Our study demonstrates that fluoroscopic-guided BoNTA injections targeting the sphenopalatine ganglion can significantly reduce pain intensity and attack frequency in patients with trigeminal neuralgia. BoNTA injections are known to be effective in treating chronic migraine [15]; however, evidence supporting the efficacy of this treatment for trigeminal neuralgia remains limited. In 2016, Morra et al. conducted a systematic review and meta-analysis, concluding that BoNTA may be an effective treatment for trigeminal neuralgia. They found that the mean VAS score at two months post-BoNTA injection was significantly lower than the baseline (-2.47, 95%CI [-3.96, -0.99], p = 0.001]16. In contrast to our study, the studies included in this systematic review administered BoNTA either intradermally or subcutaneously, with none delivering the medication directly into the SPG, as in our approach, which demonstrated a greater reduction in pain intensity two months post-procedure.

Yoshida et al. described a technique using a customized computer-aided design/computer-assisted manufacturing (CAD/CAM) needle guide to administer botulinum toxin via intraoral routes directly to the SPG. Similar to our study, they found that both pain intensity and the frequency of pain attacks were significantly reduced compared to baseline [16]. Crespi et al. reported a pilot study on the percutaneous injection of BoNTA directly into the SPG using a specialized injection device, guided by surgical CT and/or MRI navigation in patients with trigeminal neuralgia. Although their study did not show a significant reduction in the number of daily pain attacks, it did demonstrate a significant decrease in pain attack intensity and in concomitant persistent pain 5–8 weeks post-procedure [17]. We believe that our study is the first to describe percutaneous fluoroscopic-guided BoNTA injection directly into the SPG. This technique is familiar to most pain interventionists, easy to perform, and does not require specialized equipment. It also allows for confirmation of correct needle placement within the SPG by injecting contrast media before delivering the medication, and our study demonstrate that this technique is well-tolerated and provided significant pain reduction in both intensity and frequency of attacks.

The pathophysiology of trigeminal neuralgia is thought to be multifactorial, involving central and peripheral sensitization, hyperexcitability neuronal state, and widespread neural plasticity change [18]. Although, the exact link between SPG and trigeminal neuralgia has not been establish, recent evidence supports that modulating pain signal at the SPG, which alters central and peripheral sensitization in the pain pathway, can be beneficial for many painful craniofacial conditions [11, 16]. Several pilot studies have explored the use of BoNTA injection directly into the SPG for various craniofacial pain conditions, including chronic cluster headache, persistent idiopathic facial pain, and intractable chronic migraine. However, the results have been inconsistent, likely due to small sample size and differences in the pathophysiology of these complex craniofacial pain conditions [19,20,21,22].

The pterygopalatine fossa houses the SPG, the largest peripheral parasympathetic ganglion, along with some sympathetic innervation [10]. The maxillary branch of the trigeminal nerve also travels through this fossa [10]. This multi-innervation, involving both the somatic and autonomic nervous systems, makes the SPG a compelling target for intervention in conditions with complex and unclear pathophysiology, such as trigeminal neuralgia [16].

While the exact mechanism of BoNTA in pain reduction is not yet fully understood, it is believed that the medication inhibits the release of neurotransmitters and algogenic neuropeptides, such as substance P, from primary sensory neurons and modulates pain signals [9, 22]. Moreover, studies have shown that BoNTA can undergo intracellular trafficking either retrograde or anterograde along the nerve through the microtubule [23, 24]. This phenomenon may explain the observation in our study that the patient who had symptoms in the maxillary branch (V2) also benefited from this intervention.

There is no consensus on the recommended dose of BoNTA for trigeminal neuralgia, with dose reported in the existing literature ranging from 25 to 200 units [22]. Zhang et al. reported similar short-term efficacy between low-dose (25 units) and high-dose (75 units) BoNTA injections administered intradermally and/or via the oral submucosa for trigeminal neuralgia [8]. Previous pilot studies that directly injected BoNTA into the SPG for craniofacial pain conditions reported doses ranging from 25 to 50 units. While the results remain inconsistent, studies using 50 units of BoNTA tended to show more positive outcomes [17, 19,20,21].

In terms of safety profile, transient facial palsy and diplopia were observed in our study. Hemifacial palsy was also observed in the previous studies, particularly in those where BoNTA was injected submucosally or transdermally [25]. We suspect that these adverse effects arise from the backflow of the medication through the needle, leading to its spread to the facial muscles and resulting in facial muscle weakness. Diplopia may occur due to the medication spreading to the orbit through connections from the pterygopalatine fossa. We speculate that adjusting the dose and volume of the BoNTA injectate might reduce the prevalence of these adverse effects. Unlike traditional SPG radiofrequency treatment, we did not observe facial paresthesia, facial swelling, hematoma, or epistaxis in our study [12]. This is likely because this technique requires less needle manipulation and utilizes a smaller needle to navigate through such a small and dense space.

This study has several limitations. First, it is an observational study with a small sample size. Although the reductions in pain intensity and attack frequency were statistically significant, the effect size used to calculate our sample size was only weak to moderate (Cohen’s effect size = 0.399). Second, our primary objective was to demonstrate the efficacy of direct BoNTA injection into the SPG for reducing pain intensity. We did not assess improvements in other aspects of pain-related burden or quality of life following the procedure. Lastly, our follow-up period was limited to 60 days, so long-term outcomes were not explored.

Further research, including larger-scale, long-term follow-up randomized controlled trials, is needed to confirm the efficacy of this potentially beneficial intervention. Additionally, studies to determine the optimal dose and concentration of BoNTA to maximize benefits while minimizing potential complications would be valuable.