3.1 Study Selection

Across all databases, the literature search identified 2181 records. After removal of 658 duplicates, 1523 records were screened, of which 1449 were excluded for ineligibility. A total of 74 articles underwent full-text review. Following full-text assessment, 37 articles were excluded, and 37 systematic reviews were assessed for methodological quality, using the AMSTAR-2 tool. Of these, 27 systematic reviews were classified as low (n = 14) and critically low (n = 13) quality and were excluded from the umbrella review. Consequently, 10 systematic reviews, including 5 rated as high quality and 5 as moderate quality, were included in the final synthesis (Fig. 1).

Fig. 1

Preferred reporting items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of study identification, screening, eligibility assessment and inclusion for the umbrella review

3.2 Study Characteristics

The 10 systematic reviews included were published between 2015 and 2024. Most reviews included RCTs comparing BoNT-A injections with placebo (commonly saline). Some systematic reviews also included observational studies and comparisons with other pharmacological or interventional treatments. According to the included reviews, the number of primary studies ranged from 1 to 23, and the number of participants varied depending on the condition, reaching 739 individuals with TN [18, 19, 26, 27] and 125 with PHN [18, 19, 28]. Seven of the included systematic reviews conducted quantitative syntheses (meta-analyses) [26, 28,29,30,31,32,33]. The characteristics of the included systematic reviews are summarised in Table 1.

Table 1 Study characteristics of the included systematic reviews3.3 Overlap of Primary Studies Across Systematic Reviews

Considerable overlap of primary randomised controlled trials was identified across the included systematic reviews, particularly for TN. Several reviews included the same placebo-controlled BoNT-A trials, especially the studies by Wu et al. (2012), Shehata et al. (2013), Zúñiga et al. (2013), and Zhang et al. (2014) [34,35,36,37]. Overlap among PHN reviews was comparatively lower but still present, mainly involving the studies by Apalla et al. (2013) and Xiao et al. (2010) [38, 39]. To improve transparency and facilitate interpretation of the review-level evidence, the overlap of primary randomised controlled trials across included systematic reviews was mapped descriptively (Tables 2, 3).

Table 2 Descriptive overlap assessment of primary randomised controlled trials for trigeminal neuralgia across included systematic reviewsTable 3 Descriptive overlap assessment of primary randomised controlled trials for postherpetic neuralgia across included systematic reviews3.4 Doses and Injection Protocols

Botulinum toxin type A was administered using variable dosing regimens and injection protocols depending on the neuropathic pain condition and study design. Overall, total doses ranged from approximately 15–300 U per treatment session [18, 19, 26, 28]. Across the included studies, both fixed-site and “follow-the-pain” approaches were used, reflecting variability in injection patterns, number of sites, and total dose administered. Different BoNT-A formulations were reported across studies [26, 28].

In TN, BoNT-A was most administered in single-session protocols using doses typically ranging from 25 to 100 U, although higher doses of up to 200 U were also reported [18, 19, 26, 27]. Injections were performed subcutaneously or intradermally along the distribution of the affected trigeminal branches, following a multi-point injection technique. The number of injection sites varied across studies, generally ranging from a few targeted points to approximately 15–25 sites, with 2.5–5 U per injection point [18, 26, 27].

In PHN, BoNT-A was typically injected within the affected dermatomal area using multi-point injection approaches. Total doses ranged from 100 to 300 U depending on the size of the painful area, with up to 40 injection sites reported in some studies [18, 19, 28]. Both single-session and repeated injection protocols were described, with follow-up intervals of approximately 12 weeks in studies including multiple treatment sessions [18, 19, 28].

3.5 Quantitative Findings

Most of the included systematic reviews investigated the pain-reducing effects of BoNT-A for the assessed conditions using the Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS). Several reviews also evaluated treatment response, typically defined as a ≥ 50% reduction in pain intensity, whereas fewer reviews assessed quality-of-life outcomes. Adverse events associated with BoNT-A treatment were reported in most of the included systematic reviews. A quantitative presentation of these outcomes is shown in Tables 4, 5, 6, 7, 8, 9, 10 and 11.

Table 4 Table presenting quantitative findings regarding the effect of BoNT-A treatment on pain intensity in trigeminal neuralgiaTable 5 Table presenting quantitative findings regarding the effect of BoNT-A treatment on responder rate and clinical improvement in trigeminal neuralgiaTable 6 Table presenting quantitative findings regarding the effect of BoNT-A treatment on quality of life in trigeminal neuralgiaTable 7 Table presenting quantitative findings regarding the effect of BoNT-A treatment on AEs in trigeminal neuralgiaTable 8 Table presenting quantitative findings regarding the effect of BoNT-A treatment on pain intensity in post-herpetic neuralgiaTable 9 Table presenting quantitative findings regarding the effect of BoNT-A treatment on responder rate and clinical improvement in post-herpetic neuralgiaTable 10 Table presenting quantitative findings regarding the effect of BoNT-A treatment on quality of life in post-herpetic neuralgiaTable 11 Table presenting quantitative findings regarding the effect of BoNT-A treatment on AEs in post-herpetic neuralgia3.5.1 Effect of BoNT-A Treatment on Pain Intensity in TN and PHN

Evidence on TN pain intensity reduction showed variable heterogeneity across studies (Tables 4, 5, 6, 7, 8, 9, 10, 11). Most systematic reviews evaluated changes in pain intensity following BoNT-A injections compared with baseline or placebo. The overall findings generally favoured BoNT-A treatment, with reductions in pain intensity consistently reported after treatment [26, 28,29,30]. Follow-up evidence from 1–3 months further indicated that BoNT-A was associated with improvements in pain intensity over time [26, 28,29,30]. Across the included meta-analyses [26, 29, 30], BoNT-A was consistently associated with reductions in pain intensity in patients with TN. These findings were observed both in comparisons with baseline and in randomised comparisons with placebo. Pooled analyses also indicated reductions in attack frequency following BoNT-A treatment in TN. The magnitude of the effect varied across studies, with considerable heterogeneity reported [26, 29] (Tables 4, 5, 6, 7, 8, 9, 10, 11). Reported pooled effect estimates for pain reduction ranged approximately from MD − 1.38 to − 5.88 across different follow-up periods, whereas heterogeneity varied from low to substantial (I2 ranging from 0 to 96.8%).

Postherpetic neuralgia pain intensity reduction showed variability across studies (Table 8). Most systematic reviews evaluated BoNT-A against placebo, consistently reporting greater reductions in pain intensity following BoNT-A administration [28, 30]. Evidence from one network meta-analysis showed higher diminution of pain intensity after BoNT-A injections compared with subcutaneous infiltrations of lidocaine; however, direct comparative data between BoNT-A and active interventions were limited and inconsistent with other interventional and pharmacological treatments [26, 32]. The overall findings generally favoured BoNT-A treatment, with reductions in pain intensity reported after treatment. Pooled analyses [28, 30], supported by evidence from interventional network meta-analysis [32], indicated short-term (1–3 months) improvements in pain intensity following BoNT-A administration. However, effect estimates varied across studies, with moderate to high heterogeneity observed [28, 30] (Tables 4, 5, 6, 7, 8, 9, 10, 11). Reported heterogeneity in pooled PHN analyses ranged up to 98%, reflecting variability in study design, injection protocols, and outcome assessment.

3.5.2 Responder Rate and Clinical Improvement in TN and PHN

For TN, most systematic reviews evaluated responder rates (≥ 50% pain reduction) following BoNT-A injections compared with placebo. The overall findings generally favoured BoNT-A treatment, with higher responder rates consistently reported [18, 26, 29] (Table 5). Follow-up assessments, typically ranging from 2 to 3 months, indicated sustained treatment response over time [26, 29]. Across the included meta-analyses and network meta-analyses, BoNT-A was associated with improved responder rates in patients with TN [26, 29, 31]. Reported responder rates for ≥ 50% pain reduction generally ranged from approximately 70% in pooled analyses, with odds ratios favouring BoNT-A over placebo ranging from 2.87 to 14.0 across reviews. However, the magnitude of treatment response varied across studies, and some analyses reported low-certainty evidence or inconsistent findings [33] (Tables 4, 5, 6, 7, 8, 9, 10, 11).

Treatment response in PHN was reported by a limited number of the included reviews (Table 9). Generally, compared with placebo, BoNT-A treatment showed higher response rates [18, 19]. Follow-up data were limited but suggested short-term (1–3 months) improvements after treatment. However, heterogeneity was not consistently reported in the included meta-analyses, limiting the interpretation of between-study variability (Tables 4, 5, 6, 7, 8, 9, 10, 11).

3.5.3 Effect of BoNT-A Treatment on Quality of Life in TN and PHN

Evidence on quality-of-life outcomes after BoNT-A treatment for TN and PHN was limited (Tables 6 and 10). Only one systematic review with meta-analysis assessed these outcomes, focusing exclusively on sleep-related measures [28]. Botulinum toxin type A showed reductions in sleep disturbance scores and increases in sleep duration, with some findings significant versus baseline or placebo [28]. However, pooled analyses did not demonstrate statistically significant differences between BoNT-A and placebo for these outcomes [28] (Tables 4, 5, 6, 7, 8, 9, 10, 11).

3.5.4 Adverse Events of BoNT-A Treatment in TN and PHN

For TN, AEs were generally mild and transient. The most reported events were injection-related reactions, including facial asymmetry, oedema, and haematoma at the injection site. Some analyses also reported pain during injection, although the frequency of these events was comparable between BoNT-A and placebo (Table 7).

Regarding PHN, AEs were also mild and transient and were reported by a limited number of systematic reviews with meta-analysis. The most reported AEs were local injection-related reactions, including oedema and haematoma at the injection site (Table 11).

Overall, BoNT-A treatment is generally well tolerated in patients with TN and PHN.

3.6 Synthesis of Evidence

Table 12 summarises the evidence from the quantitative research synthesis regarding the effects and AEs following BoNT-A treatment. Overall, quantitative evidence indicates generally favourable effects of BoNT-A compared with placebo for TN and with placebo or other active treatments for PHN across pain intensity, attack frequency, and responder rate outcomes. The included meta-analyses reported reductions in pain intensity following BoNT-A treatment when compared to placebo/short-term follow-ups 1–3 months) for both TN and PHN [26, 28,29,30, 32]. It was reported that attack frequency was also reduced following BoNT-A treatment when compared to placebo in short-term follow-ups (1–3 months) [26, 29]. Responder rate outcomes also suggested meaningful reductions in pain intensity following BoNT-A treatment, with higher response rates generally reported among patients receiving BoNT-A compared with placebo or other interventions for TN and PHN. Evidence on quality-of-life outcomes was limited and derived from a single systematic review, which reported improvements in sleep-related outcomes that were not statistically significant. Reported AEs were generally mild and transient, and the risk of treatment discontinuation due to AEs was low. Overall, although heterogeneity across studies was observed, the available evidence suggests that BoNT-A is a safe treatment that may provide beneficial effects in the management of TN and PHN pain.

Table 12 Summary of evidence regarding botulinum toxin A (BoNT-A) treatment in orofacial neuropathic pain conditions