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Abstract
Background There are conflicting data on the efficacy of transnasal topical anesthetic approaches intended to achieve a pterygopalatine ganglion block, specifically regarding the extent to which local anesthetics reach the pterygopalatine fossa. This cadaveric study aims to determine whether bupivacaine can reach the pterygopalatine fossa following topical administration near the sphenopalatine foramen using endoscopically assisted cotton ball placement.
Methods Nine fresh cadavers underwent topical nasal administration of a solution containing bupivacaine, methylene blue, and iodine contrast. Under direct endoscopic visualization, an absorbent cotton ball was positioned intranasally adjacent to the sphenopalatine foramen. CT was used to confirm correct placement and measured relevant anatomical distances. Tissue biopsies from the pterygopalatine fossa were collected via a transmaxillary surgical approach and analyzed using high-performance liquid chromatography-mass spectrometry.
Results Bupivacaine was detected in all pterygopalatine fossa biopsy samples except one, which was the farthest (17.5 mm) from the sphenopalatine foramen. Concentrations exceeded 1.00 µg/g in 29% and 0.10 µg/g in 71% of samples. The concentration decreased exponentially with distance from the application site, following a one-phase decay model (R²=0.74).
Conclusions These findings demonstrate that bupivacaine can reach the pterygopalatine fossa from the nasal cavity when topically applied near the sphenopalatine foramen under endoscopic assistance, supporting the feasibility of such an approach. They also suggest the main mean of transport is simple diffusion, meaning that optimizing bupivacaine concentration, duration of application, and precise placement of the absorbent cotton ball are crucial for maximizing the block’s clinical efficacy.
- REGIONAL ANESTHESIA
- Autonomic Nerve Block
- Headache
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Transnasal topical administration of local anesthetics near the sphenopalatine foramen is used to achieve pterygopalatine ganglion block for headache and facial pain, but its efficacy remains controversial.
WHAT THIS STUDY ADDS
Endoscopically assisted transnasal topical application of bupivacaine at the sphenopalatine foramen leads to spread into the pterygopalatine fossa, with concentrations decreasing exponentially with distance, suggesting diffusion as the primary mechanism of transport.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The results support the feasibility of transnasal pterygopalatine ganglion block and highlight the importance of optimizing drug concentration, exposure time, and precise anatomical placement.
Introduction
The pterygopalatine ganglion is located in the pterygopalatine fossa, a limited anatomical space located between the pterygoid process of the sphenoid bone, the posterior wall of the maxillary sinus, and the vertical lamina of the palatine bone. As the largest parasympathetic ganglion in the head, it is of particular interest.1 By anesthetizing the ganglion and other neuronal networks in the pterygopalatine fossa, it is conceivable to relieve pain and eliminate autonomic symptoms in the facial and nasal region. Therefore, the pterygopalatine ganglion block is a promising approach for the treatment of a variety of conditions, including postdural puncture headache, migraine, trigeminal neuralgia, cluster headache, and vasomotor rhinitis.2–4
Various approaches to blocking the pterygopalatine ganglion have been described in the literature, each with distinct advantages and limitations. In the transoral method, a needle is inserted through the oral cavity through the greater palatine foramen and advanced through the greater palatine canal to deliver a local anesthetic directly into the pterygopalatine fossa.5 Similarly, imaging-guided techniques involve inserting a needle above or below the zygomatic arch through the infratemporal fossa and pterygomaxillary fissure, allowing injection into infratemporal or pterygopalatine fossa.6–9 While these minimally invasive procedures enhance precision, they require specialized equipment and training and pose a risk of serious complications if adjacent structures are inadvertently injured.10 In contrast, the transnasal method is non-invasive and involves inserting a cotton applicator through the nasal passages and positioning it near the sphenopalatine foramen, behind the base of the middle turbinate.11 This technique is simple and considered safer. However, its efficacy is questioned as there are conflicting reports on its clinical effectiveness and a lack of data on the possibility of passive transport of the local anesthetic into the pterygopalatine fossa through the nasal mucosa and the sphenopalatine foramen. While some observational studies suggest that transnasal pterygopalatine ganglion block is effective in treating postdural puncture headache,12–14 a small randomized controlled trial failed to confirm its efficacy.15 Additionally, some authors suggest that the distance between the pterygopalatine ganglion and the nasal mucosa may be greater than previously thought,16 challenging the assumption that local anesthetics can spread into the pterygopalatine fossa to reach the ganglion.
Accordingly, the primary aim of this cadaveric study was to determine whether bupivacaine applied topically in the nasal cavity near the sphenopalatine foramen can reach the pterygopalatine fossa. We hypothesize that sustained topical application of bupivacaine via an absorbent cotton ball, endoscopically positioned over the mucosa covering the sphenopalatine foramen, would allow spread of the bupivacaine into the pterygopalatine fossa.
Methods
Specimens
Transnasal bilateral pterygopalatine ganglion block was performed on nine fresh cadavers (four males and five females) provided by the Institute of Anatomy, Faculty of Medicine, University of Ljubljana, through the willed donation program. The donors gave their informed consent to donate their bodies after death for research purposes. Specimens with a history of recent maxillofacial trauma, history of paranasal sinus or maxillofacial surgery, or a post-mortem interval of more than 24 hours were excluded from the study.
Pterygopalatine ganglion block procedure
The specimens were carefully analyzed to confirm compliance with the stated exclusion criteria. Nasal endoscopy using a 30° optical endoscope (Hopkins, Karl Storz, Tuttlingen, Germany) was performed to localize the sphenopalatine foramen in the anatomical region near the tail of the middle turbinate. Under endoscopic assistance, an absorbent cotton ball was positioned behind the tail of the middle turbinate (figure 1a). A 2 mL solution of local anesthetic and contrast medium (consisting of 0.45% bupivacaine hydrochloride, 0.1% methylene blue and 10% iodixanol-iodine contrast agent) was then slowly infused directly onto the cotton ball using a syringe and needle (figure 1b). The absorbent cotton balls were placed on both sides.
Endoscopic placement of the absorbent cotton ball with contrast infusion and removal of the posterior maxillary sinus wall via a transmaxillary approach. (a) The cotton ball is positioned between the middle turbinate and nasal septum, while (b) the infusion of injectate containing bupivacaine, methylene blue, and iodine contrast with a syringe cannula leading to blue colorization of the cotton ball. (c) The posterior wall of the maxillary sinus is being removed using Weil-Blakesley nasal forceps, while (d) an opened posterior sinus wall with the contents of the pterygopalatine fossa.
Pterygopalatine fossa dissection and CT
Approximately 30 min after application of the local anesthetic on absorbent cotton ball, a dissection was initiated with sampling of the pterygopalatine fossa content, including the pterygopalatine ganglion, for subsequent biochemical analysis. An intraoral incision was made 3–5 mm above the mucogingival junction, followed by a bilateral extended lateral rhinotomy with division of the upper lip. A subperiosteal flap was elevated to expose the anterior wall of the maxillary sinus, which was then removed to gain access to the maxillary sinus. The mucosa on the posteromedial wall was carefully dissected, and an osteotomy of the posterior sinus wall was carefully performed, taking care not to inadvertently enter the nasal cavity (figure 1c,d). This surgical approach facilitated access to the contents of the pterygopalatine fossa while minimizing the risk of contamination from the nasal cavity. The methylene blue was used as a marker to assess possible leakage of contrast medium into the pterygopalatine fossa. All dissections were performed by an experienced ear, nose, and throat surgeon.
After harvesting the pterygopalatine fossa content, a CT scan was performed to confirm the exact placement of the absorbent cotton ball and to measure the distance between the sphenopalatine foramen and the absorbent cotton ball as well as the sphenopalatine foramen and the position of the harvested tissue biopsy sample. The distances were measured on axial planes by two independent evaluators, and the mean value was used for analysis (figure 2). A contrast agent containing iodine was used to assess the position of the absorbent cotton ball and the possible leakage of contrast agent into the pterygopalatine fossa. Imaging was performed using a Somatom Definition Flash CT scanner (Siemens, Forchheim, Germany) with an acquisition and reconstruction of 120 kV tube voltage, effective 70/150 mA/s, a pixel size of 0.383×0.383 mm, pitch of 0.65, slice thickness of 0.75 mm, and interslice distance of 0.900 mm. Visualization and measurements were performed using the Alfa Enterprise Healthcare Program (Alfa Enterprise Healthcare Program, Alfa Health Care, USA).
Measurement of the distance on axial CT scan. The yellow line represents the measured distance between the absorbent cotton ball (*), positioned adjacent to the sphenopalatine foramen within the nasal cavity, and the central portion of the pterygopalatine fossa sample (#).
In six subjects, a unilateral biopsy sample of the nasal mucosa around the sphenopalatine foramen was taken after CT imaging. Fresh instruments were used, and the procedure was performed under endoscopic assistance to obtain tissue biopsy samples for use as positive controls in the biochemical analyses.
High-performance liquid chromatography with mass spectrometry
Each biopsy sample was weighed and stored in cryogenic vials at −80°C for later analysis. Bupivacaine and methylene blue were extracted according to the method described by Istenič et al.17 To each thawed biopsy sample, which weighed between 0.14 and 0.61 g, 1 mL of acetonitrile containing 1% formic acid was added. The biopsy sample was homogenized using a glass rod and ultrasonication and then centrifuged to isolate the supernatant containing the analytes. This procedure was repeated to ensure complete recovery of the analytes. The acetonitrile phase was then washed with 1 mL of n-hexane and subsequently mixed with the vortex and centrifuged. Approximately 800 µL of the hexane layer was discarded, leaving the n-hexane-acetonitrile interphase, which contained higher analyte concentrations. The remaining acetonitrile phase with the hexane interphase was transferred to fresh vials and evaporated at 37°C overnight. The dry residues were reconstituted in 1 mL of 0.1% formic acid and filtered into high-performance liquid chromatography (HPLC) vials.
Analysis was performed using a Waters Alliance e2695 HPLC system coupled to an Aquity QDa mass spectrometry detector, a 2998 photodiode array detector, and Empower 3 software. Chromatographic separation was performed on a Phenomenex Luna Omega polar C18 column (150×4.6 mm, 5 µm, 100 Å). The temperature of the column was kept at 23°C and the flow rate of the mobile phase was set to 1.23 mL/min. The mobile phases consisted of 0.1% formic acid (mobile phase A) and 0.1% formic acid in acetonitrile (mobile phase B). The total run time was 15 min (see table 1 for the gradient profile).
Chromatographic gradient profile for both mobile phases A (0.1% formic acid) and mobile phase B (0.1% formic acid in acetonitrile)
Analytes were detected using the Aquity QDa mass spectrometry detector, which operated in positive electrospray ionization mode using nitrogen as the collision and ion source gas. The settings were as follows: cone voltage at 10 V, probe temperature at 600°C, gain at 3 and capillary voltage at 1.5 kV. The specific m/z value, and retention time of bupivacaine were 289.1 and 4.8 min, respectively.
The method for quantification of bupivacaine has already been validated in various tissue types, with parameters such as the limit of detection (LOD=5 ng/g), the lower limit of quantification (17 ng/g) and matrix effects described in detail in Istenič et al.17
Statistical analysis
Data are presented as absolute values with proportion or means with SDs (±SD), where appropriate. The bupivacaine concentration as a function of distance was modeled using an exponential one-phase decay function fitted to the data with a robust regression approach (Eq. 1)18:
(1)
where C is the concentration, A is the initial concentration, k is the rate constant, and B is the plateau. Statistical analysis was performed using GraphPad Prism V.10 (GraphPad Software, San Diego, USA). Differences were considered significant if p was less than 0.05.
Results
A total of 18 transnasal pterygopalatine ganglion block attempts were performed, of which 17 (94%) were technically successful (table 2). In the unsuccessful case, the nasal mucosa was inadvertently injured with a syringe needle, and the injectate was injected submucosally, resulting in blue colorization of the contents of the pterygopalatine fossa and greatly increased bupivacaine concentrations in the pterygopalatine fossa biopsy sample (sample 3R). On CT scans, deviation of the nasal septum or nasal spine was observed in four donors, and the procedure was technically successful in all of them.
Position of the adsorbent cotton ball, position of the pterygopalatine fossa sample, and the concentration of bupivacaine in pterygopalatine fossa biopsy samples
In five attempts (29%), the measured bupivacaine concentration in the pterygopalatine fossa tissue biopsy sample was above 1.00 μg/g, and in twelve attempts (71%), the bupivacaine concentration was above 0.10 µg/g. Only in one attempt (6%), which had the longest distance from the sphenopalatine foramen (sample 6 L) to the pterygopalatine fossa tissue biopsy sample, was the bupivacaine concentration in the biopsy sample below the LOD. The mean distance between the sampling site and the sphenopalatine foramen was 7.4±4.1 mm.
In all but one specimen, the absorbent cotton ball was detected at the level of the sphenopalatine foramen. Bupivacaine was still detectable (0.07 μg/g) in the biopsy sample where the absorbent cotton ball was 6.5 mm below the sphenopalatine foramen. The mean concentration of bupivacaine in the nasal mucosa of the control biopsy samples was 287.25±199.56 µg/g (range 98.42–629.06 µg/g), and all control biopsy samples were strongly blue in color due to methylene blue.
Bupivacaine concentrations in pterygopalatine fossa tissue biopsy samples decreased exponentially with increasing distance from the adsorbent cotton ball and sphenopalatine foramen (figure 3). The one-phase exponential decay model reached a coefficient of determination of 0.74. When a Gaussian function 
was fitted to the same data, the coefficient of determination decreased to 0.58.
One-phase decay model of bupivacaine concentration in pterygopalatine fossa samples in relation to the shortest distance from the absorbent cotton ball (R2=0.74). The figure illustrates exponential decrease in bupivacaine concentration with an increasing distance.
Discussion
The results of this study demonstrate that topically applied bupivacaine can spread from the nasal cavity into the pterygopalatine fossa when administered near the sphenopalatine foramen under endoscopic guidance. This provides indirect evidence supporting the mechanistic feasibility of a transnasal topical approach to the pterygopalatine ganglion block. The exponential decrease in bupivacaine concentration with distance strongly suggests diffusion as the primary mechanism of transport. Therefore, the optimization of diffusion conditions, such as the concentration of the local anesthetic, the duration of application, and the correct position of the can adsorbent cotton ball is crucial for the block’s success.
Previous studies have raised doubts as to whether transnasally topically administered bupivacaine near the sphenopalatine foramen can effectively spread to the pterygopalatine ganglion.16 The authors frequently refer to Sluder’s original 1908 report suggesting that a deeper location of the pterygopalatine ganglion may reduce the efficacy of pterygopalatine ganglion block in some patients.11 Since the bupivacaine concentration rapidly decreased with distance from the adsorbent cotton ball, this variability may affect the accessibility of the pterygopalatine ganglion for therapeutic interventions like transnasal local anesthetic techniques, especially in cases where the ganglion is situated deeper. The range of distance between the sphenopalatine foramen and pterygopalatine fossa sample taken in our study is in line with this and accounts for significant individual variability in the location of the pterygopalatine ganglion.19 The average measured distance between the sphenopalatine foramen and pterygopalatine sample taken in our study (7.4 mm) is comparable to MRI-measured distances between the sphenopalatine foramen and pterygopalatine ganglion by Crespi et al (6.8 mm), which strongly supports the validity of our harvesting location.16
An exponential decrease in bupivacaine concentration with distance from the adsorbent cotton ball was observed, supporting that the main transport of bupivacaine through the tissue is by diffusion. This observed exponential decrease differs from the classical diffusion behavior described in homogeneous media, where the diffusion equation solution predicts a Gaussian positional probability density. In contrast, the pterygopalatine fossa is a compartmentalized medium characterized by a heterogeneous structure that includes cellular boundaries, extracellular matrix components, and confined areas. These structural barriers form complex physical and biochemical barriers that impede diffusion and result in position probability densities that exhibit an exponential decay rather than a Gaussian distribution.18 This is further supported by solving the Smoluchowski equation for bupivacaine diffusion through heterogeneous medium with coordinate-dependent chemical potential.20
The acidic environment in cadaveric specimens promotes the protonation of methylene blue and limits its ability to readily penetrate cell membranes.21 Therefore, the coloration within the pterygopalatine fossa was not expected, except in one attempt in which the mucosa was accidentally injured with a syringe needle, and the injectate was administered submucosally. Conversely, the lipophilic bupivacaine with the larger octanol-water partition coefficient is expected to cross biological membranes efficiently.22 The acidic environment also promotes the protonation of bupivacaine, reducing its partition coefficient compared with the neutral form of the molecule. Nevertheless, the cationic form of bupivacaine still exhibits an octanol-water partition coefficient of over one,23 allowing it to cross cell membranes rapidly. Solutions of the Smoluchowski equation show that neutral and even protonated bupivacaine cross the cellular membrane faster than the equivalent distance in water.20 Accordingly, bupivacaine was able to reach the contents of the pterygopalatine fossa in all but one attempt, in which the cotton ball was furthest away from the sphenopalatine foramen.
An important factor that influences the transport of local anesthetic into the pterygopalatine fossa is time. As diffusion is time-dependent, the local anesthetic must remain under the nasal turbinate for a prolonged period of time to optimize its efficacy. The contact of the cotton swab that remains under the turbinate varies from study to study and is usually between 5 and 30 min.12 24 25 These differences may influence the results reported in different studies and highlight the need for standardized protocols to accurately assess effectiveness. In the study by Jespersen, a similar efficacy of bupivacaine compared with saline was reported in a cohort of patients,15 with swabs placed under the middle turbinate for 10 min, whereas in our study, the interval was up to four times longer. This prolonged contact could improve the diffusion of local anesthetic and its therapeutic efficacy, which could lead to more successful outcomes.
Variability in techniques for performing pterygopalatine ganglion blocks can lead to variability in techniques that can affect the consistency and reliability of clinical studies. There is wide variation in the anatomical location of the sphenopalatine foramen, which can make it difficult to localize.26 For this reason, endoscopic assistance has been used for accurate localization of the middle turbinate and more precise positioning of the cotton ball near the sphenopalatine foramen, which is not usually done in the clinical setting.16 Our subjective observations suggest that endoscopic placement was very beneficial and allowed us to avoid anatomical obstacles such as deviated septum or nasal spines that could interfere with the insertion and positioning of the cotton balls. These results emphasize the potential value of endoscopic assistance, and its benefits should be systematically investigated in future studies, including comparisons with angiocaths or commercial intranasal delivery devices for potentially quicker and more comfortable drug delivery.27
This study has limitations. Active blood flow in the vessels of the nasal mucosa and pterygopalatine fossa continuously washes out the bupivacaine by convection, a process that does not occur ex vivo. Future studies should clarify whether the simultaneous use of vasoconstrictors is beneficial for transnasal pterygopalatine ganglion block. Another limitation is that the experiment was performed at room temperature and acidic pH that is present in postmortem tissues, which reduces the diffusion rate and maximal reached concentrations of bupivacaine.28 Furthermore, as the effective tissue concentrations of local anesthetics required for successful pterygopalatine ganglion block remain unknown, it is not possible to predict the proportion of successful block attempts. The final limitation is that the pterygopalatine fossa and its contents were considered as a uniform compartment, the exact concentrations in the ganglion itself were not determined. However, due to the similar composition of the ganglion and adipose tissue, it can be assumed that the concentrations would be comparable.
In conclusion, this study confirms that bupivacaine applied topically near the sphenopalatine foramen under endoscopic assistance can spread into the pterygopalatine fossa. The exponential decrease in local anesthetic concentration with increasing distance strongly indicates diffusion as the primary transport mechanism. To improve the accuracy and effectiveness of anesthetic delivery, the adsorbent cotton ball should be positioned as close to the sphenopalatine foramen as possible, and the local anesthetic formulation with the highest non-toxic available concentration should be administered. In addition, the adsorbent cotton ball should remain in place for a prolonged period of time to allow sufficient time for diffusion of local anesthetic into the pterygopalatine fossa.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by National Medical Ethics Committee of the Republic of Slovenia (approval number: 0120-538/2019/4). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We are thankful to Majda Črnak-Maasarani for technical support.
References
Footnotes
Contributors Conceptualization: SI, TSP, and NU; methodology: SI, AJ and NU; formal analysis: SI, LP and NU; investigation: SI, AJ, LP, TSP and NU; resources: TSP and NU; data curation: SI, LP and NU; writing—original draft preparation: SI, LP and NU; writing—review and editing: AJ and SP; supervision: NU. All authors have read and agreed to the published version of the manuscript. NU is the guarantor. The InstaText AI was used for text proofreading.
Funding This research was supported by the Slovenian Research Agency grants J3-50106 and P3-0043.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.