Clinical and electromyographic evaluation of botulinum toxin type A in the treatment of gummy smile: A prospective clinical study

Although botulinum toxin type A (BT-A) is approved for chronic migraine treatment, its site and mechanism of action are still elusive. Recently our group discovered that suppression of CGRP release from dural nerve endings might account for antimigraine action of pericranially injected BT-A. We demonstrated that central antinociceptive effect of BT-A in sciatic region involves endogenous opioid system as well. Here we investigated possible interaction of BT-A with endogenous opioid system within the trigeminal region. In orofacial formalin test we investigated the influence of centrally acting opioid antagonist naltrexone (2mg/kg, s.c.) versus peripherally acting methylnaltrexone (2mg/kg, s.c.) on BT-A's (5 U/kg, s.c. into whisker pad) or morphine's (6mg/kg, s.c.) antinociceptive effect and the effect on dural neurogenic inflammation (DNI). DNI was assessed by Evans blue-plasma protein extravasation. Naltrexone abolished the effect of BT-A on pain and dural plasma protein extravasation, whereas peripherally acting methylnaltrexone did not change either BT-A's effect on pain or its effect on dural extravasation. Naltrexone abolished the antinociceptive and anti-inflammatory effects of morphine, as well. However, methylnaltrexone decreased the antinociceptive effect of morphine only partially in the second phase of the test and had no significant effect on morphine-mediated reduction in DNI. Morphine acts on pain in trigeminal region both peripherally and centrally, whereas the effect on dural plasma protein extravasation seems to be only centrally mediated. However, the interaction of BT-A with endogenous opioid system, with consequent inhibition of nociceptive transmission as well as the DNI, occurs primarily centrally. Botulinum toxin type A (BT-A)'s axonal transport and potential transcytosis suggest that its antinociceptive effect might involve diverse neurotransmitters at different sites of trigeminal system. Here we discovered that the reduction in pain and accompanying DNI involves the interaction of BT-A with central endogenous opioid system (probably at the level of trigeminal nucleus caudalis).

This review systematically examines the effects of botulinum toxin type A (BTX-A) on patient-reported outcomes across disorders using evidence-based criteria. The evidence provided by these studies ranged from randomized, controlled trials to case series. The effects of BTX-A on quality of life or global treatment outcomes were assessed in 48 studies across 16 different conditions. All but 7 of these reported benefits of BTX-A over baseline or the comparator condition (placebo or other treatment). The effects of BTX-A on impairment, activities, or participation were assessed in 46 studies across 17 different conditions. All but 4 reported benefits of BTX-A over baseline or the comparison group. The effects of BTX-A on satisfaction or preference were assessed in 14 studies across 11 different conditions, all of which reported high rates of satisfaction with BTX-A or preference over the comparator. These studies provide evidence that BTX-A exerts meaningful benefits on the quality of life of patients treated with this biologic agent.

Therapeutic effects of botulinum toxin type A in subjects with gummy smile: A longitudinal sEMG approach

Botulinum toxin type A (Botox) for the neuromuscular correction of excessive gingival display on smiling (gummy smile)

Botulinum toxin type A (BTX-A) is a potent neurotoxin that causes relaxation of striated muscle by inhibiting the release of acetylcholine at the neuromuscular junction. Some studies have suggested that BTX-A treatment for Raynaud syndrome is safe and effective with few adverse reactions. However, the underlying mechanism remains unclear. In the present study, we used both arterial rings isolated from rabbits and human microvascular endothelial cells (HMEC-1) to evaluate the mechanism underlying the effects of BTX-A on arterial vasoconstriction induced by 5-hydroxytryptamine. The roles of calcium sensitization and the endothelial nitric oxide synthase (eNOS)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway were investigated. BTX-A caused a concentration-dependent decrease in the contraction of endothelium-intact arteries and significantly reduced calcium sensitization in the arteries. Inhibitors of eNOS (L-NAME) and sGC (methylene blue) both significantly abolished the vasodilatory action of BTX-A. Furthermore, BTX-A increased eNOS activity and the cGMP level in dose- and time-dependent manners and increased eNOS and sGC protein levels in a time-dependent manner in HMEC-1. Taken together, these findings indicate that BTX-A suppresses arterial vasoconstriction by regulating smooth muscle calcium sensitization and the eNOS/sGC/cGMP pathway. Impact statement Raynaud syndrome (RS), usually caused by cold or mental stress, may lead to cyanosis and reactive hyperemia accompanied by pain or paresthesia. Although a variety of drugs have been used to alleviate the symptoms, the effects have not been satisfactory, so there is an urgent need to explore new alternative treatments. The present study investigated the mechanism underlying the effects of botulinum toxin type A (BTX-A) on arterial vasoconstriction, which may provide new approaches for RS. We found that BTX-A suppresses arterial vasoconstriction by regulating smooth muscle calcium sensitization and the endothelial nitric oxide synthase (eNOS)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway. These findings clarify the underlying mechanism of the effects of BTX-A on arterial vasoconstriction and provide new theoretical support for the use of BTX-A on RS. It may also help us to develop new medicines which regulate calcium sensitization and the eNOS/sGC/cGMP pathway against RS.

The effects of Botulinum Toxin type A on capsaicin-evoked pain, flare, and secondary hyperalgesia in an experimental human model of trigeminal sensitization

BackgroundHypertrophic scar formation may be related to cutaneous neurogenic inflammation (CNI) through the substance P-neurokinin 1 receptor (SP-NK1R) signaling pathway. As a widely used drug in aesthetic clinical work, botulinum toxin type A (BTX-A) has a therapeutic effect on scars, but the actual mechanism remains unclear. This study aimed to clarify the potential mechanism by which BTX-A inhibits CNI in hypertrophic scars both in vitro and in vivo.MethodsTissue samples were obtained from surgical excisions. Immunohistological analysis was used to locate SP in human hypertrophic scars and normal skin. RT-PCR and western blot analysis were used to evaluate the expression of collagens after SP/BTX-A treatment. A rabbit ear scar model was used to explore the in vivo effect of BTX-A on scar treatment.ResultsSP and NK-1R were overexpressed in hypertrophic scars compared to normal skin tissues. Collagen secretion of hypertrophic scar-derived fibroblasts increased with increasing doses of SP. However, BTX-A may downregulate collagen expression through SP-NK1R pathway with or without the presence of SP inducing agent capsaicin. Meanwhile, SP inhibited the expression of NK-1R, and this inhibition was blocked by pretreatment with BTX-A. In vivo, intralesional BTX-A injection can also reduce the volume of scars and inhibit collagen secretion. Capsaicin may cause more severe scar manifestations, while the therapeutic effect of BTX-A remains.ConclusionOur research confirms that CNI stimulates fibroblasts during scar formation, while BTX-A can reduce collagen secretion by inhibiting the SP-NK1R signaling pathway, thus identifying a novel therapeutic target for this benign solid skin tumor.

To evaluate therapeutic effectiveness and safety of botulinum toxin type A in the treatment of idiopathic trigeminal neuralgia in patients older than 70 years. The total 64 patents were involved from neurology clinic and inpatient department from Aug 2008 to Sep 2013. They were divided into two groups according to the age (older than 70 years versus younger than 60 years. The therapeutic dose, safety, effectiveness were compared between two groups. Visual analog scores were employed to measure the degree of pain. The mean dosage was (88 ± 30) U in the group aged above 70 years old, and (72 ± 33) U in the group aged below 60 years old respectively. There was no significant difference of dosage between the two groups. The average visual analog score of all patients was (7.7 ± 2.2) before the treatment and decreased to (4.4 ± 2.9) one month after the treatment. To be precise, the average visual analog score of the group aged above 70 years old was (8.2 ± 1.9) before and (4.5 ± 3.2) after the treatment, and the visual analog score of the group aged below 60 years old was (7.2 ± 2.4) before and (4.4 ± 2.5) after the treatment. The effect of botulinum toxin type A in the treatment of idiopathic trigeminal neuralgia was considered statistically significant. The D-value of visual analog score in the elderly group was (3.5 ± 3.6), and (2.8 ± 3.5) in the younger group. There was no significant difference in the D-value between the two groups. Five patients had transient minor side effects in the former group and two patients had transient minor side effects in latter group. There was no significant difference in the incidence rate of side effects between the two groups (P > 0.05). Botulinum toxin type A is safe and effective in the treatment of idiopathic trigeminal neuralgia for the patients older than 70 years and the dosages of it are approximate to the patients under 60 years old.

A recent study reported that Botulinum toxin type A (BTXA) could inhibit the growth of hypertrophic scars and improve their appearance. However, the mechanism of BTXA’s action on hypertrophic scars is still unknown. Some in vitro studies had shown BTXA could alleviate hypertrophic scars by acting on the biological behavior of fibroblasts, but there are few in vivo experiments, especially animal model experiments, supporting these findings. The aim of the study reported herein was to investigate the effect of BTXA on collagen deposition on hypertrophic scars in a rabbit ear model and partially clarify the mechanism of BTXA on the hypertrophy of scars. The rabbit hypertrophic scar model was used and eight rabbits were employed. BTXA was injected into the hypertrophic scar tissue of one ear; and the other ear in the same rabbit was the control without BTXA injection. The scar thickness and deposition of collagen was examined through immune histochemistry including haematoxylin and eosin (H&E) and Masson trichrome staining. The thicknesses of hypertrophic scars in the BTXA treatment group were obviously lower than in the control groups (P < 0.01). H&E and Masson staining showed that collagen fibers were stained blue. Compared with the treatment group, the collagen fibers were thicker and the arrangement of collagen fibers were disordered in the control group. This study used the rabbit ear model of hypertrophic scars to assess the effects of BTXA on scar hypertrophy. The application of BTXA may be useful for inhibiting hypertrophic scars.

Botulinum toxin type A (BTX-A) is increasingly used to manage painful temporomandibular disorders (TMD). However, the effect of BTX-A on muscular TMD remains unclear. To assess the efficacy, safety and optimal dose of BTX-A for treating TMD. We conducted systematic literature searches in MEDLINE, Embase, Web of Science, ClinicalTrials.gov and Cochrane Library until March 2023. We extracted data from randomized controlled trials (RCTs) that evaluated the efficacy and safety of BTX-A in treating muscular TMD. We performed a meta-analysis using a random-effects model. Fifteen RCTs involving 504 participants met the inclusion criteria. BTX-A was significantly more effective than placebo in reducing pain intensity, as measured on a 0-10 scale, at 1 month (MD [95% CI] = -1.92 [-2.87, -0.98], p < .0001) and 6 months (MD [95% CI] -2.08, [-3.19 to -0.98]; p = .0002). A higher dosage of BTX-A (60-100 U bilaterally) was associated with a greater reduction in pain at 6 months (MD [95% CI] = -2.98 [-3.52, -2.44]; p < .001). BTX-A also resulted in decreased masseter muscle intensity (μV) (MD [95% CI] = -44.43 [-71.33, -17.53]; p = .001) at 1 month and occlusal force (kg) at 3 months (MD [95% CI] = -30.29 [-48.22 to -12.37]; p = .0009). There was no significant difference in adverse events between BTX-A and placebo. BTX-A is a safe and effective treatment for reducing pain and improving temporomandibular muscle and joint function in muscular TMD patients. A bilateral dose of 60-100 U might be an optimal choice for treating muscular TMD pain.

Botulinum toxin type A (BTX-A) has a long-lasting antinociceptive activity and less clear effect on inflammation. It was proposed that these two effects share the same mechanism--the inhibition of neurotransmitter exocytosis from peripheral nerve endings. However, till now possible anti-inflammatory action of BTX-A did not evoke much attention. In the present paper, we investigate possible anti-inflammatory action of the toxin in carrageenan and capsaicin models of inflammation in rats. BTX-A (5 and 10 U/kg) was injected into the plantar surface of the rat right hind-paw pad 5 days before the injection of the carrageenan (1%) or capsaicin (0.1%) at the same site. Carrageenan-induced paw oedema and capsaicin-induced protein extravasation were measured. Control, inflamed and BTX-A pretreated inflamed paws were photographed and histopathological analysis (haematoxylin & eosin) was performed. Pretreatment with BTX-A had no effect on the size of carrageenan-induced paw oedema, measured as paw volume and weight or capsaicin-induced plasma extravasations, measured by Evans blue as a marker of protein leakage. Neither macroscopic nor microscopic analysis showed a significant difference between BTX-A pretreated and control inflamed tissue. Results show dissociation between the effect of BTX-A on pain and inflammation thus questioning the validity of the suggested assumption about the common peripheral mechanism of action.

Background:The purpose of this meta-analysis was to assess the effectiveness of botulinum toxin type A (BoNT-A) in reducing pain associated with fasciitis. By synthesizing the findings from multiple studies, we aimed to provide a comprehensive evaluation of the current evidence regarding the efficacy of BoNT-A in the treatment of fasciitis pain.Methods:To identify studies for our report, we conducted electronic database searches of Embase, PubMed, Web of Science, and the Cochrane Library from their inception to November 20, 2022. We included only randomized controlled trials that examined the therapeutic effects of BoNT-A on fasciitis pain, with the primary outcome measure being the visual analog scale. We conducted statistical analyses using RevMan 5.4 software.Results:Our final meta-analysis comprised 14 randomized controlled trials involving 537 participants, with 271 patients in the BoNT-A group and 266 patients in the control group. The overall effectiveness of BoNT-A in reducing fasciitis pain was significant, with a mean difference (MD) in visual analog scale score of −2.59 (95% confidence interval [CI], −3.36, −1.82); P < .00001; I2 = 88%. Subgroup analysis revealed that BoNT-A was particularly effective in treating plantar fasciitis (MD = −3.34 [95% CI, −4.08, −2.78]; P < .00001; I2 = 75%), lumbar back fasciitis (MD = −2.17 [95% CI, −3.82, −0.52]; P = .001; I2 = 93%), and neck and shoulder fasciitis (MD = −1.49 [95% CI, −2.76, −0.22]; P = .02; I2 = 61%).Conclusion:BoNT-A has a significant analgesic effect on fasciitis pain. Therefore, BoNT-A presents a promising alternative treatment option for fasciitis (PROSPERO 2022: CRD42022382805).

The treatment of gummy smile (GS) with polymethyl methacrylate (PMMA)-based implants is suggested in specific cases such as those in which there is a lack of lip support due to a marked depression of the anterior maxillary process; however, it can be associated with certain complications related to the material and the surgical approach. A patient with a GS of combined etiology was treated with clinical crown lengthening and lip repositioning surgery with placement of a PMMA-based bone cement implant to fill the subnasal depression. Surgical planning was performed using a 3-dimension resin-printed model to achieve an optimal fit of the PMMA implant to the geometry of the bone defect and to avoid any damage related to heat exposure from the polymerization process and any possible damage to the tooth roots with the fixation screws. In addition, the use of an antibiotic cement can help prevent any possible infection. The patient reported edema and mild pain. After 5 months an increase in the length of the dental crowns, a reduction of the exposed gingiva to 1mm and a new support of the upper lip were clinically observed. Cone-beam computed tomography showed proper PMMA implant fit. The use of PMMA-based bone cement appears to be an effective technique for the treatment of cases of GS associated with hypermobile upper lip and maxillary subnasal depression. The use of a printed resin model avoids complications during curing of the material, such as high exothermic reactions and associated infections. Identification of the etiologic factors of gummy smile is fundamental to the treatment of gummy smile. Once the diagnosis is established, therapy focuses on the treatment of these factors, which may be single or combined. The use of a PMMA-based bone cement implant in conjunction with clinical crown lengthening surgery is an effective treatment option for the management of EGD related to upper lip hypermobility, passive altered eruption and, maxillary subnasal depression. A possible clinical dilemma could arise when considering some complications associated with the use of PMMA implants such as allergies or infections. However, the use of a 3D printed resin model facilitates handling and fitting outside the mouth by eliminating heat exposure from the polymerization of the cement and to avoid any possible damage to the tooth roots with the fixation screws. In addition, the use of an antibiotic cement can help prevent any possible infection. The treatment of gummy smile will depend on its etiological factor. In some cases of combined etiology, the use of polymethyl methacrylate (PMMA) implants has been suggested, such as those in which there is a lack of lip support due to a marked depression of the maxillary anterior process; however, the use of PMMA can be associated with certain complications such as allergies and infections. To avoid this, surgical planning was performed using a 3D resin-printed model to achieve an optimal fit of the PMMA implant to the geometry of the bone defect and to avoid any complications such as damage related to the heat exposure of the polymerization process and any possible damage to the dental roots with the fixation screws, obtaining satisfactory results after 5 months.

Botulinum toxin injection to treat a gummy smile: A few observations

Despite the extensive use of botulinum toxin type A (BoNT-A) in treatments for glabellar frown lines, the dose-response effect in the glabellar muscles remains unknown. The aim of this randomized, double-blind, placebo-controlled prospective study was to characterize the neurophysiological parameters that correlate with the effect of BoNT-A in the glabellar muscles and its diffusion to surrounding ocular muscles. Sixteen healthy women were recruited and randomized to 3 different dose-groups of onabotulinumtoxin A (Vistabel®) or placebo and followed 24 weeks by neuro-physiological examinations. Efficacy of treatment on corrugator supercilii muscles was measured by compound motor action potential (CMAP) and electromyography (EMG). Photographs were used to score glabellar frown lines. Diffusion of the drug to surrounding muscles was assessed by CMAP of the nasalis muscle, EMG and concentric needle electrode jitter analysis (CNE) of the orbicularis oculi muscle. CMAP reduction correlated well with intramuscular BoNT-A dose. Muscle paralysis, measured by EMG, began from 2 weeks and was not entirely reversed at 24 weeks in individuals who received high dose of onabotulinumtoxin. Limited diffusion of orbicularis oculi was detected with CNE. In conclusion, we developed a novel neurophysiological strategy for effect evaluation of BoNT-A in glabellar muscles. CMAP and EMG correlated with given BoNT-A dose and are more defined effect measures than clinical glabellar photo scales.