulus [41] and it is standardized in a psychophysical assessment like the UPSIT, therefore limited during a 4‐time points assessment. Also, it has been reported that peripheral encoding in the olfactory system appears to be less subject to desensitization compared to the decrease of intensity estimates [42], enabling the authors to compensate for the granularity of olfactory change regardless of a potential odor habituation. The other aspect of repeat rapid testing is the potential for the participants to “learn” the test and thus improve over multiple time points. If anything, this potential confounding factor would have led to better scores at the second time point, and we may not have seen the significant drop in scores. This suggests that either the test is too complex to truly “learn” without much more time‐intensive study, or that taking this factor into account means our results may have been even more significantly different than what resulted at the second time point.

The present study has limitations. HV were used as study subjects, as those with normal olfactory ability can show us best a decrease as well as when normal ability returns. However, we cannot know at this time whether we can assume the same amplitude or timeline of suppression and recovery for those with OD. Secondly, we used the UPSIT, which is an identification test, as time constraints made it impossible to also test threshold or discrimination at the same setting, as we had less than 10 min to perform each test. Thus, we do not know the effect on those other components at this time. As noted in more detail above, although a potential limitation is that it has been shown that repetitive tests using the UPSIT have demonstrated an increasing familiarity with the odors so as to bias the results positively, when paired with potential olfactory fatigue which biases negatively, in a rapidly repeated measure as occurred in this study, these appear to cancel each other out.

5. Conclusion

To conclude, although prior literature has shown recovery at 15 min, in today's busy practice environment where every minute counts, demonstrating that sensitivity is back at 10 min, 5 min earlier than shown before, can significantly change practitioners' likelihood of utilizing whatever future intervention or test that may potentially follow.

Ethics Statement

Stanford University Institutional Review Board (IRB) approved the protocol #73562.

Consent

Informed consent was obtained from all participants.

Conflicts of Interest

The authors declare no conflicts of interest.

Fieux M., Wang E., Liu D. T., and Patel Z. M., “Topical Anesthesia and Olfactory Capability: A Pilot Study,” Laryngoscope Investigative Otolaryngology 10, no. 5 (2025): e70250, 10.1002/lio2.70250.

Data Availability Statement

Data is available on private request.