Botulinum toxin A for the treatment of first bite syndrome—a systematic review
Review Article

Botulinum toxin A for the treatment of first bite syndrome—a systematic review

Noah E. Shaikh1^, Haseeb A. Jafary2^, John W. Behnke1^, Meghan T. Turner1^

1Department of Otolaryngology-Head and Neck Surgery, West Virginia University Health Sciences Center, Morgantown, WV, USA; 2Marshall University School of Medicine, Huntington, WV, USA

Contributions: (I) Conception and design: NE Shaikh, MT Turner; (II) Administrative support: MT Turner; (III) Provision of study materials or patients: NE Shaikh, HA Jafary; (IV) Collection and assembly of data: NE Shaikh, HA Jafary; (V) Data analysis and interpretation: NE Shaikh, HA Jafary, JW Behnke; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

^ORCID: Noah E. Shaikh, 0000-0002-4834-2769; Haseeb A. Jafary, 0000-0003-2951-5801; John W. Behnke, 0000-0002-6359-7700; Meghan T. Turner, 0000-0001-8621-6168.

Correspondence to: Meghan T. Turner, MD. Department of Otolaryngology-Head and Neck Surgery, West Virginia University Health Sciences Center, PO Box 9200, 4525 HSN, Morgantown, WV 26506-9200, USA. Email: meghan.turner@hsc.wvu.edu.

Background: First bite syndrome (FBS) is a rare post-surgical complication resulting in peri-parotid pain after the first bite of meals. Intra-parotid Botulinum toxin A may offer relief for these symptoms. There is no consensus on the optimal dosage, timing to symptom improvement, need for repeat injections, and safety of this treatment. The objective of this systematic review was to assess the efficacy and safety of intra-parotid Botulinum toxin A injection in treating FBS.

Methods: The MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar were searched from the inception until July 2020. Case reports, case series, prospective and retrospective trials in which patients with post-surgical FBS were treated with intra-parotid botulinum toxin A injection were included. The primary outcome was improvement of FBS symptoms. Secondary outcomes were time to symptom improvement and complications. Risk of bias was assessed with National Institute of Health (NIH) Quality Assessment Tools.

Results: Search results yielded 41 studies. Thirty-three articles were excluded after screening titles, abstracts, and full texts, yielding eight studies, from which 22 patients were included. No studies included a control. All studies were of lower quality and had at least moderate risk of bias. The initial botulinum toxin A injection dose ranged from 10–75 U. Time from surgical treatment to injection ranged from 1 month to 3 years. Seven studies, containing 17 patients, reported individual patient outcomes. Clinical improvement was reported in 16 patients lasting between 1–30 months post injection. Eight of 8 (100%) patients receiving at least 40 U botulinum toxin A had symptom improvement. Ten of 22 (45.5%) patients received a second botulinum toxin A injection due to return of pain at a mean of 3.8 months after the first injection. Seven of 22 (38.1%) patients had complete symptom resolution at a mean of 12.1 months. There were no reported injection complications, including: facial paralysis, infection, injection site reaction, and allergic reaction.

Discussion: There are no controlled studies comparing intra-parotid botulinum toxin A to observation for FBS. However, botulinum toxin A appears to be a potentially safe, effective treatment.

Keywords: First bite syndrome (FBS); botulinum toxin A; botox; parotid; systematic review

Submitted Feb 19, 2022. Accepted for publication May 18, 2022.

doi: 10.21037/gs-22-112

Introduction

First bite syndrome (FBS) is a rare, often temporary, postoperative pain syndrome that is characterized by pain in the parotid region with the first bite of a meal that diminishes in severity with each succeeding bite (1-3). It is an iatrogenic complication of surgery involving the parotid gland, parapharyngeal space (PPS), or infratemporal fossa (ITF) (3-12). The pathophysiologic mechanism was first described by Netterville et al. (4), and is caused by damage to the sympathetic branches innervating the parotid gland during surgery and development of sequent denervation hypersensitivity from unopposed parasympathetic contractions of the salivary gland myoepithelial cells that elicit pain during onset of gustatory salivation (1,4,13).

Botulinum toxin is produced by the anaerobic bacteria Clostridium botulinum (14). The use of botulinum toxin prevents acetylcholine release from the synapse via cleavage of SNARE proteins, which prevents acetylcholine containing vesicles from binding to the intracellular membrane. The resulting blockade of acetylcholine release leads to a decrease in the parotid gland’s physiologic secretion of saliva (14,15). Injection of botulinum toxin type A (BTA) for the treatment of FBS has been hypothesized to induce medical parasympathetic nerve blockade at the myoepithelial neuromuscular junction and to therefore, decrease pain during parotid gland salivation (16-18).

While FBS may spontaneously resolve in 6–20% of patients (2,5,19,20) and partially improve in 69–82% of patients (2,5,20); 15–18% of patients may develop undiminished, chronic pain (5,19). The time to spontaneous resolution has been reported to be from 1–18 months (10,20-24). Prior medical treatments aimed at FBS include carbamazepine with and without concomitant amitriptyline (19-21,25,26), nonsteroidal anti-inflammatory drugs (20,27), opioids (28), hyoscine (28), gabapentin (19,21), pregabalin (19,29), and local anesthetics (16,19,21,28). Procedural treatments such as acupuncture (16), tympanic neurectomies (16,20), radiation (19,27), tumor remnant excision (30-33), and parasympathetic removal have also been attempted. These medical and surgical treatments have yielded limited therapeutic responses in patients (2,16,19-21,25-33).

Botulinum toxin is widely used in many fields of medicine today to treat various conditions pertaining to nerve and muscle hyperactivity, including auriculotemporal syndrome (Frey syndrome), strabismus, rhytids, focal dystonia, hemifacial spasms, spastic muscular disorders, headaches, hypersalivation, and hyperhidrosis (34-38). Ali et al. (16), reported the first use of BTA injection for treatment of FBS in a 53-year-old patient who had undergone several surgical resections for a right neck lymphangioma. The patient had trialed multiple treatments, including tympanic neurectomy, acupuncture, and narcotics, for the treatment of FBS with limited success. She received a BTA injection and had near complete resolution of symptoms within 2 days. Since this first successful treatment report, multiple further studies (39-45) have investigated the use of BTA for surgically caused FBS. Additionally, there is evidence for its benefit in idiopathic FBS (46). No consensus is present on the optimal dosage, timing of repeat injections, timing to symptom improvement, or safety for this treatment option. The aim of this systematic review was to assess the dosing in units, success of injection, the average time to improvement of FBS and complications after intra-parotid BTA in the literature. We present the following article in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist (47) (available at https://gs.amegroups.com/article/view/10.21037/gs-22-112/rc).

Methods

Research Questions and analytic framework

Our systematic review was designed to assess whether intra-parotid injection of BTA is an effective treatment of FBS. Our secondary objective was to assess dosages used for FBS, time to improvement of symptoms after BTA injection and complications of treatment. Table 1 presents the PICO question.

Table 1

PICO: inclusion and exclusion criteria

PICO elements Inclusion criteria Exclusion criteria
Population FBS secondary to surgery FBS secondary to non-surgical etiology
All ages No age restriction
Human studies Animal studies
All languages Cadaver studies
All publication types
Intervention Intra-parotid botulinum toxin injection Not utilizing botulinum treatment for FBS
Not discussing treatment methodology or dosage
Comparison Patients not receiving intra-parotid botulinum toxin or patients receiving intra-parotid saline injection NA
Outcome Resolution of symptoms of FBS NA
Time to improvement of FBS

PICO, Population, Intervention, Comparison, Outcome; FBS, first bite syndrome; NA, not applicable.

Protocol and registration

We had registered our systematic review with the International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42020201836.

Ethical considerations

This study is a systematic review of literature and does not require institutional review board (IRB) approval.

Eligibility criteria

Studies of patients with FBS of surgical etiology receiving treatment with intra-parotid BTA injection were included. All ages, genders, study methodologies, geographies, languages, publication types were included. Additionally, patients who had failed observation or medical or surgical treatments of FBS prior to intra-parotid BTA injection were included. All surgical approaches and surgical indications were included. Randomized and non-randomized control trials, prospective studies, retrospective studies, case series and case reports were eligible for inclusion. Exclusion criteria included: FBS due to non-surgical etiology (including idiopathic and oncogenic origin), animal studies, and cadaver studies. Studies in which intra-parotid BTA was administered but treatment dosage, etiology or outcomes were not reported were also excluded.

Data source and search strategy

An electronic search of the MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar databases was performed from time of inception to July 1, 2020. A table with the specific search terms used for the search for each database is included in Table 2.

Table 2

Database search criteria

Database searched Search terms
PubMed/MEDLINE (first bite syndrome) AND (botu* OR botox)
Embase (‘first bite syndrome’/exp OR ‘first bite syndrome’ OR (first AND (‘bite’/exp OR bite) AND (‘syndrome’/exp OR syndrome))) AND botulinum
Cochrane Library (first bite syndrome) AND (botu* OR botox)
Google Scholar (first bite syndrome) AND (botulinum OR botox)

*, this symbol is used at the root of a word to find multiple endings.

Study selection and data extraction

Studies were screened by title, abstract, and full text by two independent reviewers (NS and HJ). Data extracted from each study included: study ID, study title, year of publication, study design, number of patients, age of patients, sex of patients, presence of tumor, pathology of tumor, surgical approach, botulinum toxin treatment strategy, number of repeated injections, timing of repeated injections, cause for repeat injections, improvement in symptoms, timing to improvement in symptoms, length of resolution of symptoms, length of follow-up, symptoms duration after surgery, resolution of symptoms, time to resolution of symptoms, time to return of symptoms of significant intensity, injection technique, use of multi-site injection, and complications. Data extraction was performed by two independent reviewers (NS and HJ). At the beginning of data collection, an attempt was made to contact authors for full text article when only available as a poster or when a limited data set was presented (46,48,49).

Risk of bias and study quality assessment

The National Institute of Health (NIH) Quality Assessment Tools provides methodological frameworks for systematically assessing risk of bias in controlled and uncontrolled studies (50). While the NIH tool is not traditionally used to assess for bias, we used it as a proxy given the limitations provided by the types of studies included. The quality assessment tools for both before-after studies with no control group and case series studies were used as applicable for the studies included. These tools study multiple domains including objectivity, patient similarity, selection criteria, blinding, classification of interventions, missing data, measurement of outcomes, follow-up adequacy, and result clarity. Studies were assigned an overall score of risk of good, fair, or poor.

Results

Study selection

A total of 41 studies were identified from literature search. Twenty-eight studies remained after removal of duplicate studies. Twenty articles were excluded after reviewing the full text for reasons including: not treating with botulinum toxin, no report of treatment dose or treatment effects, patient did not have FBS, and non-surgical etiology of FBS. Eight studies were included in the final review, of which the poster only was available for one article (45). This poster contained all the necessary treatment details for the purposes of the review. However, an attempt was still made to retrieve the full-length manuscript for this poster with no response from the author. The literature search protocol for selection of eligible studies is presented as a PRISMA flow diagram in Figure 1.

Figure 1 PRISMA flowchart of study selection process. From 41 initial studies identified with database search, 28 full-text articles were assessed for eligibility after screening by title and abstract and removal of duplicates. Eight studies were included in final systematic review. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Study characteristics

The eight studies included a total of 22 patients. There was one prospective study (42), two retrospective studies (40,41), one case series (39), and four case reports (16,43-45) included. The population size in the studies varied from one to five patients. All studies were single center studies. None of the studies had control data and only two patients demonstrated no improvement within the time frame assessed (41,42). As such, the results of this study are purely descriptive and not sufficient for meta-analysis.

Risk of bias in studies

All studies were determined to be of fair to poor quality. Tables 3,4 present the assessments of study quality.

Table 3

Study Quality Assessment for before-after studies with no control group

Criteria Costales-Marcos et al. (42) Ghosh et al. (41) Lee et al. (40)
Was the study question or objective clearly stated? Y Y Y
Were eligibility/selection criteria for the study population prespecified and clearly described? Y Y N
Were the participants in the study representative of those who would be eligible for the test/service/intervention in the general or clinical population of interest? Y Y Y
Were all eligible participants that met the prespecified entry criteria enrolled? CD Y CD
Was the sample size sufficiently large to provide confidence in the findings? N N N
Was the test/service/intervention clearly described and delivered consistently across the study population? N Y Y
Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed consistently across all study participants? Y N Y
Were the people assessing the outcomes blinded to the participants’ exposures/interventions? N N N
Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted for in the analysis? Y Y Y
Did the statistical methods examine changes in outcome measures from before to after the intervention? Were statistical tests done that provided p values for the pre-to-post changes? Y Y Y
Were outcome measures of interest taken multiple times before the intervention and multiple times after the intervention (i.e., did they use an interrupted time-series design)? N Y N
If the intervention was conducted at a group level (e.g., a whole hospital, a community, etc.) did the statistical analysis take into account the use of individual-level data to determine effects at the group level? NA NA NA
Quality rating (good, fair, or poor) Fair Fair Fair

†, Study Quality Assessment Tool offered by the National Institute of Health (Source: National Heart, Lung, and Blood Institute; National Institute of Health; U.S. Department of Health and Human Services) (50). Y, yes; CD, cannot determine; N, no; NA, not applicable.

Table 4

Study Quality Assessment for case-series studies†

Criteria Ali et al. (16) Harirchian et al. (45) Mikolajczak et al. (43) Sims et al. (39) Wang et al. (44)
Was the study question or objective clearly stated? Y N Y Y N
Was the study population clearly and fully described, including a case definition? Y Y Y Y Y
Were the cases consecutive? NA NA NA N NA
Were the subjects comparable? NA NA NA N NA
Was the intervention clearly described? Y Y Y Y N
Were the outcome measures clearly defined, valid, reliable, and implemented consistently across all study participants? N N N N N
Was the length of follow-up adequate? Y Y Y Y N
Were the statistical methods well-described? NA NA NA NA NA
Were the results well-described? Y Y Y Y N
Quality rating (good, fair, or poor) Fair Fair Fair Fair Poor

†, Study Quality Assessment Tool offered by the National Institute of Health (Source: National Heart, Lung, and Blood Institute; National Institute of Health; U.S. Department of Health and Human Services) (50). Y, yes; NA, not applicable; N, no.

Results of individual studies

Nineteen patients developed FBS secondary to tumor excision requiring PPS dissection (16,39-42), one due to superficial parotidectomy (43), and two due to carotid endarterectomy (44,45). Three studies commented on the occurrence of FBS following external carotid artery (ECA) ligation, from which only three patients had ECA ligation (39,40,42). As expected, there were no cases of FBS following total parotidectomy. One study commented on sympathetic chain sacrifice, totaling five patients, of whom, three had sympathetic chain sacrifice (42). Four studies commented on the presence of Horner’s syndrome, totaling 16 patients, of whom six had Horner’s syndrome (16,40-42).

Six studies reported specifically the use of multi-site injection technique over 20 patients (16,39-43,45). Five studies reported specifically on the use of ultrasound-guided injection in 13 patients (16,40,41,43,45). None of the studies divided the research population into two separate treatment groups, one receiving BTA treatment and a control group not receiving BTA treatment. All studies were case series or case reports and were of low quality. The characteristics of the studies and patients are included in Tables 5,6.

Table 5

Study characteristics

Reference Year Country/language Design Size Sex [age]
Ali et al. (16) 2008 USA/English Case report 1 F [53]
Costales-Marcos et al. (42) 2017 Spain/Spanish Prospective case series 5 M, M, F, F, F; individual age not stated
Ghosh et al. (41) 2016 USA/English Retrospective case series 5 M [46], M [29], F [77], F [67], F [49]
Harirchian et al. (45) 2011 USA/English Case report 1 M [70]
Lee et al. (40) 2009 Korea/English Retrospective case series 5 M [34], M [58], F [55], F [45], F [38]
Mikolajczak et al. (43) 2015 Germany/German Case report 1 M [60]
Sims et al. (39) 2013 USA/English Retrospective case series 3 M [67], F [44], F [34]
Wang et al. (44) 2013 New Zealand/English Case report 1 M [75]

M, male; F, female.

Table 6

Patient characteristics

Reference Path FBS cause Previous treatments
Ali et al. (16) Lymphangioma PPS [1] Tympanic neurectomy
Costales-Marcos et al. (42) Schwannoma: 2, carotid paraganglioma: 2, vagal paraganglioma PPS [5] NA
Ghosh et al. (41) Pleomorphic adenoma: 2, carotid body tumor:2, giant cell tumor PPS [5] NA
Harirchian et al. (45) NA Carotid endarterectomy [1] Gabapentin
Lee et al. (40) Carotid body tumor: 2, pleomorphic adenoma, sympathetic chain schwannoma, metastatic papillary cancer PPS [5] NA
Mikolajczak et al. (43) Warthin tumor Parotidectomy [1] NA
Sims et al. (39) Metastatic SCC, lymphatic malformation, AV malformation PPS [3] None
Wang et al. (44) NA Carotid endarterectomy [1] NA

Patient number is in square brackets. SCC, squamous cell carcinoma; NA, not applicable; FBS, first bite syndrome; PPS, parapharyngeal space.

Outcomes assessment

Sixteen of 17 patients with individual level data reported improvement in symptoms during the follow-up period, which ranged from 1–30 months (median, 6 months) post injection (16,39,41-45). One retrospective study, treating five patients, measured a mean improvement in symptoms across the cohort, but did not report individual level data (40). Two studies reported resolution of symptoms in seven patients (39,41). No study reported a complication from BTA injection.

Six studies assessed patients within 1 month of treatment (16,39,40,42-44), and four studies specifically mentioned individual patient’s symptoms within 1 month of treatment of botulinum toxin (16,39,43,44). Six of 6 (100%) patients assessed within this time frame reported an improvement in symptoms. Seven studies assessed patients within 4 months of treatment (16,39-44), and five studies specifically mentioned individual patient’s symptoms within 4 months of treatment of botulinum toxin (16,39,41,43,44). Ten of 11 (90.9%) patients assessed within this time frame reported an improvement in symptoms. Average time to improvement with non-scheduled assessments was 8.3 days. Four patients reported an improvement in symptoms within less than a week of injection (16,41). Eight of 8 (100%) of patients receiving at least 40 U of BTA (Botox) had improvement of symptoms at an average of 1.3 months (range, 1 day to 4 months) (16,39,41,43,44). Ten of 22 (45.5%) patients received second injection of botulinum toxin due to return of pain (39,41-43,45). The second injection was administered on average 3.8 months following the initial injection (range, 6 weeks to 7 months). Two patients received up to five injections of BTA (39,41), and the maximum cumulative injected dose was 160 U (41). In total, 31.8% of patients had complete resolution of symptoms at a mean of 12.1 months (range, 3 days to 28 months). Table 7 presents treatment dosing and schedule.

Table 7

Botulinum toxin A injection treatment dosing and schedule

Reference Time from causative surgery to injection† First injection dose‡ Injection technique Time to improvement Total dose Total injections Follow up times in months§
Ali et al. (16) 3 years 75 U [1] USG, dose diluted in 2 mL NS, multi-site, focused on areas of most pain 2 days 75 U 1 [1] 2.5
Costales-Marcos et al. (42) Mean and individual times not specified [2–17] months 30 U [5] USG not specified, diluted in NS, multi-site, 1.5 cm anterior to tragus, 1 mL syringe, 25-G needle, without LA 6 months (4/5) 30–80 U 1 [2], 2 [3] 1, 3, 6
Ghosh et al. (41) 4.8 [4–6] months 10 U [1], 20 U [1], 22.5 U [1], 40 U [2] USG, diluted in NS, multi-site, focused on areas of most pain 4 months (3/5) 20–160 U 1 [1], 2 [1], 4 [2], 5 [1] 4 [10–28]
Harirchian et al. (45) Not specified Dysport 280 U USG, multi-site, superficial and deep lobes Not specified 280 U Dysport + 50 U Botox 2 [1] 17
Lee et al. (40) 39.4 [22–60] months 33 U [5] USG, diluted in NS, multi-site, without LA 1–3 months 33 U 1 [5] 1, 3, 6
Mikolajczak et al. (43) 3 months 35 U [1] USG, dose diluted in 2 mL NS, multi-site 10 days 70 U 1 [1] 3
Sims et al. (39) 9.7 [4–18] months 75 U [3] USG not specified, multi-site, focused on areas of most pain 1–4 days 75–200 U 1 [1], 3 [1], 5 [1] [4–11.5]
Wang et al. (44) Not specified 50 U [1] USG not specified, multi-site not specified 1 month 50 U 1 [1] 1

Patient number is in square brackets. †, time from causative surgery to first injection is provided as a mean, with the range in square brackets. If a study was a case report, only a single value is reported. ‡, all dosage units are reported for botulinum toxin A, Botox, unless otherwise specified. §, follow up times provided as scheduled times, and range in square brackets. USG, ultrasound-guided; NS, normal saline; LA, local anesthesia.

Discussion

In 1998, Netterville et al. (4), was the first to propose the mechanism of FBS after observing multiple patients develop FBS after removal of vagal paragangliomas who suffered sympathetic denervation and unopposed parasympathetic innervation of parotid myoepithelial cells. In their study, eight out of nine patients with sympathetic chain injury (Horner’s syndrome) developed FBS, characterized by pain during onset of oral intake. In 2002, Chiu et al. (20), reported a series of 12 patients that developed FBS after surgery of the PPS, in which six underwent ligation of the ECA and the other six patients had sacrifice of sympathetic chain with Horner’s syndrome.

Linkov et al. (2), demonstrated three major variables that were significant predictors of FBS: sacrifice of the sympathetic chain, the extent of parotidectomy, and PPS dissection. Surgery involving the PPS, ITF, and deep lobe of the parotid significantly increased the risk of FBS, in addition to transcervical approach and sacrifice of the sympathetic chain or total parotidectomy. In their analysis, the three tumors most associated with development of FBS included schwannoma, paraganglioma, and pleomorphic adenoma. Additionally, female gender, and absence of prior radiation predisposed to FBS. They concluded that all 12 patients likely had loss of sympathetic innervation to the parotid gland. Multiple other studies have confirmed loss of sympathetic function to be associated with FBS including reports of pretreatment FBS in cases of ECA or sympathetic chain invasion by tumors, including mucoepidermoid carcinoma (31), adenoid cystic carcinoma (30), schwannoma (51), and synovial sarcoma (32).

This systematic review examines the potential of BTA to treat FBS resulting as a surgical complication. As previously discussed, while some patients develop resolution of symptoms within 1–18 months (5,10,19-23,27,52,53), up to 88% of patients continue to experience symptoms (2,5,19,24,53-55). Botulinum toxin has had multiple applications in otolaryngology, including dystonia of the larynx (56), laryngeal granulomas (57), laryngeal joint dislocation (58), cricopharyngeal spasm (57), posterior glottic synechiae (59), blepharospasm (60), hemifacial spasm (60), temporomandibular joint disorders (61), and oromandibular dystonia (60). BTA treatments generally last for 3 to 6 months (62,63).

While use of BTA is not commonly associated with many adverse side effects, the few that are present tend to be more transient in nature, such as pain in the injection site with local edema (64), erythema (65), and numbness (66). Generalized systemic side effects include headache (64), malaise (66), and nausea (66). Specifically reported complications from use in the head and neck include injection site bruising (65), local infection (65), and toxin spread locally or systemically with unintended paralysis (67,68), which can cause oculomotor disturbances (67), dysphagia (69,70), breathiness (71), and even delayed gall bladder emptying (72).

BTA is contraindicated in myasthenia gravis, Eaton-Lambert Syndrome, and concurrent use of agents that can interfere with neuromuscular junction (i.e., aminoglycosides, penicillamines, and quinines). After receiving BTA injections, patients are advised to stay upright for 3 to 4 hours, avoid strenuous activity, and refrain from undergoing any facial massage for 1 or 2 weeks because any increase in pressure or blood circulation may dislodge the toxin from the appropriate site. This generally does not last more than a few months and can resolve in a few weeks depending on the strength of the dose and the site of injection (34). Ultrasound can assist in precise injection (73).

We found eight relevant studies involving the treatment of FBS using BTA in a total of 22 patients. All treatments involved varying dosages of BTA and ranged from 10 to 75 U and were given at least once and up to five times in some patients (39,41). Most patients received BTA (Botox) as the only treatment for FBS; however, there was one patient that underwent two prior tympanic neurectomies (16) and one patient that received gabapentin, BTA (Dysport), and then BTA (Botox) (45). There have been other attempts to treat FBS with various medications, procedures, and acupuncture; however only around 12% of individuals experience complete resolution of symptoms (2,16,19-21,25-33).

This study has demonstrated promise of BTA in the improvement of symptoms in patients with FBS. From the limited data, it does appear that doses as low as 20 U can be effective (41). All patients receiving a dose of at least 40 U of BTA demonstrated improvement in symptoms (16,39,41,43,44). In certain patients, botulinum toxin appears to have rapid effect on symptom treatment, improving symptoms in as little as 1 day after treatment (39). Doses as high as 75 U and multiple sets of injections have been performed in a limited set of patients with no reported complications (16,39,41-43,45). Patients can have significant worsening of symptoms after treatment within a wide time frame between 6 weeks to 7 months after injection. Repeat injections can offer benefit to these patients. In our study, 31.8% of patients had complete resolution of their symptoms in a mean time of 12.1 months, compared to literature reports of persistent disease in up to 88% of patients (2).

The mechanism by which botulinum toxin injection improves FBS is unclear. Currently, there are no cellular or animal disease models of FBS, making the more basic study of the pathophysiology and pharmacologic mechanism of action difficult. However, we postulate BTA may improve resolution of the disease secondary to decreases in salivary gland weight, cholinergic output, secretory capacity, cellular size, and myoepithelial function after injection (74-76). Additionally, nerve growth factor (NGF) expression can be increased by BTA (77), which may lead to improved parotid gland sympathetic reinnervation (78). This may explain the potential long-term improvements some patients experience. Finally, since resolution occurs spontaneously (10,19-23), it may be that BTA serves as a bridge, treating the symptoms until time allows for natural recovery.

Our review has several important limitations. Very few patients in the literature have undergone botulinum toxin injection for the treatment of FBS (16,39-45). None of the included studies were randomized and all studies had at least a moderate risk of bias. None of the included studies had a control group at the start of the data collection for identifying patients who did or did not receive BTA. Most of the studies were small case series with a mixed patient population with varying surgical etiologies of FBS. Finally, there is no uniform subjective symptom score or objective measure of post injection symptom relief, so efficacy outcomes are purely based on subjective patient reported improvement or resolution.

The main objective of this study was to assess the efficacy and safety of BTA in the treatment of surgically induced FBS. However, due the limited data available in the literature as discussed above, we were not able to compare the outcomes of BTA to observation only. This is an important consideration given that FBS is known to improve or resolve spontaneously (10,19-23). Studies in this review utilized BTA from 2–60 months after development of FBS, which makes it difficult to parse the benefit of BTA over observation, especially in studies that started injections shortly after development of FBS. As such, observations about the efficacy of BTA over observation or placebo effect in the treatment of this syndrome cannot be made.

Implications

Currently, BTA is not used regularly to treat FBS. While it has demonstrated utility in a non-controlled context, a case-control or case cross-over trial might better assess the efficacy, time to improvement of symptoms and length of significant improvement in symptoms with the use of a standardized visual analog score (VAS).

Acknowledgments

We would like to acknowledge the support of Dr. Cara Stokes from the Department of Otolaryngology-Head and Neck Surgery at West Virginia University for support in study design and data review.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-22-112/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-22-112/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-22-112/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study is a systematic review of literature and therefore does not require IRB approval.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Laccourreye O, Werner A, Garcia D, et al. First bite syndrome. Eur Ann Otorhinolaryngol Head Neck Dis 2013;130:269-73. [Crossref] [PubMed]
  2. Linkov G, Morris LG, Shah JP, et al. First bite syndrome: incidence, risk factors, treatment, and outcomes. Laryngoscope 2012;122:1773-8. [Crossref] [PubMed]
  3. Lammek K, Tretiakow D, Skorek A. The first bite syndrome after parotidectomy. Oral Oncol 2021;113:105028. [Crossref] [PubMed]
  4. Netterville JL, Jackson CG, Miller FR, et al. Vagal paraganglioma: a review of 46 patients treated during a 20-year period. Arch Otolaryngol Head Neck Surg 1998;124:1133-40. [Crossref] [PubMed]
  5. Avinçsal MÖ, Hiroshima Y, Shinomiya H, et al. First bite syndrome - An 11-year experience. Auris Nasus Larynx 2017;44:302-5. [Crossref] [PubMed]
  6. Lombardi D, McGurk M, Vander Poorten V, et al. Surgical treatment of salivary malignant tumors. Oral Oncol 2017;65:102-13. [Crossref] [PubMed]
  7. Wahlberg P, Anderson H, Biörklund A, et al. Carcinoma of the parotid and submandibular glands--a study of survival in 2465 patients. Oral Oncol 2002;38:706-13. [Crossref] [PubMed]
  8. Boros MJ, Wysong ST. Syndromes after resection of a cervical schwannoma. Ear Nose Throat J 2011;90:431-3. [Crossref] [PubMed]
  9. Nicolai P, Paderno A, Farina D, et al. Microdebrider cavitation and transcervical removal of parapharyngeal schwannomas approaching the skull base. Eur Arch Otorhinolaryngol 2014;271:3305-11. [Crossref] [PubMed]
  10. Wong EH, Farrier JN, Cooper DG. First-bite syndrome complicating carotid endarterectomy: a case report and literature review. Vasc Endovascular Surg 2011;45:459-61. [Crossref] [PubMed]
  11. Tao MJ, Roche-Nagle G. First bite syndrome: a complication of carotid endarterectomy. BMJ Case Rep 2016;2016:bcr2015213996. [Crossref] [PubMed]
  12. Shiozaki E, Izumo T, Morofuji Y, et al. First Bite Syndrome Following Carotid Endarterectomy. J Stroke Cerebrovasc Dis 2020;29:105364. [Crossref] [PubMed]
  13. Redon S, Graillon N, Régis J, et al. First Bite Syndrome After Trigeminal Radiosurgery: Case Report and Pathophysiology. Headache 2018;58:1680-1. [Crossref] [PubMed]
  14. Dressler D, Saberi FA, Barbosa ER. Botulinum toxin: mechanisms of action. Arq Neuropsiquiatr 2005;63:180-5. [Crossref] [PubMed]
  15. Malgorzata P, Piotr C, Edward K. The Mechanism of the Beneficial Effect of Botulinum Toxin Type a Used in the Treatment of Temporomandibular Joints Dysfunction. Mini Rev Med Chem 2017;17:445-50. [Crossref] [PubMed]
  16. Ali MJ, Orloff LA, Lustig LR, et al. Botulinum toxin in the treatment of first bite syndrome. Otolaryngol Head Neck Surg 2008;139:742-3. [Crossref] [PubMed]
  17. Maharaj S, Mungul S, Laher A. Botulinum toxin A is an effective therapeutic tool for the management of parotid sialocele and fistula: A systematic review. Laryngoscope Investig Otolaryngol 2020;5:37-45. [Crossref] [PubMed]
  18. Taib BG, Williams SP, Sood S, et al. Treatment of sialorrhoea with repeated ultrasound-guided injections of botulinum toxin A into the parotid and submandibular glands. Br J Oral Maxillofac Surg 2019;57:442-8. [Crossref] [PubMed]
  19. Abdeldaoui A, Oker N, Duet M, et al. First Bite Syndrome: a little known complication of upper cervical surgery. Eur Ann Otorhinolaryngol Head Neck Dis 2013;130:123-9. [Crossref] [PubMed]
  20. Chiu AG, Cohen JI, Burningham AR, et al. First bite syndrome: a complication of surgery involving the parapharyngeal space. Head Neck 2002;24:996-9. [Crossref] [PubMed]
  21. Albasri H, Eley KA, Saeed NR. Chronic pain related to first bite syndrome: report of two cases. Br J Oral Maxillofac Surg 2011;49:154-6. [Crossref] [PubMed]
  22. Kamal A, Abd El-Fattah AM, Tawfik A, et al. Cervical sympathetic schwannoma with postoperative first bite syndrome. Eur Arch Otorhinolaryngol 2007;264:1109-11. [Crossref] [PubMed]
  23. Gunter AE, Llewellyn CM, Perez PB, et al. First Bite Syndrome Following Rhytidectomy: A Case Report. Ann Otol Rhinol Laryngol 2021;130:92-7. [Crossref] [PubMed]
  24. Xu V, Gill KS, Goldfarb J, et al. First Bite Syndrome After Parotidectomy: A Case Series and Review of Literature. Ear Nose Throat J 2020; Epub ahead of print. [Crossref] [PubMed]
  25. Cernea CR, Hojaij FC, De Carlucci D Jr, et al. First-bite syndrome after resection of the styloid process. Laryngoscope 2007;117:181-2. [Crossref] [PubMed]
  26. Borràs-Perera M, Fortuny-Llanses JC, Palomar-Asenjo V, et al. First-bite syndrome. Acta Otorrinolaringol Esp 2009;60:144-5. [Crossref] [PubMed]
  27. Costa TP, de Araujo CEN, Filipe J, et al. First-bite syndrome in oncologic patients. Eur Arch Otorhinolaryngol 2011;268:1241-4. [Crossref] [PubMed]
  28. Phillips TJ, Farquhar-Smith WP. Pharmacological treatment of a patient with first-bite syndrome. Anaesthesia 2009;64:97-8. [Crossref] [PubMed]
  29. Casserly P, Kiely P, Fenton JE. Cervical sympathetic chain schwannoma masquerading as a carotid body tumour with a postoperative complication of first-bite syndrome. Eur Arch Otorhinolaryngol 2009;266:1659-62. [Crossref] [PubMed]
  30. Deganello A, Meccariello G, Busoni M, et al. First bite syndrome as presenting symptom of parapharyngeal adenoid cystic carcinoma. J Laryngol Otol 2011;125:428-31. [Crossref] [PubMed]
  31. Diercks GR, Rosow DE, Prasad M, et al. A case of preoperative "first-bite syndrome" associated with mucoepidermoid carcinoma of the parotid gland. Laryngoscope 2011;121:760-2. [Crossref] [PubMed]
  32. Lieberman SM, Har-El G. First bite syndrome as a presenting symptom of a parapharyngeal space malignancy. Head Neck 2011;33:1539-41. [Crossref] [PubMed]
  33. Guss J, Ashton-Sager AL, Fong BP. First bite syndrome caused by adenoid cystic carcinoma of the submandibular gland. Laryngoscope 2013;123:426-8. [Crossref] [PubMed]
  34. Nigam PK, Nigam A. Botulinum toxin. Indian J Dermatol 2010;55:8-14. [Crossref] [PubMed]
  35. Münchau A, Bhatia KP. Uses of botulinum toxin injection in medicine today. BMJ 2000;320:161-5. [Crossref] [PubMed]
  36. Busey B, Esparza MJA. The evidence for noncosmetic uses of botulinum toxin. J Fam Pract 2020;69:447-53. [Crossref] [PubMed]
  37. Motz KM, Kim YJ. Auriculotemporal Syndrome (Frey Syndrome). Otolaryngol Clin North Am 2016;49:501-9. [Crossref] [PubMed]
  38. Wood CB, Netterville JL. Temporoparietal frey syndrome: An uncommon variant of a common syndrome. Laryngoscope 2019;129:2071-5. [Crossref] [PubMed]
  39. Sims JR, Suen JY. First bite syndrome: case report of 3 patients treated with botulinum toxin and review of other treatment modalities. Head Neck 2013;35:E288-91. [Crossref] [PubMed]
  40. Lee BJ, Lee JC, Lee YO, et al. Novel treatment of first bite syndrome using botulinum toxin type A. Head Neck 2009;31:989-93. [Crossref] [PubMed]
  41. Ghosh A, Mirza N. First bite syndrome: Our experience with intraparotid injections with botulinum toxin type A. Laryngoscope 2016;126:104-7. [Crossref] [PubMed]
  42. Costales-Marcos M, López Álvarez F, Fernández-Vañes L, et al. Treatment of the first bite syndrome. Acta Otorrinolaringol Esp (Engl Ed) 2017;68:284-8. [Crossref] [PubMed]
  43. Mikolajczak S, Ludwig L, Grosheva M, et al. First Bite Syndrome: Successful Treatment with Botulinum Toxin A. Laryngorhinootologie 2015;94:524-5. [Crossref] [PubMed]
  44. Wang TK, Bhamidipaty V, MacCormick M. First bite syndrome following ipsilateral carotid endarterectomy. Vasc Endovascular Surg 2013;47:148-50. [Crossref] [PubMed]
  45. Harirchian S, Benson B. Multiple Cranial Neuropathies and First Bite Syndrome after Carotid Endarterectomy. Laryngoscope 2011;121:S74. [Crossref]
  46. Stoopler ET, Elmuradi S, Sollecito TP, et al. Idiopathic First Bite Syndrome. J Oral Maxillofac Surg 2016;74:872. [Crossref] [PubMed]
  47. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372: [PubMed]
  48. Harlow R, Carter L. Botulinum toxin type a for first bite syndrome-a case report. British Journal of Oral and Maxillofacial Surgery 2019;57:e66-7. [Crossref]
  49. Silva A, Gens H, Luzeiro I. First bite syndrome-a clinical case seen at the headache consultation. Cephalalgia 2018;38:112.
  50. National Heart, Lung, and Blood Institute; U.S. Department of Health and Human Services. Study Quality Assessment Tools. Available online: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
  51. Navaie M, Sharghi LH, Cho-Reyes S, et al. Diagnostic approach, treatment, and outcomes of cervical sympathetic chain schwannomas: a global narrative review. Otolaryngol Head Neck Surg 2014;151:899-908. [Crossref] [PubMed]
  52. Yang X, Yang X, Wang W, et al. Primary First Bite Syndrome of the Parotid Gland: Case Report and Literature Review. Ear Nose Throat J 2020; Epub ahead of print. [Crossref] [PubMed]
  53. Topf MC, Moritz E, Gleysteen J, et al. First bite syndrome following transcervical arterial ligation after transoral robotic surgery. Laryngoscope 2018;128:1589-93. [Crossref] [PubMed]
  54. Huang S, Huang CP, Shen CY, et al. First bite syndrome: clinical study of six cases and review of the literature. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2019;33:1196-9. [PubMed]
  55. Charles-Harris H, Rodriguez B. First Bite Syndrome: Presentation of a Patient Status-Post Right Carotid Endarterectomy. Vasc Endovascular Surg 2021;55:64-8. [Crossref] [PubMed]
  56. Dressler D, Adib Saberi F, Rosales RL. Botulinum toxin therapy of dystonia. J Neural Transm (Vienna) 2021;128:531-7. [Crossref] [PubMed]
  57. Yılmaz T, Kayahan B, Günaydın RÖ, et al. Botulinum Toxin A for Treatment of Contact Granuloma. J Voice 2016;30:741-3. [Crossref] [PubMed]
  58. Rontal E, Rontal M. Botulinum toxin as an adjunct for the treatment of acute anteromedial arytenoid dislocation. Laryngoscope 1999;109:164-6. [Crossref] [PubMed]
  59. Nathan CO, Yin S, Stucker FJ. Botulinum toxin: adjunctive treatment for posterior glottic synechiae. Laryngoscope 1999;109:855-7. [Crossref] [PubMed]
  60. Karp BI, Alter K. Botulinum Toxin Treatment of Blepharospasm, Orofacial/Oromandibular Dystonia, and Hemifacial Spasm. Semin Neurol 2016;36:84-91. [Crossref] [PubMed]
  61. Sipahi Calis A, Colakoglu Z, Gunbay S. The use of botulinum toxin-a in the treatment of muscular temporomandibular joint disorders. J Stomatol Oral Maxillofac Surg 2019;120:322-5. [Crossref] [PubMed]
  62. Wright G, Lax A, Mehta SB. A review of the longevity of effect of botulinum toxin in wrinkle treatments. Br Dent J 2018;224:255-60. [Crossref] [PubMed]
  63. Benninger MS, Smith LJ. Noncosmetic uses of botulinum toxin in otolaryngology. Cleve Clin J Med 2015;82:729-32. [Crossref] [PubMed]
  64. Sethi N, Singh S, DeBoulle K, et al. A Review of Complications Due to the Use of Botulinum Toxin A for Cosmetic Indications. Aesthetic Plast Surg 2021;45:1210-20. [Crossref] [PubMed]
  65. Zagui RM, Matayoshi S, Moura FC. Adverse effects associated with facial application of botulinum toxin: a systematic review with meta-analysis. Arq Bras Oftalmol 2008;71:894-901. [Crossref] [PubMed]
  66. Lee KC, Pascal AB, Halepas S, et al. What Are the Most Commonly Reported Complications With Cosmetic Botulinum Toxin Type A Treatments? J Oral Maxillofac Surg 2020;78:1190.e1-9. [Crossref] [PubMed]
  67. Blitzer A, Sulica L. Botulinum toxin: basic science and clinical uses in otolaryngology. Laryngoscope 2001;111:218-26. [Crossref] [PubMed]
  68. Borodic GE, Pearce LB, Smith K, et al. Botulinum a toxin for spasmodic torticollis: multiple vs single injection points per muscle. Head Neck 1992;14:33-7. [Crossref] [PubMed]
  69. Schneider I, Thumfart WF, Pototschnig C, et al. Treatment of dysfunction of the cricopharyngeal muscle with botulinum A toxin: introduction of a new, noninvasive method. Ann Otol Rhinol Laryngol 1994;103:31-5. [Crossref] [PubMed]
  70. van Hoeij FB, Tack JF, Pandolfino JE, et al. Complications of botulinum toxin injections for treatment of esophageal motility disorders†. Dis Esophagus 2017;30:1-5. [PubMed]
  71. Shogan AN, Rogers DJ, Hartnick CJ, et al. Use of botulinum toxin in pediatric otolaryngology and laryngology. Int J Pediatr Otorhinolaryngol 2014;78:1423-5. [Crossref] [PubMed]
  72. Schnider P, Brichta A, Schmied M, et al. Gallbladder dysfunction induced by botulinum A toxin. Lancet 1993;342:811-2. [Crossref] [PubMed]
  73. Barbero P, Busso M, Artusi CA, et al. Ultrasound-guided Botulinum Toxin-A Injections: A Method of Treating Sialorrhea. J Vis Exp 2016;54606. [Crossref] [PubMed]
  74. Ellies M, Laskawi R, Götz W, et al. Immunohistochemical and morphometric investigations of the influence of botulinum toxin on the submandibular gland of the rat. Eur Arch Otorhinolaryngol 1999;256:148-52. [Crossref] [PubMed]
  75. Teymoortash A, Sommer F, Mandic R, et al. Intraglandular application of botulinum toxin leads to structural and functional changes in rat acinar cells. Br J Pharmacol 2007;152:161-7. [Crossref] [PubMed]
  76. Regueira LS, Baratella-Evêncio L, de Oliveira JB, et al. Effects of chronic treatment with botulinum toxin type A in salivary glands of rats: Histological and immunohistochemical analyses. J Oral Pathol Med 2019;48:728-34. [Crossref] [PubMed]
  77. Belinskaia M, Zurawski T, Kaza SK, et al. NGF Enhances CGRP Release Evoked by Capsaicin from Rat Trigeminal Neurons: Differential Inhibition by SNAP-25-Cleaving Proteases. Int J Mol Sci 2022;23:892. [Crossref] [PubMed]
  78. Proctor GB, Carpenter GH. Regulation of salivary gland function by autonomic nerves. Auton Neurosci 2007;133:3-18. [Crossref] [PubMed]
Cite this article as: Shaikh NE, Jafary HA, Behnke JW, Turner MT. Botulinum toxin A for the treatment of first bite syndrome—a systematic review. Gland Surg 2022;11(7):1251-1263. doi: 10.21037/gs-22-112

Article Options

Download Citation

Share