Table 1.
The list of studies, in chronological order, regarding the efficacy of BoNT/A on humans with TN. Legend: N/A—not available; IM—intramuscular; VAS—visual analogic scale; SC—subcutaneous; TN—trigeminal neuralgia.
| Study Type | Toxin Type and Dilution, Injection Route, and Dose | Patients | Major Findings | Adverse Events | |
|---|---|---|---|---|---|
| [85] Micheli et al., 2002 | Case report | Type: onabotulinumtoxinA Dilution: N/A Approach: IM Dose: 2.5 per site (two sites) Location: orbicular oculi, buccinator muscles |
One patient with painful convulsive tic (hemifacial spasm and Type 1 classical TN) | Pain ameliorated for 10 weeks and then reappeared. The procedure was repeated every 12 weeks with significant improvement. | N/A |
| [86] Allam et al., 2005 | Case report | Type: onabotulinumtoxinA Dilution: N/A Approach: IM Dose: Two per site (eight sites) Location: V1 and V2 branches |
One idiopathic type 1 TN (left V2); after the failure of CBZ and then glycerol rhizotomy, burning pain spread in all three branches. | VAS Pain score significantly reduced from 82 to 54, 25, 25, and 45 at 7-day, 30-day, 60-day, and 90-day follow-up. | Mild paresis of the left frontal muscle. |
| [87] Türk et al., 2005 | Open-label study | Type: onabotulinumtoxinA Dilution: 50 U/mL Approach: N/A Dose: 50 U per site (two sites) Location: one site above and one site below the zygomatic arch |
Eight patients with idiopathic type 1 TN refractory to medical treatment. | Significant reduction in pain intensity and frequency at 1-week, 2-month, and 6-month follow-up. No quantitative data. | One patient reported chewing impairment for 3–4 days; one patient reported dysesthesia affecting the site treated. |
| [88] Piovesan et al., 2005 | Open-label study | Type: onabotulinumtoxinA Dilution: N/A Approach: SC Dose: mean 3.22 U/cm2 Location: “follow the pain” technique |
13 patients with TN (three performed previous surgery for TN). There was no information regarding the etiology and type of TN. | Significant reduction in pain and pain area in every branch studied. Maximum effect was observed at 20-day and 30-day follow-up. There was a positive correlation between pain area and intensity of pain. The effect lasted >60 days. | None |
| [89] Volcy et al., 2006 | Case report | Type: N/A Dilution: N/A Approach: IM Dose: 7.5 U Location: in the left masseter and zygomatic muscles |
One patient with idiopathic Type I TN (left V2) | Significant reduction in pain (over 90% reduction) over two months; the procedure was repeated two other times. | N/A |
| [90] Boscá-Blasco et al., 2006 | Case series | Type: onabotulinumtoxinA Dilution: 25U/mL Approach: IM Dose: 15–17.5 U Location: orbicularis oculi |
Four patients with painful convulsive tic (hemifacial spasm and classical TN); the type was not reported. | Significant reduction in pain (not quantified); 3–5 months duration. | None |
| [91] Zúñiga et al., 2008 | Open-label study | Type: onabotulinumtoxinA Dilution: N/A Approach: SC Dose: 20–50U Location: in the trigger zone and painful areas. |
12 patients with idiopathic TN. Did not specify the type of TN. | Pain significantly reduced from 8.83 ± 1.19 to 4.08 ± 4.44 after 8 weeks. The paroxysms reduced from 23.42 ± 13.5 to 8.67 ± 12.4 at the 8-week follow-up. Two patients did not respond to the treatment. Complete pain relief for 7 weeks and then gradual resumption of pain. Higher doses correlated with an earlier onset of action. Pain free for 60 days; at the 12-week follow-up pain gradually reprised. | Facial asymmetry in only one case |
| [92] Ngeow et al., 2010 | Case report | Type: onabotulinumtoxinA Dilution: 40U/mL Approach: SC Dose: 40–60 U Location: in the right mental nerve territory and in the right nasal trigger zone. |
One patient with idiopathic type 1 TN (right V2-V3); 14 neurectomies were performed and she later developed persistent neuropathic pain. | Complete resolution of pain for five months in the right nasal region; partial response in the right mental region. 5 months duration. Pain reduction is not quantified. | Facial asymmetry |
| [93] Bohluli et al., 2011 | Open-label study | Type: N/A Dilution: N/A Approach: N/A Dose: 50–100 U Location: in the trigger zones. |
15 patients with type 1 TN; not specified etiology. | Significant pain and frequency reduction at 1-week and 1-month follow-up. The duration of the effect was reported to be up to 6 months. | Facial asymmetry in three cases (one severe paralysis) |
| [94] Shehata et al., 2012 | Randomized, double-blinded, placebo-control study | Type: onabotulinumtoxinA Dilution: 50 U/mL Approach: SC Dose: 40–60 U, 5 U per site Location: “follow the pain” technique |
20 idiopathic TN patients; 10 treated with BoNT/A and 10 with placebo. Not specified the type. | Pain significantly reduced in the group treated with BoNT/A (6.5 NRS mean reduction) at the 12-week endpoint; the placebo group did not improve (0.3 NRS mean reduction). Paroxysm frequency significantly reduced at the two-week follow-up and persisted till the endpoint. No correlation between the dose and the pain reduction or paroxysm frequency. | The group treated with BoNT/A presented four cases of facial asymmetry, one case of hematoma, one case of itching, and one case of pain in the injection site. The placebo group did not present facial asymmetry, but there were two cases of hematoma, 1 case of pain, and one case of itching in the injection site. |
| [95] Wu et al., 2012 | Randomized, double-blinded, placebo-controlled study | Type: lanbotulinumtoxinA Dilution: 50 U/mL Approach: intradermal or intraoral Dose: 75 U, 5 U per site Location: “follow the pain” technique |
40 patients with classical TN; 21 treated with BoNT/A and 19 with placebo. Not specified the type. | 68.18% of patients in the BoNT/A group had > 50% pain reduction at 12-week endpoint; 15% of the patients in the placebo group had > 50% pain reduction at 12-week follow-up. The frequency in the BoNT/A group significantly reduced at 1-week follow-up and persisted to the endpoint. | Five patients in the BoNT/A group experienced facial asymmetry; three with patients presented edema in the injection site (one of them was in the placebo group). |
| [96] Zúñiga et al., 2013 | Randomized, double-blinded, placebo-controlled study | Type: onabotulinumtoxinA Dilution: 50U/mL Approach: SC Dose: 50U Location: “follow the pain” technique |
36 TN patients; 20 treated with BoNT/A and 16 with placebo. Classical and idiopathic. Not specified the type. | Pain significantly reduced from 8.85 to 4.9 and 4.75 in the BoNT/A group at 2-month and 3-month follow-up, respectively; in the placebo group the pain significantly changed from 8.19 to 6.63 and 6.94 at two-month and 3-month follow-up respectively. The number of paroxysms in the BoNT/A group significantly reduced from 29.1 to 7.1 at 3-month follow-up. In the placebo group paroxysms reduced from 31.06 to 21.25 per day at 3-month follow-up, although this difference was not statistically significant. Duration of BoNT/A effect was reported to be at least 3 months. | None |
| [97] Li et al., 2014 | Open-label study | Type: lanbotulinumtoxinA Dilution: 50U/mL Approach: SC or intraoral Dose: 20–170 U, 2.5–5 U per site Location: “follow the pain” technique |
88 patients with classical TN; the sample was then divided into three groups based on BoNT/A dose (<50, 50–100, >100). Not specified the type. | 92% had at least >50% pain reduction at one moth follow-up; 100% and 77% had >50% pain reduction at 2-month and 3-month follow-up, respectively. At 14-month follow-up, 38.6% had still at least >50% improvement and 22% were completely pain free. No significative difference between the different dose groups. | Local swelling in three patients; muscle weakness in 10 cases. |
| [98] Wang et al., 2014 | Open-label study | Type: lanbotulinumtoxinA Dilution: N/A Approach: N/A Dose: N/A Location: N/A |
16 patients with classical TN. Not specified the type. | Pain significantly reduced from 9.12 ± 0.65 to 2.8 ± 1.36, 2.2 ± 1.26, 1.3 ± 1.45, 1.3 ± 1.45, and 1.2 ± 2.52 at 1-week, 2-week, 1-month, 3-month, and 6-month follow-up, respectively. | NA |
| [99] Zhang et al., 2014 | Randomized, double-blinded, placebo-controlled study | Type: lanbotulinumtoxinA Dilution: 100U/mL Approach: intradermal or intraoral Dose: 25 or 75 U Location: “follow the pain” technique |
84 patients with classical TN; 27 treated with 25 U and 29 treated with 75 U. 28 patients were treated with placebo. Not specified the type. | The responders (>50% pain reduction), at 8-week follow-up, were 70.4%, 86.2%, and 32.1% for the 25 U group, 75 U group, and placebo, respectively. There was a significant pain reduction in both groups treated with BoNT/A but not for the placebo group. There was no difference in efficacy between the 25 U and 75 U groups. | Three patients treated with BoNT/A (two in the 25 U group and one in the 75 U group) presented with facial asymmetry. Transient edema in the injection site in two patients treated with 25 U of BoNT/A. |
| [100] Xu et al., 2015 | Open-label study | Type: lanbotulinumtoxinA Dilution: 25 U/mL Approach: intradermal or intraoral Dose: 88 ± 30 U in the > 70 years old group, 72 ± 33 in the <60 years old group. Dose range 30–200 U, 2.5–5 U per site. Location: “follow the pain” technique |
64 patients with idiopathic TN; sub-analysis of >70 years old and <60 years old. Not specified the type. | Pain significantly reduced from 7.7 ± 2.2 to 4.4 ± 2.9 at 1-month follow-up. No differences between the two age groups. | Seven patients with minor side effects. |
| [101] Xia et al., 2015 | Open-label study | Type: lanbotulinumtoxinA Dilution: 50U/mL Approach: intradermal or subcutanoeus Dose: N/A Location: N/A |
87 patients with classical TN, only one branch involved. Not specified the type. | Pain reduced significantly from 6.59 to 1.95 at 8-week follow-up. | Local swelling in two patients; facial weakness in seven patients. |
| [102] Lunde et al., 2016 | Case report | Type: N/A Dilution: 100 U/mL Approach: SC and intradermal Dose: 75 U, 2.5–5 U per site Location: along the course of the three branches. |
One patient with idiopathic type II secondary TN (all the three left branches affected). | Complete resolution of pain after 19 days. Gradual reprisal of pain at week 9. | N/A |
| [103] Zhang et al., 2016 | Open-label, randomized trial | Type: lanbotulinumtoxinA Dilution: 50 U/mL Approach: intradermal or intraoral Dose: 70–100 U if single injection or 50–70 U each session in case of 2 injection (2 weeks apart). Location: “follow the pain” technique |
81 patients with classic TN; 44 treated with a single injection and 37 treated with two injections 2 weeks apart. Not specified the type. | 90.9% and 61.4% of the single injection group had pain reduction of at least > 50% at 2-month and 6 -month follow-up, respectively; 83.3 and 51.4% % of the double injection group had at least > 50% pain reduction at 2-month and 6-month follow-up respectively. Pain reduced significantly in the first group from 7.99 ± 1.60 to 1.59 ± 2.17 and 3.02 ± 3.29 at 3-month and 6-month follow-up respectively; the second group had similar results with pain reduction from 8.27 ± 1.69 to 2.36 ± 3.01 and 4.32 ± 3.61 at 3-month and 6-month follow-up, respectively. There were no statistical differences between the two groups. | 14 patients with unspecified side effect (seven in both groups). |
| [104] Türk et al., 2017 | Open-label study | Type: onabotulinumtoxinA Dilution: 50 U/mL Approach: near nerve Dose: 50U per branch Location: “follow the pain” technique |
27 patients with classical TN; not specified the type. | Pain significantly reduced from 9.7 ± 0.6 to 2.4 ± 3.1 and 1.6 ± 2.4 at two-month and six-month follow-up, respectively. 74.1% and 88.9% had >50% pain reduction at 2-month and 6-month follow-up respectively. 44.4% were pain-free at 6-month follow-up. The frequency improved from 217 ± 331.5 paroxysms per day to 54.8 ± 196.2 and 55.15 ± 196.2 at 2-month and 6-month follow-up. | One patient with facial asymmetry; two patients with masseter weakness. |
| [105] Wu et al., 2018 | Case report | Type: lanbotulinumtoxinA Dilution: 100 U/mL Approach: IM (masseter muscle) and intraoral Dose: 50 U Location: “follow the pain” technique |
One patient with type 1 classical TN | No significant improvement with intraoral injection; significant pain reduction after intramuscular injection in the masseter muscle with complete remission of pain after 2 weeks. | N/A |
| [106] Liu et al., 2018 | Open-label study | Type: lanbotulinumtoxinA Dilution: 25 U/mL Approach: intradermal or intraoral Dose: 30–200 U Location: “follow the pain” technique |
43 patients with classical TN distributed in 14 >80 years and 29 < 60 years. Not specified the type. | Pain reduced significantly from 8.5 and 8.0 to 4.5 and 4.0 for the >80 years and <60 years groups respectively at 1-month follow-up. | Four patients with facial asymmetry (two in each group). |
| [107] Caldera et al., 2018 | Open-label study | Type: N/A Dilution: N/A Approach: intradermal Dose: 15–50 U Location: “follow the pain” technique |
22 with type 1 and type 2 idiopathic TN patients with insufficient control with first-line treatment. | Pain significantly reduced from 7.41 ± 2.2 to 5.59 ± 2.7, 5.68 ± 2.6, 5.27 ± 3.2, 4.77 ± 3.7, and 5.32 ± 4.0 at 10-day, 20-day, 30-day, 60-day, and 90-day follow-up, respectively. No differences between high dose vs. low dose of BoNT/A. | None |
| [108] Crespi et al., 2019 | Open-label study | Type: onabotulinumtoxinA Dilution: 50 U/mL Approach: into the sphenopalatine ganglia Dose: 25 U Location: into the sphenopalatine ganglia |
10 patients with refractory classical Type 2 TN. | Pain significantly reduced from 6.0 (3.0–8.5) to 3.0 (0.0–9.0) at 5/8-week follow-up. Frequency of paroxysms did not reduce significantly. Concomitant persistent pain not improved after adjustment for multiplicity. | There were four cases of swelling, five cases of jaw dysfunction, two cases of facial asymmetry, one case of dry eye, one case of diplopia, one case of cutaneous rash, and one case of dysphagia. |
| [109] Wu et al., 2019 | Retrospective | Type: lanbotulinumtoxinA Dilution: 50 U/mL Approach: intradermal or intraoral Dose: 2.5–5 U per site Location: “follow the pain” technique |
104 patients with refractory classical TN. Not specified the type. | 87 patients reported pain reduction > 50% at 8-day follow-up (41 had complete pain control); 17 patients reported mild improvement, no improvement, or worsening. Patients with age > 50 years had better outcomes. | 17 patients reported facial asymmetry. |
| [110] Calejo et al., 2019 | Case report | Type: N/A Dilution: N/A Approach: N/A Dose: 45U, 5 U per site and three sites per branch Location: “follow the pain” technique |
One patient with secondary (multiple sclerosis) type 1 TN, with all the branches involved. | There was 75% pain reduction that lasted 3 months. | Facial asymmetry |
| [111] Yoshida et al., 2019 | Open-label study | Type: onabotulinumtoxinA Dilution: 50 U/mL Approach: into the sphenopalatine ganglia Dose: 50 U Location: into the sphenopalatine ganglia |
10 patients with classical TN (V2), refractory to submucosal BoNT/A injections. Not specified the type. | Pain significantly reduced from 8.1 ± 1.0 to 1.9 ± 1.4 at 4-week, 8-week, and 12-week follow-up. Pain frequency decreased from 19.4 ± 8.8 to 4.8 ± 5.4, 3.8 ± 5.5, and 4.8 ± 5.4 at 4-week, 8-week, and 12-week follow-up. | None |
| [112] Zhang et al., 2019 | Retrospective | Type: lanbotulinumtoxinA Dilution: 50 U/mL Approach: intradermal or intraoral Dose: 1.25–5 U per site Location: “follow the pain” technique |
152 patients with classical TN; subdivided in low dose (<40 U), medium dose (40–70 U), and high dose (>70 U). Not specified the type. | 89.4% reported reduction in pain intensity of at least >50% at 2-week follow-up; the effect was sustained throughout the first 6 months of follow-up. Patients who received high and medium dose had cases of more complete pain relief than the low dose group (21.1% and 22.7% vs. 11.2%); however, the difference was not statistically significant, and the overall efficacy was similar. High dose was associated with longer duration effect of BoNT/A on pain. 58 patients had follow-up longer than 7 months without increment in pain scores. | 21 patients presented facial asymmetry. |
| [113] Dinan et al., 2020 | Case report study | Type: onabotulinumtoxinA Dilution: N/A Approach: intraoral and SC Dose: 30 U subcutaneously and 20 U intraorally Location: “follow the pain” technique |
One patient with idiopathic type 1 TN (V2 and V3 involvement). | Complete pain relief 3 days after the treatment; 3-month duration. | Facial asymmetry |
| [114] Mingazova et al., 2021 | Open-label study | Type: onabotulinumtoxinA Dilution: N/A Approach: SC and IM (masseter muscle) Dose: mean dose 80 U (35 frontal; 20 U temporal region; 10–16 in middle and lower part of the face, 10 U into the masseter muscle) Location: along the course of the branches. |
20 patients with classical and idiopathic TN. Not specified the type. | Pain intensity did not reduced significantly at 1-month follow-up (8.5 vs. 7.2) while at 2-month and 3-month follow-up this difference was significant (6.1 and 4.9, respectively). The frequency of the paroxysms significantly reduced from 31.2 per day to 22.5, 17.7, and 9.2 at 1-month, 2-month, and 3-month follow-up, respectively. 50% and 38% of the patients were pain-free at 90-days and 115-days follow-up. | N/A |
| [115] Yoshida et al., 2021 | Open-label study | Type: onabotulinumtoxinA Dilution: 50 U/mL Approach: SC and intraoral Dose: 43.1 ± 5.3 U Location: “follow the pain” technique |
28 patients with TN. Not specified etiology and type. | Pain significantly reduced from 89.3 ± 7.5 to 35.1 ± 6.6, 25.9 ± 6.8, 20.8 ± 7.0, and 19.5 ± 7.3 at 2-week, 4-week, 8-week, and 12-week follow-up. Frequency significantly reduced from 19.1 ± 7.7 paroxysms per day to 9.8 ± 4.9, 5.6 ± 3.5, 4.2 ± 2.9, and 3.7 ± 2.6 at 2-week, 4-week, 8-week, and 12-week follow-up | Muscle weakness and and tenderness at the injection site; not quantified. |
| [116] Asan et al., 2022 | Retrospective | Type: onabotulinumtoxinA Dilution: N/A Approach: SC and intraoral Dose: 32.5–50 U, 2.5 U per site Location: “follow the pain” technique |
53 patients with idiopathic TN (22) or secondary TN (31) due to MS (RR or PP); Type 2 TN present in 12 patients in the first group and 17 patients in the second group. | Pain reduced significantly from 9 to 6. The idiopathic TN group had significant pain reduction from 8 to 7; the MS TN group had significant pain reduction from 9 to 5. Efficacy was higher in the type 2 TN (62% vs. 33%; p 0.047). | BoNT/A was administered also in the contralateral side to prevent facial asymmetry. Only two patients reported facial asymmetry. |
| [117] Pearl et al., 2022 | Case report | Type: N/A Dilution: 50 U/mL Approach: intraoral Dose: 20 U Location: in the left mental foramen |
Two patients with type 1 TN (one classical left V3 TN; one secondary left V3 TN due to MS). | Patient 1 had complete pain relief for 6 weeks, 10 weeks, 5 months and 18 months after the first, second, third, and fourth treatments, respectively. Patient 2 had complete pain relief for 5 months and 18 months after the first and second treatments, respectively. | N/A |
| [118] Xiromerisiou et al., 2023 | Retrospective | Type: onabotulinumtoxinA Dilution: 50–25 U/mL Approach: SC Dose: 5–2.5 U per site Location: “follow-the pain” approach |
15 patients with TN (11 with idiopathic or classical TN and four with secondary TN). Not specified the type. | Pain decreased from a baseline VAS of 9.3 ± 1.1 to 3.7 ± 1.2 at 2-week follow-up. | Five patients with mild and transient erythema and/or tenderness, resolved within 48 h. No facial asymmetry. |
| [119] Tereshko et al., 2023 | Open-label study | Type: onabotulinumtoxinA Dilution: 100 U/mL Approach: SC and intradermal Dose: 29.7 ± 11.4 U Location: “follow-the pain” technique, along the course of the branches involved. |
40 TN patients (18 type 1 TN and 22 type 2 TN); 18 patients with classical TN and 22 with idiopathic TN. | Pain reduced from 8.1 ± 1.4 (VAS) to 3.3 ± 2.3 and 3.4 ± 2.4 at the 1-month and 3-month follow-ups (p < 0.001). Type 1 TN and type 2 TN groups had baseline pain scores of 7.8 ± 1.65 and 8.4 ± 1.1, respectively. Pain significantly improved (p < 0.001) in both groups to 3.1 ± 2.3 (type 1 TN) and 3.5 ± 2.3 (type 2 TN) at the 1-month follow-up and to 3.2 ± 2.5 (type 1 TN) and 3.6 ± 2.5 (type 2 TN) at the 3-month follow-up. There was no difference between the two groups (p 0.345). | 14 patients had mild transient facial asymmetry (six type 1 TN and eight type 2 TN patients). |