Intra- and Postoperative Botulinum Toxin Injection in Postsurgical Pain Management: A Literature Review.

1. Introduction
Postoperative pain is a significant challenge in surgical care. Each year in the USA, more than 70 million patients undergo surgery, and 4 out of 5 of them experience acute postoperative pain [1]. If the pain is not managed, it can lead to longer hospital stays and secondary complications such as deep vein thrombosis, postsurgical infections, and prolonged recovery [2, 3]. Moreover, inadequate control of acute pain contributes to the development of chronic postoperative pain (CPSP) [4, 5]. This condition affects 5%–58% of individuals who undergo surgical procedures and imposes significant costs on both patients and the healthcare system [6, 7]. These challenges emphasize the crucial need for minimally invasive techniques and early postsurgical pain management with an interdisciplinary approach to prevent further negative consequences [8, 9].
Opioids and nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs), form the cornerstones of postoperative pain management. However, excessive use of opioids can result in various adverse effects, such as respiratory depression, gastrointestinal disturbances, and cognitive impairments [10–12]. Additionally, opioid-induced tolerance, paradoxical hyperalgesia, and physical dependence can complicate pain management [11, 13, 14]. While NSAIDs are effective for relieving pain and inflammation, they also have potential side effects, including gastrointestinal and cardiovascular issues, renal impairments, and central nervous system effects [15]. NSAIDs also increase the risk of pseudarthrosis and impaired bone healing when used early after spinal fusions [16]. Local approaches, such as regional blocks and local infiltration analgesia, mitigate pain while minimizing the risk of analgesic-related side effects. Integrating these methods with systemic analgesics can further enhance pain control [17–19].
Botulinum neurotoxin (BoNT) is commonly used for conditions such as overactive bladder, strabismus, blepharospasm, cervical dystonia, hyperhidrosis, and extremity spasticity. BoNT has also been indicated for the prophylactic management of chronic migraine [20]. Beyond its approved applications, its potential for pain treatment is increasingly recognized [21]. BoNT has demonstrated effectiveness in reducing pain through several biochemical processes, including inhibition of neurotransmitter release, regulation of pain-related receptors, suppression of glial activity, and interaction with opioidergic and GABAergic systems [22, 23]. BoNT's analgesic effect has been investigated in conditions such as spinal cord injuries, diabetic neuropathy, myofascial syndrome, headaches, and pelvic pain syndrome [24–26]. Moreover, when administered during or after surgeries such as hemorrhoidectomy, mastectomy, and limb lengthening surgeries, BoNT has demonstrated promising results in the prevention and treatment of postsurgical pain [27–29]. This review aims to evaluate the existing literature on the intra- and postoperative application of BoNT in the management of postsurgical pain.

2. Materials and Methods
We searched the PubMed database on January 13, 2025, using the appropriate keywords, “postoperative pain” and “botulinum neurotoxin”. The detailed search strategy in PubMed is presented in Supporting Table 1. Inclusion criteria were original articles in English that focused on the intra- or postoperative use of BoNT in the management of postoperative pain. We applied no publication date limits to our search.
Nonhuman and non-English studies, review articles, abstracts, protocols, letters to the editor, conference papers, case reports, or case series with fewer than 10 participants were excluded. In addition, studies addressing preoperative BoNT application for postsurgical pain were also removed.
Additionally, we performed a manual search of the most relevant search results from Google Scholar and citations of related articles to ensure no appropriate studies were overlooked. All the obtained articles were imported into the EndNote library. The studies were screened by reviewing their titles and abstracts. Subsequently, the full text of the remaining articles was examined to select eligible articles. The data from the included studies were extracted and recorded on the pre-prepared table.

3. Results

3.1. Overview of Study Characteristics

Figure 1 shows the detailed screening process. Initial searching of the PubMed database yielded 248 articles. Of these, 195 studies were excluded during the title and abstract screening. A total of 53 studies were screened in full text. From this group, 31 reports were excluded because they were irrelevant, not in English, were case reports or case series with fewer than 10 participants, review articles, or nonclinical studies. Two extra articles were added from a manual search. Ultimately, a total of 24 articles were included [27, 29–51].
Most of the included studies were randomized clinical trials (RCT) [30, 31, 33–39, 46–52], followed by retrospective [40, 41, 43, 44], pilot studies [32, 42, 45], and a nonrandomized prospective clinical trial [29]. Sample sizes ranged from 8 to 281 participants. BoNT's efficacy was investigated in various surgical specialties, including orthopedic, gastrointestinal, mastectomy and reconstruction, head and neck, and urological surgeries. In 19 articles, the BoNT was injected intraoperatively, while 5 of them followed postoperative injection. Pain intensity was commonly assessed using the visual analog scale (VAS). The interventions differed in BoNT dosage (ranging from 10 to 400 U), injection methods (intramuscular, subcutaneous, intraarticular, or intersphincteric), and timing (intra- or postoperative). Comparators typically included placebo (saline injections). Table 1 indicates the characteristics of the included studies.

3.2. Pain Intensity

3.2.1. Orthopedic Surgeries

Table 2 summarizes the results of the included studies on the effect of BoNT in postoperative pain reduction and analgesic requirement. In orthopedic surgeries, the efficacy of intraoperative BoNT for postoperative pain management differed depending on the procedure. For limb lengthening, an RCT of 125 patients showed significantly lower maximum pain on the first day following surgery in the BoNT group compared to the placebo group, which suggests the potential of BoNT in immediate postoperative pain reduction; however, the analgesic effect did not extend to days 2–4 [35].
Two other trials reported no significant differences in pain relief between the BoNT and placebo groups at any follow-up time points, ranging from 4 to 48 weeks [34, 36]. [NO_PRINTED_FORM] These findings show that although BoNT may provide immediate pain control, its efficacy for long-term pain relief after limb-lengthening surgeries remains uncertain.
Regarding total knee arthroplasty, an RCT reported that a significantly greater proportion of patients in the BoNT group reported substantial pain improvement (VAS score reduction of ≥ 2 points) at 2 months compared to the placebo group. This difference in the proportion of responders remained significant across all of the three time points of 2, 3, and 4 months. The BoNT group also experienced a significantly longer duration of pain relief [33]. These findings suggest that BoNT may be effective for managing postoperative pain after large joint surgeries, such as total knee arthroplasty, and its effect can persist for at least 4 months after the surgery.

3.2.2. Gastrointestinal Surgeries
BoNT has provided significant pain relief in managing pain following hemorrhoidectomy, with significant pain reduction from the immediate postoperative period through the first 2 weeks.
Multiple RCTs confirm that BoNT significantly reduced pain within the first 24 h following hemorrhoidectomy [46, 48]. One study focusing on Ferguson's closed technique hemorrhoidectomy reported significantly lower pain scores in the BoNT group compared to the control group at both 12 and 24 h [46]. Similarly, another study found significantly lower VAS scores on the first day after Milligan–Morgan hemorrhoidectomy in patients receiving BoNT [48].
The analgesic effect of BoNT extended consistently throughout the first week. One RCT demonstrated significantly lower resting pain on each of the first 7 days and during the first five defecations in the BoNT group compared to placebo [47]. Further studies confirmed this superiority at different time points later in the first week, with significant differences observed on day 3, day 5, day 6, and day 7 [48, 49]. Research also showed that the benefits of BoNT persisted up to 14 days postsurgery, with continued reductions in pain at rest and during defecation [50].
When compared to topical glyceryl trinitrate (GT) ointment, pain intensity during defecation was comparable between the two groups following Milligan–Morgan hemorrhoidectomy (p=0.16). However, BoNT demonstrated superior relief of resting pain over the first 7 days (p=0.01) [51].
For fissurectomy, BoNT injection when combined with fissurectomy yielded a higher rate of pain relief at 2 weeks postsurgery compared to fissurectomy alone (89.9% vs. 80.9%) [44]. BoNT also significantly reduced both the intensity and duration of postdefecation pain during the first postoperative defecation compared to preoperative levels (p < 0.0001) [45].
Overall, these findings highlight the efficacy of BoNT in reducing postoperative pain after anorectal surgeries such as hemorrhoidectomy and fissurectomy. The evidence shows that BoNT provides an additive benefit when combined with surgical interventions, such as fissurectomy, highlighting its potential as an adjunct therapy in this setting.
For pain following cholecystectomy, 72% of patients achieved at least 4 weeks of pain relief without requiring analgesics following the injection of BoNT into the sphincter of Oddi, particularly in individuals with functional biliary pain. The onset of this effect occurred at a mean of 7 days postinjection, with the pain relief lasting for a median of 8 weeks. Moreover, of the patients who initially responded to BoNT injection, 96% subsequently experienced complete pain resolution following endoscopic sphincterotomy (ES). This finding highlights the BoNT's application as a diagnostic tool for selecting ES candidates, as a safer potential alternative to sphincter of Oddi manometry (SOM) [40].

3.2.3. Mastectomy and Reconstructive Surgeries
In mastectomy and reconstruction surgeries, the efficacy of BoNT for managing postoperative pain and facilitating tissue expansion demonstrates notable variability across studies. Some trials have demonstrated significant benefits. For example, one study found that BoNT significantly reduced pain scores during the immediate postoperative period, initial expansion, and final expansion after mastectomy with immediate tissue expander placement [29]. Similarly, another trial found significant pain relief between 7 and 45 days after the same surgery type with a lower dose of BoNT [39]. In contrast, other RCTs reported no measurable difference in pain relief between BoNT and placebo at any follow-up point from the first day up to 12 weeks postsurgery [37, 38].
This lack of efficacy has also been noted in other procedures, such as open abdominal wall reconstruction, where one study found no statistically significant difference in pain intensity between the treatment and control groups on any of the first five postoperative days [43]. This variability in outcomes across these studies suggests that the analgesic efficacy of BoNT is influenced by procedural factors such as dosage, injection technique, and target site. Future studies should optimize these parameters to maximize BoNT's efficacy for postoperative pain control in reconstructive surgeries.

3.2.4. Head and Neck Surgeries
In head and neck surgery, BoNT demonstrated significant reductions in postoperative pain following uvulopalatopharyngoplasty (UPPP) in an RCT, in which the BoNT group experienced significantly lower overall pain intensity on postoperative days 2 and 6 (p < 0.01) [31]. This analgesic effect might arise from BoNT's ability to mitigate inflammation and reduce muscle tension in the pharyngeal musculature [53].

3.3. Analgesic Use
The evidence for BoNT's effect on analgesic consumption after hemorrhoidectomy is conflicting. While two studies reported significantly lower analgesic consumption in the BoNT group compared to control groups [47, 51], another study on the same procedure found comparable acetaminophen usage over the week following Ferguson's closed technique hemorrhoidectomy [46].
The data for mastectomy and reconstruction were more consistent, and BoNT provided both early and long-term reductions in narcotic use. One study demonstrated a significant reduction in narcotic demand on the first day after surgery and throughout the tissue expansion phases, with sustained benefits noted in both the initial and final periods [29]. Another trial reported significantly lower narcotic consumption in the BoNT group between 7 and 45 days postsurgery [39].
BoNT's effect in reducing analgesic consumption has been observed in other surgical fields. In bladder reconstruction, BoNT reduced morphine-equivalent use by more than half compared to controls [41]. Moreover, in patients undergoing UPPP, the BoNT group required significantly fewer NSAIDs during the first six postoperative days than the placebo group [31].
However, several studies have not shown this benefit in analgesic consumption. After open abdominal wall reconstruction, a study showed that total median use of morphine milligram equivalents (MME) was lower in the BoNT group (405 vs. 568.1), although the difference did not reach statistical significance (p=0.07) [43]. In a study on damage-control laparotomy (DCL), no significant differences were found in total MME use between the BoNT and placebo groups during hospitalization [42]. Another trial reported only slight decreases in NSAID use in the BoNT group compared to placebo following total knee arthroplasty, with no statistically significant differences in acetaminophen or MME consumption [33].

3.4. Complications

Table 2 provides a review of the side effects in the included studies. While BoNT injection is generally safe, it can be associated with a range of adverse effects, from minor and localized complications to systemic effects [54]. Many of these were procedure-specific complications and not directly attributable to BoNT itself. Across the reviewed studies, there were no serious side effects of BoNT, and most were mild and transient. Eight studies reported statistically comparable side effects between BoNT and control groups [33, 37–39, 41, 42, 44, 46].

3.4.1. Localized Effects
Muscle weakness, a known side effect when BoNT is injected into muscles, predominantly occurs with higher doses [55]. For instance, muscle weakness was reported in two patients treated with high-dose BoNT during neck dissection surgery [30]. Similarly, four cases of transient weakness and instability were observed following intraarticular injections in knee arthroplasty patients [33]. A localized maculopapular rash was reported in the injection site in one patient, which resolved within 4 weeks [32].

3.4.2. Systemic Effects
Across the reviewed studies, systemic toxicity or severe BoNT-associated adverse events were not observed, which reveals its favorable systemic safety profile. Mild systemic symptoms, potentially resulting from off-target diffusion of the toxin, were noted in several studies. For example, headaches, dry mouth, and upper respiratory issues occurred similarly in both the BoNT and control groups after total knee arthroplasty [33]. Dry mouth was also observed in two patients, receiving a high-dose BoNT injection [30]. One study on hemorrhoidectomy reported headaches only in the GT control group, not in the BoNT group [51].

3.4.3. Procedure-Specific Complications
Minor transient fecal incontinence is a known issue in anal surgeries. One study reported three cases with incontinence, resolved within weeks after fissurectomy [45]. Another trial reported mild incontinence in four BoNT patients and five placebo patients, which resolved within 3 weeks [47]. However, other posthemorrhoidectomy studies observed no cases of incontinence posthemorrhoidectomy [46, 49, 52].
Bleeding was rare and comparable between the BoNT and control groups. Minor posthemorrhoidectomy bleeding was noted in a few patients receiving BoNT injections [46, 52]. Posthemorrhoidectomy urinary retention occurred significantly more in the placebo group in one study [50], while another found one case of urinary retention in each group [47].
In a cholecystectomy study, pancreatitis occurred in 15% of patients undergoing SOM but did not occur in any patients in the BoNT group [40].
Following knee arthroplasty, increased joint pain was reported in six patients in the BoNT group compared to two in the control group [33]. Conversely, after limb lengthening or deformity correction surgery, pin-site infections were significantly less frequent in the BoNT group (p=0.03) [35]. No difference in joint range of motion or thigh circumference was found between groups after bilateral femoral lengthening [36].
Complications such as seromas, hematomas, infection, and tissue necrosis were documented in mastectomy cases. However, these were consistent across BoNT and placebo groups, suggesting that BoNT did not exacerbate procedure-related complications [37, 38].

3.4.4. Severe Outcomes
Serious adverse events were rare. One study noted while more patients in the placebo group experienced at least one serious adverse event, the difference was not statistically significant [33]. The same study also described a death from causes unrelated to BoNT, emphasizing the importance of assessing patient comorbidities. In another report, two patients of the BoNT group required readmission and reoperation for complications unrelated to the injection after open abdominal wall reconstruction [43].

4. Discussion
This review examines the current literature on using BoNT for postsurgical pain management. Across 24 selected studies, BoNT demonstrated effectiveness and an acceptable safety profile in this context. However, the review also revealed variability in the analgesic response, which may be attributed to several factors. Differences in demographics and baseline characteristics of the study populations, such as age, comorbidities, and type of surgery, can affect response rates. Additionally, the dosage and mode of BoNT administration, including subcutaneous, intramuscular, or intraarticular injections, influence the efficacy.
The distribution of multiple injection sites may also be a key contributor. For instance, promising results were observed when BoNT was injected into the pectoralis major, serratus anterior, and rectus abdominis during mastectomy with tissue expander placement [39]. In contrast, other studies that focused only on pectoralis major injections reported nonsignificant pain improvement [37, 38].
Although BoNT shows satisfactory analgesic effects, the timing of postinjection pain assessments influences the reported outcomes, as short-term follow-ups may fail to address the sustainability of BoNT's action. Moreover, the duration of pain relief varies across reports [56–58]. While some studies included in this review report prolonged pain relief following BoNT administration [32, 33, 39, 40], others found no evidence of long-term benefit [34–36]. This inconsistency necessitates future studies with extended follow-up periods to assess the long-term analgesic potential of BoNT.
The dose-response aspect of BoNT in pain management is critical to its therapeutic application. Generally, higher doses of BoNT are associated with lower pain intensity scores in conditions like muscular temporomandibular disorder [59]. While higher doses of BoNT may provide greater efficacy in pain relief for conditions such as lateral epicondylitis, they are also associated with a higher risk of side effects [60]. Thus, systemic side effects of BoNT, particularly muscle weakness, often necessitate the use of suboptimal doses, which can result in insufficient analgesic effects.
To address the challenge of balancing therapeutic efficacy with motor side effects, bioengineers are developing novel BoNT derivatives. One strategy is modifying the BoNT domain that targets motor neurons, substituting it with a domain that targets sensory neurons. This modification allows the resulting toxin to inhibit pain neurotransmitters, such as substance P (SP) and CGRP, while preventing muscle paralysis [61]. Another approach is to create larger toxins using methods such as SNARE-stapling. This increased molecular size limits the toxin's ability to enter the small and tight synaptic vesicles of the neuromuscular junction, thereby prohibiting local muscular weakness. This increased size does not prevent the toxin's access to open nerve endings of sensory neurons, thus maintaining its potential for pain relief [61, 62].
Ultimately, while the dose and concentration of BoNT influence its potential for pain relief, optimal dosing strategies must be further investigated to achieve the best results with the fewest side effects. For example, one study demonstrated that low doses of BoNT-A (20 U) effectively reduced chronic pain related to sleep bruxism and awake bruxism, with significant pain reduction observed up to 90 days posttreatment [63]. Similarly, when investigating the analgesic effect of BoNT for trigeminal neuralgia, both low and high doses significantly diminished pain compared to placebo, with no significant difference in efficacy between them [64]. In our review of Wittekindt et al.'s study, low-dose BoNT showed a significant improvement in VAS scores, while the high-dose regimen showed no significant impact [30].
There is limited data on the BoNT's application for postoperative pain after neurosurgical operations. A French study investigated BoNT's effectiveness in the treatment of postoperative neck pain following cervical spine surgeries, including 38 patients. Repeated injections of BoNT into the neck muscles yielded significantly better results compared to conservative treatment with muscle relaxants and physical therapy [65]. BoNT also showed benefit in one patient with intractable pain unresponsive or intolerant to a variety of conventional pharmacological and physical interventions over approximately 2 years after spinal fusion when combined with Pulsed Electromagnetic Field (PEMF) [66].
BoNT also showed promise for CPSP after craniotomy, but the evidence is mainly limited to case reports and case series. A systematic review investigated the effectiveness of BoNT for treating postcraniotomy headache (PCH). The review included five case reports and case series with a total of 15 participants who had persistent PCH. More than 70% of patients experienced a notable pain reduction and achieved 75%–100% relief within 10–15 days after the injection, without any serious complications. The patients also reported improvement in daily function and a reduced demand for pain medication. This analgesic effect lasted more than 5 years in some individuals. These results present BoNT as a potential alternative for managing refractory PCH [67]. Further larger studies are necessary to determine the optimal dosage, injection site, and number of injections for PCH.

5. Limitation
This review aimed to evaluate the literature on the application of BoNT for postoperative pain management. However, limitations should be considered. Our search was limited to the PubMed database, and some studies indexed in other databases might be overlooked. Most of the included studies had small sample sizes. Variations in the timing of BoNT injections, dosage, concentration, injection technique, and follow-up durations further contribute to the heterogeneity of the results. Future large, double-blind, RCT with consistent BoNT injection protocols and follow-up assessments are essential to clarify the efficacy and safety of BoNT for postoperative pain. Furthermore, high-quality systematic reviews and meta-analyses are needed to provide an analysis of the findings, considering the heterogeneity of studies.

6. Conclusion
The findings of this literature review emphasize the potential of BoNT injection as an effective adjunct in the management of postoperative pain in a broad spectrum of surgeries when used intra- and postoperatively. BoNT has shown promising results in reducing pain intensity and decreasing analgesic use with minimal side effects of the procedure, highlighting its safety. However, variability in outcomes between studies necessitates further randomized controlled trials with larger samples to confirm efficacy and long-term safety and optimize application protocols.