**Botulinum Toxin** for **Orofacial Pain** **Dr Lasanthini Weerakkody** **Oral Medicine Specialist** **Dr Lasanthini Weerakkody** **Oral Medicine Specialist** # Contents * Overview * Mechanism of action * BoNT Preparations * Indications * Practical applications & protocols * Adverse effects * Complications * Contraindications #### Table of Contents - Overview - Mechanism of action - BoNT Preparations - Indications - Practical applications & protocols - Adverse effects - Complications - Contraindications **BoNT- Overview** **a** **BoNT-A Supramolecular Complex** **Hemagglutinin** **Proteins** **Nontoxic** **Nonhemagglutinin** **Protein** **Core** **Neurotoxin** ~760-kDa Assembly **b** **Purified Core Neurotoxin** **Core** **Neurotoxin** **150 kDa** **Branch names** **Dysport,** **Botox,** **Xeomin** **BoNT/A** **BoNT/F5A** **(BoNT/HA)** **BoNT/F** **BoNT/E** **In clinical trials** **PMP1** **BoNT/En** **BoNT/Wo** **BoNT/X** **BoNT/C-D** **TeNT** **BoNT/G** **BoNT/B** **NeuroBloc,** **Myobloc** **Newjin** **process of approval!** (Carr et al., 2021) (Dong & Stenmark, 2019)   #### Structural Composition of Botulinum Toxin (BoNT) **BoNT-A Supramolecular Complex (~760-kDa Assembly)** - **Core Neurotoxin (150 kDa):** The active component. - **Nontoxic Proteins (Complexing Proteins):** - Hemagglutinin (HA) Proteins - Nonhemagglutinin (NHA) Protein #### Classification and Commercial Brands - **BoNT/A:** Botox, Dysport, Xeomin - **BoNT/B:** NeuroBloc, Myobloc - **Other Serotypes (Clinical Trials/Research):** BoNT/F, BoNT/E, BoNT/F5A, BoNT/HA, PMP1, BoNT/En, BoNT/Wo, BoNT/X, BoNT/C-D, TeNT, BoNT/G, Newjin Labelled figure showing the structure of BoNT-A. Panel 'a' displays a 'BoNT-A Supramolecular Complex' (~760-kDa Assembly) with color-coded components: brown for Hemagglutinin Proteins, tan for Nontoxic Nonhemagglutinin Protein, and blue for Core Neurotoxin. Panel 'b' shows the isolated 'Purified Core Neurotoxin' (150 kDa) in blue. Phylogenetic tree diagram illustrating BoNT subtypes and commercial brand names. Key nodes include BoNT/A (linked to Dysport, Botox, Xeomin), BoNT/B (linked to NeuroBloc, Myobloc), BoNT/E (marked 'In clinical trials'), and TeNT. Handwritten annotations identify 'Brand names' pointing to BoNT/A and 'Newjin process of approval!' pointing to BoNT/B. Citations '(Carr et al., 2021)' and '(Dong & Stenmark, 2019)' are present. [BoNT- Mechanism of Action] <div style="width:100%; overflow:auto;"> <table style="width:100%;"> <tr> <td style="width:60%; padding:10px; border:1px solid #ccc;"> **Motor neuron** ↓ <span style="background:yellow; opacity:0.3;"><b>Acetylcholine</b></span> ↓ **Muscle contraction** BTX ↱ ↲ <b>Acetylcholine</b> → **PAIN** ← Pain signal transmission **Neurotransmitters** | Substance P, CGRP, Glutamate Central or peripheral Sensitization **Nociceptor** </td> <td style="padding:10px; vertical-align:top;"> (1) Endocytosis of botulinum toxin. (2) Cleavage of light chain of botulinum toxin. (3) The light chain cleaves SNARE proteins. (4) Prevents exocytosis of ACh into synaptic cleft. (5) Temporary paralysis of targeted muscle fibres. </td> </tr> </table> </div> (last ~3 months) <div style="width:100%; overflow:auto;"> <table style="width:100%;"> <tr> <td style="width:50%; padding:10px; border:1px solid #ccc; vertical-align:top;"> <b>A</b> Normal neurotransmitter release Nerve terminus ↓ Synaptic cleft ↓ Muscle cell SNARE proteins → Synaptobrevin, SNAP-25, Syntaxin → Synaptic fusion complex → Vesicle and terminal membranes fuse → Neurotransmitter released → Acetylcholine → Acetylcholine receptor → Muscle fiber contracts </td> <td style="width:50%; padding:10px; border:1px solid #ccc; vertical-align:top;"> <b>B</b> Exposure to botulinum toxin Botulinum toxin endocytosed ↓ Light chain cleaves specific SNARE proteins → Heavy chain, Light chain → Types B, D, F, G; Types A, C, E; Type C → SNARE complex does not form → Membranes do not fuse → Neurotransmitter not released → Muscle fiber paralyzed </td> </tr> </table> </div> www.openanesthesia.org/   #### Physiological Pathway 1. **Normal Motor Neuron Function:** Acetylcholine (ACh) release leads to muscle contraction. 2. **Pain Transmission:** ACh and other neurotransmitters (Substance P, CGRP, Glutamate) contribute to pain signaling and central/peripheral sensitization. #### Cellular Mechanism of Action 1. **Endocytosis:** Botulinum toxin is taken up by the nerve terminus. 2. **Cleavage:** The light chain of the toxin is released and cleaves specific SNARE proteins. - **Types A, C, E:** Cleave SNAP-25. - **Types B, D, F, G:** Cleave Synaptobrevin. - **Type C:** Cleaves Syntaxin. 3. **Inhibition:** The SNARE complex fails to form, preventing the fusion of synaptic vesicles with the terminal membrane. 4. **Effect:** Exocytosis of ACh into the synaptic cleft is blocked, resulting in temporary paralysis of targeted muscle fibers (typically lasting ~3 months). Flowchart diagram titled 'BoNT- Mechanism of Action'. The diagram illustrates the interaction between a Motor neuron and Nociceptor. On the left, it shows the pathway from Motor neuron to Acetylcholine release leading to Muscle contraction and Pain. In the center, BTX (Botulinum toxin) is depicted interfering with this process. On the right, the Nociceptor pathway releases Neurotransmitters (Substance P, CGRP, Glutamate), causing Pain signal transmission via Central or peripheral Sensitization. A list of five steps on the right summarizes the mechanism: Endocytosis, Cleavage of light chain, SNARE protein cleavage, Prevention of exocytosis, and Temporary paralysis. Comparative biological illustration showing two panels labeled 'A' and 'B'. Panel A depicts 'Normal neurotransmitter release', illustrating synaptic vesicles releasing Acetylcholine into the synaptic cleft to cause muscle fiber contraction. Panel B depicts 'Exposure to botulinum toxin', showing how the toxin endocytosed in the nerve terminus uses its heavy and light chains to cleave specific SNARE proteins (Types B, D, F, G; A, C, E). This prevents the formation of the SNARE complex and fusion of membranes, resulting in the neurotransmitter not being released and the muscle fiber becoming paralyzed.    Clinical photograph of a glass vial labeled 'Dysport' (Botulinum toxin type A). The label indicates it is a human botulinum toxin complex with a strength of 500 units. The image provides visual identification of the specific brand and dosage. Clinical photograph of a glass vial labeled 'XEOMIN'. The blue band on the neck indicates a strength of 100 LD50 units. This image visually identifies the Merz pharmaceutical preparation. Clinical photograph of a glass vial labeled 'BOTOX' (Botulinum Toxin Type A). The purple label indicates it is a purified neurotoxin complex with a strength of 100 units. This image visually identifies the Allergan pharmaceutical preparation. <!-- 3-4-1 --> --><!-- BOTULINUM TOXIN (BoNT) PREPARATION --> --><!-- BOTULINUM TOXIN (BoNT) [Excipients] --> --><!-- NEUROTOXIN [NON-TOXIC PROTEINS (COMPLEXING PROTEINS)] --> --><!-- LIGHT CHAIN [HEAVY CHAIN] [HA | NHA] --> **Contents of botulinum toxin preparation.** Abbreviations: **HA**, Hemagglutinin; **NHA**, Non-Hemagglutinin <div style="padding-top: 50px; text-align: left;">Park J, Lee MS, Harrison AR. *Profile of Xeomin*(incobotulinumtoxinA) for the treatment of blepharospasm. *Clinical Ophthalmology*. 2011 Jun 1:725-32.</div>  #### Composition of BoNT Preparations - **Neurotoxin Core:** Consists of a Light Chain and a Heavy Chain. - **Complexing Proteins (NAPs):** Includes Hemagglutinin (HA) and Non-Hemagglutinin (NHA) proteins. - **Excipients:** Added substances for stability and formulation. Hierarchical flowchart diagram illustrating the composition of Botulinum toxin (BoNT) preparation. The top-level node is 'Botulinum toxin (BoNT) preparation', which branches into 'Botulinum toxin (BoNT)' and 'Excipients'. The BoNT component further divides into 'Neurotoxin' and 'Non-toxic proteins (Complexing proteins)'. Neurotoxin splits into 'Light chain' and 'Heavy chain', while Non-toxic proteins split into 'HA' (Hemagglutinin) and 'NHA' (Non-Hemagglutinin). A caption below reads: 'Contents of botulinum toxin preparation. Abbreviations: HA, Hemagglutinin; NHA, Non-Hemagglutinin'. ```mermaid graph TD A[Therapeutic botulinum neurotoxin preparations<br/>Clostridium botulinum neurotoxin + excipients] --> B[BoNT/A + NAPs] A --> C[Isolated BoNT/A] A --> D[BoNT/B + NAPs] B --> E[Botox®] B --> F[Dysport®] C --> G[Xeomin®] D --> H[Myobloc®] ```   #### Classification of Therapeutic Preparations - **BoNT/A + NAPs (Neurotoxin Associated Proteins):** - Botox® - Dysport® - **Isolated BoNT/A (Pure Neurotoxin):** - Xeomin® - **BoNT/B + NAPs:** - Myobloc® Flowchart titled 'Therapeutic botulinum neurotoxin preparations (Clostridium botulinum neurotoxin + excipients)'. The diagram branches into three categories: 'BoNT/A + NAPs' leading to 'Botox®' and 'Dysport®'; 'Isolated BoNT/A' leading to 'Xeomin®'; and 'BoNT/B + NAPs' leading to 'Myobloc®'. Source cited as Kukreja et al., 2015. Clinical photograph showing three vials of therapeutic botulinum toxin products. From left to right: Dysport (white cap), Xeomin (silver/blue cap, labeled 100 LD50 units), and Botox (purple cap, labeled 100 Units). Visualizes the physical appearance of the commercial preparations discussed in the flowchart. # Australian Government ## Department of Health and Aged Care ### Therapeutic Goods Administration | **Australian Product Information** | | | :--- | :--- | | **DYSPORT** | | | *clostridium botulinum type A toxin - haemagglutinin complex* | | **powder for injection vial** | | **Abobotulinumtoxin A** **Ipsen-Pharma, Berkshire, UK** # Australian Product Information - BOTOX® (BOTULINUM TOXIN TYPE A) POWDER FOR INJECTION **Onabotulinumtoxin A** **Allergan, Irvine, CA, USA** # Australian Product Information – XEOMIN® **Incobotulinumtoxin A** **Merz Pharma, Frankfurt am Main, Germany** (incobotulinumtoxinA) powder for solution for injection There are currently three botulinum toxin agents with TGA registration (Botox®, Dysport® and Xeomin®). Each has undergone a separate evaluation of its safety and efficacy by the TGA as they are neither bioequivalent, nor dose equivalent. #### TGA Registered Agents in Australia There are currently three botulinum toxin agents with TGA registration. They are not bioequivalent or dose equivalent. 1. **BOTOX® (Onabotulinumtoxin A)** - Manufacturer: Allergan, Irvine, CA, USA - Formulation: Powder for injection 2. **DYSPORT® (Abobotulinumtoxin A)** - Manufacturer: Ipsen-Pharma, Berkshire, UK - Formulation: Clostridium botulinum type A toxin - haemagglutinin complex; powder for injection vial 3. **XEOMIN® (Incobotulinumtoxin A)** - Manufacturer: Merz Pharma, Frankfurt am Main, Germany - Formulation: Powder for solution for injection **Biologic activity = MU (mouse units)** **Proprietary brand unit** Based on prior studies on movement disorders, ratios often used in clinical practice: * • onabotulinumtoxinA:incobotulinumtoxinA = 1:1 (Yoshida 2022, Anadan & Jankovic 2021, Jankovic 2017 ) * • onabotulinumtoxina: abobotulinumtoxina = 1:2.5 * • onabotulinumtoxina:rimabotulinumtoxnb = 1:50 The potency labelling of ONA and INCO may be compared with a conversion factor of 1:1 (Dressler et al. 2012, 2014, 2018). Conversion factors between ONA/INCO and other BT drugs are still controversial. (Dressler 2021) Yoshida K. Botulinum toxin therapy for oromandibular dystonia and other movement disorders in the stomatognathic system. Toxins 2022; 14: 282 [Internet]. Anandan C, Jankovic J. Botulinum toxin in movement disorders: an update. Toxins. 2021 Jan 8;13(1):42. Jankovic J. Botulinum toxin: State of the art. Movement Disorders. 2017 Aug;32(8):1131-8. Dressler D, Altavista MC, Altenmueller E, Bhidayasiri R, Bohlega S, Chana P, Chung TM, Colosimo C, Fheodoroff K, Garcia-Ruiz PJ, Jeon B. Consensus guidelines for botulinum toxin therapy: general algorithms and dosing tables for dystonia and spasticity. Journal of Neural Transmission. 2021 Mar;128:321-35. #### Potency Measurement - Biologic activity is measured in Mouse Units (MU). - Units are proprietary to each brand. #### Clinical Conversion Ratios Based on movement disorder studies, the following ratios are often utilized in clinical practice: - **OnabotulinumtoxinA : IncobotulinumtoxinA** = 1:1 - **OnabotulinumtoxinA : AbobotulinumtoxinA** = 1:2.5 - **OnabotulinumtoxinA : RimabotulinumtoxinB** = 1:50 Note: While the 1:1 ratio for ONA and INCO is widely accepted, conversion factors for other preparations remain controversial. • Diluted with 0.5-5 mL saline per vial prior to injection. • condition being treated • size of the muscle • risk of spread beyond the muscle • effect of previous injection courses • methods used to determine the injection site. • Localisation of muscle/gland to be injected: • Palpation and anatomical landmarks • Electrical stimulation • Electromyography • Ultrasound • Combinations Article **Clinical use of botulinum toxin** Adam Scheinberg Aust Prescr 2009;32:39-42 | 1 April 2009 | DOI: 10.18773/austprescr.2009.020 Scheinberg A. Clinical use of botulinum toxin. Aust Prescr 2009;32:39-42  #### Preparation and Dilution - Vials are typically diluted with 0.5–5 mL of saline prior to injection. #### Factors Influencing Administration - Condition being treated - Size of the target muscle - Risk of toxin spread beyond the target muscle - Response to previous injection courses #### Localization Techniques Methods used to determine and confirm the injection site include: - Palpation and anatomical landmarks - Electrical stimulation - Electromyography (EMG) - Ultrasound - Combination of the above methods Clinical photo showing a gloved hand holding a syringe attached to a vial of botulinum toxin. The image demonstrates the preparation or administration context relevant to the article's discussion on dilution and injection techniques. | Head and neck movement disorders | | --- | | TMD | | Neuropathic OFP | | Other: Facial paralysis/Sialorrhea/H &N cancer complications | | Headache disorders | | Applications in OFP & dysfunction |  #### Applications in Orofacial Pain and Dysfunction - **Head and Neck Movement Disorders** - **Temporomandibular Disorders (TMD)** - **Neuropathic Orofacial Pain (OFP)** - **Headache Disorders** - **Other Conditions:** - Facial paralysis - Sialorrhea - Head and neck cancer complications Concept map diagram illustrating the relationship between Head and neck movement disorders, TMD, Neuropathic OFP, Headache disorders, and other conditions. The diagram features colored nodes connected by lines: an orange node for 'Head and neck movement disorders', a green node for 'Headache disorders', a blue node for 'Applications in OFP & dysfunction', a yellow node for 'TMD' (highlighted with a red dashed oval), and a light green node for 'Neuropathic OFP' (also highlighted with a red dashed oval). A separate green node lists 'Other: Facial paralysis/Sialorrhea/H &N cancer complications'. Arrows indicate connections between these concepts.  Central concept diagram titled 'Botulinum Toxins in Movement Disorders'. The center features a large circle containing the title text and a molecular structure model of botulinum toxin. Surrounding this central circle is a ring of blue ovals, each representing a specific movement disorder or condition treated with botulinum toxins. The conditions listed are: Spasticity, Blepharospasm, Oromandibular Dystonia, Bruxism, Laryngeal Dystonia, Cervical Dystonia, Limb Dystonia, Hemifacial spasm, Tremors, Parkinson's Disease, Tics, Myoclonus, and Restless Legs Syndrome. Oromandibular Dystonia **Injection sites for the masseter** **and temporalis muscles** **Injection methods for the medial** **pterygoid muscle; intraoral approach** **(blue arrow)** and extraoral oral approach **(red arrow)** **Injection methods for the lateral** **pterygoid muscle: intraoral approach** **(blue arrow)** and extraoral oral approach **(red arrow)** Yoshida K. Botulinum toxin therapy for oromandibular dystonia and other movement disorders in the stomatognathic system. Toxins. 2022 Apr 14;14(4):282.  #### Injection Sites and Approaches - **Masseter and Temporalis Muscles:** Standard injection sites for dystonia management. - **Medial Pterygoid Muscle:** Can be accessed via intraoral or extraoral approaches. - **Lateral Pterygoid Muscle:** Can be accessed via intraoral or extraoral approaches. Lateral profile diagram of a human head demonstrating injection sites for the masseter and temporalis muscles. The temporalis muscle is highlighted in red on the temple with yellow dots indicating specific injection points. The masseter muscle is also highlighted in red along the jawline with corresponding yellow dots. Temporomandibular Disorders Temporomandibular Disorders Muscular TMD ### Journal of Oral Rehabilitation. 2024 **Effect of botulinum toxin type A on muscular temporomandibular disorder: A systematic review and meta-analysis of randomized controlled trials** Kaiyang Li | Kenneth Tan | Alexandra Yacovelli | Wei Guang Bi **Effect of botulinum toxin type A** * **BTX-A** **↓ pain intensity.** * **Improvement** in **range of movement.** * **Decreased masseter muscle intensity (μV)** & **occlusal force (kg).** Currently no consensus on optimal dosage of BTX-A in pain mx. **Conclusions:** 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. *! muscle contraction * Analgesic effect Li K, Tan K, Yacovelli A, Bi WG. Effect of botulinum toxin type A on muscular temporomandibular disorder: A systematic review and meta-analysis of randomized controlled trials. Journal of Oral Rehabilitation. 2024 May;51(5):886-97. ### British Journal of Oral and Maxillofacial Surgery. 2020 **Review** **Botulinum toxin in the management of temporomandibular disorders: a systematic review** S. Thambar, S. Kulkarni, S. Armstrong, D. Nikolarakos **Conclusion** We have found variation in the study designs, inconsistent reporting on assessment tools, and heterogeneous study groups. Overall, the level of bias was moderate to high, making the evidence moderate to low. Despite showing benefits, **clear consensus is lacking on the therapeutic benefit of BTX in the management of myofascial TMD.** Further RCT with minimal bias, larger sample sizes, and longer follow-up periods are now needed. We must find the optimal target site and dose, conduct feasibility tests for the cost of BTX, and find out whether the benefit:cost ratio is clinically acceptable. Nevertheless, this review has shown that **in patients with myofascial TMD who have had at least three months**’ appropriate conservative management, BTX can improve outcomes. #### Efficacy in Muscular TMD Recent systematic reviews (Li et al., 2024) indicate that BTX-A: - Reduces pain intensity. - Improves range of movement. - Decreases masseter muscle intensity (μV) and occlusal force (kg). - **Optimal Dosage:** A bilateral dose of 60–100 U is suggested, though no universal consensus exists. #### Clinical Considerations and Limitations - **Conservative Management:** Evidence suggests BTX can improve outcomes in patients who have failed at least three months of appropriate conservative management. - **Evidence Quality:** Some reviews (Thambar et al., 2020) note moderate to high bias in existing studies, leading to a lack of clear consensus on therapeutic benefits. - **Mechanism:** Provides both muscle relaxation and analgesic effects. # TMJ dislocation ► Articular TMDs **J Stomatol Oral Maxillofac Surg, 2024** | Original Article | | --- | | **IncobotulinumtoxinA in refractory temporomandibular disorder due to disk dislocation: A prospective study** | | Eduardo Freitas Ferreira${}^{a,*}$, Alexandre Camões-Barbosa${}^{b}$ | *•* Tx with EMG or ultrasound guided injection of incobotulinumtoxin A: * 20 U into each **masseter** & 20U in each **L pterygoid** m. * 1 point injected per muscle. Inj. bilaterally. * ↓ in **pain** & ↓ in **max unassisted mouth opening**. **British Journal of Oral and Maxillofacial Surgery, 2010** | • | Long-term efficacy of botulinum toxin type A for the treatment of habitual dislocation of the temporomandibular joint | | --- | --- | | • | Kaiser Yan Fu${}^{,}$, Hui Min Chen${}^{b}$, Zhi Peng Sun${}^{}$, Zhen Kang Zhang${}^{c}$, Xu Chen Ma${}^{a}$ | *•* 5 patients. *•* BTX-A inj given after reduction of dislocation by manual repositioning. *•* Inj. into lateral pterygoid muscle. 20-25U. *•* No recurrences. Ferreira EF, Camões-Barbosa A. IncobotulinumtoxinA in refractory temporomandibular disorder due to disk dislocation: a prospective study. Journal of Stomatology, Oral and Maxillofacial Surgery. 2024 Sep 1;125(5):101804.: Fu KY, Chen HM, Sun ZP, Zhang ZK, Ma XC. Long-term efficacy of botulinum toxin type A for the treatment of habitual dislocation of the temporomandibular joint. British Journal of Oral and Maxillofacial Surgery. 2010 Jun 1;48 (4) 281-4.: #### Refractory TMD and Disk Dislocation - **IncobotulinumtoxinA Treatment:** - Protocol: 20 U into each masseter and 20 U into each lateral pterygoid muscle. - Guidance: EMG or ultrasound-guided. - Outcomes: Reduction in pain and maximum unassisted mouth opening. #### Habitual TMJ Dislocation - **BTX-A Treatment:** - Protocol: 20–25 U injected into the lateral pterygoid muscle following manual reduction. - Outcomes: Studies have shown no recurrences in treated patients. * Injecting into lateral ptyggl .-O Parotid gland Condyle process **Maxillary artery** Coronoid process <span style="color: #FF0000;">Lateral Pterygoid m</span> (Guo et al., 2023) **Lateral pterygoid muscle and surrounding tissue by ultrasound image.** The vessel enhanced in color **Doppler** imaging is the **maxillary artery**. The arrow line illustrates the needle trajectory and needle positioning during ultrasound-guided BTX-A injection. Guo HJ, Wu CC, Li TC. Ultrasound-guided lateral pterygoid muscle botulinum toxin: an injection for recurrent temporomandibular joint dislocation in a brain injury patient. Oral and Maxillofacial Surgery. 2023 **Jun**;<span style="color:#0000ff;">27(2):365-71.</span> #### Ultrasound-Guided Injection Technique - **Target:** Lateral Pterygoid muscle. - **Anatomical Landmarks:** Parotid gland, Condyle process, Coronoid process. - **Vascular Considerations:** Color Doppler imaging is used to identify the maxillary artery to ensure safe needle trajectory and positioning. Ultrasound-guided medical procedure image showing the lateral pterygoid muscle injection. The image displays anatomical landmarks including the parotid gland, condyle process, coronoid process, and maxillary artery (enhanced in color Doppler). A needle trajectory is illustrated with an arrow line pointing to the lateral pterygoid muscle (Lateral Pterygoid m), indicating the site of BTX-A injection. # Bruxism • Numerous RCT’s & systematic reviews – **controversial results**. • Reported effects: ↓ bruxism events, ↓ clenching force or MBF/ ↓ intensity of muscle contractions/↓ pain severity/ ↑ MMO *Chen et al., 2023, Buzatu et al., 2024, Hosgor et al, 2020, Patel et al., 2019, De la Torre Canales et al., 2017* • Effect may last for 3-4 months. Transient nature of some tx effects with symptoms resurfacing – requiring ongoing mx. ? **Cost-benefit in the long-term**. *Buzatu et al., 2024* • Some studies – mixed outcomes/ no improvement in ROM or max occl force/ pain reduction not significantly better than placebo/control. *Saini et al., 2024, Thambar et al., 2020, Ågren et al., 2020* Chen Y, Tsai CH, Bae TH, Huang CY, Chen C, Kang YN, Chiu WK. Effectiveness of botulinum toxin injection on bruxism: a systematic review and meta-analysis of randomized controlled trials. Aesthetic plastic surgery. 2023 Apr;47(2):775-90. Thambar S, Kulkarni S, Armstrong S, Nikolarakos D. Botulinum toxin in the management of temporomandibular disorders: a systematic review. British Journal of Oral and Maxillofacial Surgery. 2020 Jun 1;58(5):508-19. Patel J, Cardoso JA, Mehta S. A systematic review of botulinum toxin in the management of patients with temporomandibular disorders and bruxism. British dental journal. 2019 May;226(9):667-72. Buzatu R, Luca MM, Castiglione L, Sinescu C. Efficacy and safety of botulinum toxin in the management of temporomandibular symptoms associated with sleep bruxism: a systematic review. Dentistry Journal. 2024 May 23;12(6):156. #### Clinical Outcomes in Bruxism Research into BTX for bruxism has yielded controversial results across various RCTs and systematic reviews. **Reported Positive Effects:** - Reduction in bruxism events and clenching force. - Decreased intensity of muscle contractions. - Reduction in pain severity. - Increase in maximum mouth opening (MMO). **Limitations and Mixed Findings:** - Effects are transient, typically lasting 3–4 months, requiring ongoing management. - Some studies show no significant improvement in range of motion or occlusal force compared to placebo. - Long-term cost-benefit ratio remains a concern. # Botulinum Toxin for Treating Temporomandibular Disorders: What is the Evidence? Robert Delcanho<sup>1,2,3</sup>, Matteo Val<sup>4,5,6</sup>, Luca Guarda Nardini<sup>4,5,6</sup>, Daniele Manfredini<sup>7,8,9,10</sup> * **24 RCTs.** * **Categories identified:** 1. Myofascial pain (and/or myospasm) 2. TMJ articular disorders 3. Bruxism 4. Masseter hypertrophy * Wide variability in methods of injection & doses. * Majority evaluated BTX type A. * Most commonly injected: **masseter + temporalis** together (( other: **masseter alone/ lat.pterygoid alone**) * Most used palpation to establish injection sites. (other: EMG/US). * Units injected & dose per individual muscle varied greatly. * **Not necessarily superior** to currently available less invasive & less expensive conservative tx. ## Key findings: * **Sufficient evidence** for use in **masseter hypertrophy**. * **Equivocal evidence** for use in **masticatory myofascial pain**. * Re. **bruxism**: available research is **inconclusive** & **does not show enough evidence** for its use in tx. * **Insufficient evidence** for its effectiveness in **TMJ articular disorders.** * Need for further controlled studies. Delcanho R, Val M, Nardini LG, Manfredini D. Botulinum toxin for treating temporomandibular disorders: what is the evidence?. Journal of oral & facial pain and headache. 2022 Jun 2;36(1):3023. #### Evidence Summary for TMD and Bruxism A review of 24 RCTs (Delcanho et al., 2022) highlighted the following: - **Masseter Hypertrophy:** Sufficient evidence for use. - **Masticatory Myofascial Pain:** Equivocal evidence; not necessarily superior to less invasive, less expensive conservative treatments. - **Bruxism:** Inconclusive research; insufficient evidence to support routine use. - **TMJ Articular Disorders:** Insufficient evidence for effectiveness. #### Administration Variability - **Target Muscles:** Most commonly masseter and temporalis together; occasionally masseter or lateral pterygoid alone. - **Guidance:** Palpation is most common, followed by EMG and Ultrasound. - **Dosing:** Significant variability exists in the units injected per muscle. # Neuropathic OFP Neuropathic OFP • Efficacy of BTX A in treatment of classical TN: Jabbari B., 2022 • Zhang et al, 2014, Wu et al, 2002 (randomized, double-blind, placebo-controlled trials) Toxins. 2021 **Effects of Botulinum Toxin Type A on Pain among Trigeminal Neuralgia, Myofascial Temporomandibular Disorders, and Oromandibular Dystonia** by Kazuya Yoshida 📧 iD • 16 patients with third-division TN: Injected submucosally or subcutaneously into trigger **zones**. • 12 patients with second-division TN: Injected into **sphenopalatine ganglion**. • Average dose per injection: 43 U. • Mean pain improvement: ~83% - 91% ### 4. Conclusions Injection of botulinum toxin type A can be a highly effective and safe way to treat TN, myofascial TMD, and OMD. Yoshida K. Effects of botulinum toxin type A on pain among trigeminal neuralgia, myofascial temporomandibular disorders, and oromandibular dystonia. *Toxins*. 2021 Aug 29;13(9):605. Jabbari B. Botulinum Toxin Treatment of Chronic Facial Pain: Trigeminal Neuralgia and Temporo-Mandibular Disorders. *In* Botulinum Toxin Treatment of Pain Disorders 2022 Jun 3 (pp. 191-213). Cham: Springer International Publishing. #### Efficacy in Classical Trigeminal Neuralgia (TN) - **Third-Division TN:** Injected submucosally or subcutaneously into trigger zones. - **Second-Division TN:** Injected into the sphenopalatine ganglion. - **Dosing and Outcomes:** - Average dose: 43 U. - Mean pain improvement reported between 83% and 91%. - **Conclusion:** BTX-A is considered a highly effective and safe treatment for TN, myofascial TMD, and Oromandibular Dystonia (OMD). # Systematic Review **Is Botulinum Toxin Effective in Treating Orofacial Neuropathic Pain Disorders?** **Matteo Val**<sup>1,*</sup><img src="https://www.researchgate.net/profile/Matteo-Val-2" alt="Research Gate Logo" height="18" width="18">, **Robert Delcanho**<sup>2</sup>, **Marco Ferrari**<sup>1</sup>, **Luca Guarda Nardini**<sup>3</sup> and **Daniele Manfredini**<sup>1</sup><img src="https://www.researchgate.net/profile/Daniele-Manfredini" alt="Research Gate Logo" height="18" width="18"> • 6 RCTs. **TN** (5) and **post-herpetic neuralgia** (1) • Site selection: subjective pain perception & tactile allodynia. • Amount injected, technique, site, & no. of injections varied. * Amount injected: **25U - 140U** * No. of injection sites: **8 - 25** • All studies: anti-epileptics were maintained. • All studies- **↓ pain intensity** vs placebo & lidocaine. • Most studies: **↑ QoL.** • **Not possible to identify a common or recommended protocol.** • **Probably has a clinically significant benefit.** • **Weak evidence to say further ↓ pain intensity when used as an adjunct anti-epileptic drugs.** Toxins. 2023 Val M, Delcanho R, Ferrari M, Guarda Nardini L, Manfredini D. Is Botulinum Toxin Effective in Treating Orofacial Neuropathic Pain Disorders? A Systematic Review. Toxins. 2023 Sep 1;15(9):541. #### Systematic Review Findings A review of 6 RCTs covering TN and post-herpetic neuralgia found: - **Site Selection:** Based on subjective pain perception and tactile allodynia. - **Dosing Variability:** 25 U to 140 U across 8 to 25 injection sites. - **Clinical Benefits:** - Significant reduction in pain intensity compared to placebo and lidocaine. - Improvement in Quality of Life (QoL). - **Adjunct Therapy:** Weak evidence suggests further pain reduction when used alongside anti-epileptic drugs. - **Protocol:** No common or recommended protocol has been identified yet. Other Orofacial Conditions: PTTNP, PIDAP Journal of Oral Rehabilitation, 2020 The effect of botulinum toxin A on patients with persistent idiopathic dentoalveolar pain—A systematic review Andreas Dawson^{1,2,3} \^{iD} | Jenny Dawson^{1} | Malin Ernberg^{3,4} \^{iD} Conclusions: This systematic review shows that presently the **level of scientific evidence is insufficient** to evaluate the pain-relieving effect of BONT-A injections in patients with PIDP. There are indications that BONT-A injections **could be a possible management option** for patients with PIDP that seems to be safe and with few adverse events. There is a need for well-designed placebo-controlled, double-blind RCTs. • Effect of BTX-A in PIDAP and PTTNP. • No. of injection sessions ranged from 1-10. • Dose and no. of sites also differed: **10-30U** & **3-12 sites.** • **Pain reducing effect: 50-72%** J Oral Facial Pain Headache, 2024 Onabotulinum toxin a treatment for posttraumatic trigeminal neuropathic pain: case series and literature review Huann Lan Tan^{1,2}, Pankaew Yakkaphan^{1,3}, Amandine Beke^{1}, Tara Renton^{1,*} • BTX-A on refractory PTTNP. • 3 - 35 units of BTX-A inj. directly subcutaneously &/or submucosally into affected regions. • Submucosal IO inj: **buccal vestibule**, **gingiva** & **hard palate.** • BTX-A may be a **potential tx modality for refractory PTTNP.** • Large scale RCTs required. Dawson A, Dawson J, Ernberg M. The effect of botulinum toxin A on patients with persistent idiopathic dentoalveolar pain—A systematic review. Journal of Oral Rehabilitation. 2020 Sep;47(9):1184-91. Tan HL, Yakkaphan P, Beke A, Renton T. Onabotulinum toxin a treatment for posttraumatic trigeminal neuropathic pain: case series and literature review. Journal of Oral & Facial Pain and Headache. 2024 Mar 12;38(1):93. #### Persistent Idiopathic Dentoalveolar Pain (PIDAP) - **Evidence Level:** Currently insufficient to fully evaluate pain-relieving effects, though it appears to be a safe management option. - **Reported Outcomes:** Pain reduction of 50–72% in some cases. - **Dosing:** 10–30 U across 3–12 sites over 1–10 sessions. #### Post-Traumatic Trigeminal Neuropathic Pain (PTTNP) - **Administration:** 3–35 units injected subcutaneously or submucosally into affected regions (e.g., buccal vestibule, gingiva, hard palate). - **Status:** Potential treatment modality for refractory cases; large-scale RCTs are required. # Other Orofacial Pain Conditions: BMS > Burning Mouth Syndrome # • No. of studies is scarce. Only one placebo controlled clinical trial – Restivo et al., 2017. *<sup>Etemad-Moghdam et al., 2022</sup>* # • Dosage ranges from 50U – 100U. # • Injected into **masticatory muscles**, the **tongue**, and **lip**. # • Effects starting from 48 h to 3 wks later and lasting up to 20 wks. # • **A conclusion cannot be drawn on efficacy.** <sup>Etemad-Moghdam et al., 2022</sup> | Authors | Patients | History | Symptoms | BoNT | Dose | Injection site | Outcome | Time to effect | Lasting effect | | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | :--- | | Seo et al. 2009 [118] | *N = 1* <br> Female 54 y | Neuroleptic therapy | Tongue dyskinesia + severe<br>oral burning 5 y after<br>therapy for neuroleptic<br>therapy | BoNT-A | 50U | Tongue muscles | Both issues<br>improved | 10 d | NS, injections<br>given each<br>month for 2 y | | Restivo et al. 2017 [119] | *N = 6*<br>Females: 5<sup>a</sup><br>Male: 1<br>67–76 y | Diabetes in 3 patients | Anterior 2/3 of tongue +<br>lower lip for at least 6 m | Inco-<br>botulinumtoxinA | 16U | Bilateral lower<br>lip + bilateral<br>anterolateral<br>tongue | Initial<br>60–90 VAS<br>reduced<br>to 0 | 48h | 12–20 w | | Kwon and Park 2020 [120] | *N = 1*<br>Female<br>60 y | N/S | Burning + dryness | Meditoxin | 100U | 60U in both<br>masseters +<br>40U in both<br>temporalis | Initial 5<br>NRS<br>reduced<br>to 2 | 3 w | N/S | Etemad-Moghdam S, Alaeddini M, Jabbari B. Botulinum Toxin in Dentistry and Treatment of Chronic Orofacial Pain. In *Botulinum Toxin Treatment of Pain Disorders* 2022 Jun 3 (pp. 311-357). Cham: Springer International Publishing.  #### Clinical Data for Burning Mouth Syndrome - **Evidence:** Scarce; only one placebo-controlled trial exists. - **Dosing:** Ranges from 50 U to 100 U. - **Injection Sites:** Masticatory muscles, tongue, and lips. - **Onset and Duration:** Effects start between 48 hours and 3 weeks, lasting up to 20 weeks. - **Conclusion:** Efficacy cannot be definitively drawn due to limited data. A structured table summarizing clinical studies on Botulinum Toxin for Burning Mouth Syndrome (BMS). Columns include Authors, Patients, History, Symptoms, BoNT type, Dose, Injection site, Outcome, Time to effect, and Lasting effect. Rows detail specific cases: Seo et al. 2009 (N=1 female, tongue dyskinesia, 50U dose), Restivo et al. 2017 (N=6, diabetes history, 16U dose, bilateral lip/tongue injection), and Kwon and Park 2020 (N=1 female, burning/dryness, 100U dose, masseter/temporalis injection). #### Case Study Summaries - **Tongue Dyskinesia/Burning:** 50 U BoNT-A injected into tongue muscles; improved both issues (Seo et al. 2009). - **Anterior Tongue/Lower Lip Burning:** 16 U IncobotulinumtoxinA injected into bilateral lower lip and anterolateral tongue; VAS reduced from 60–90 to 0 (Restivo et al. 2017). - **Burning and Dryness:** 100 U (60 U masseters, 40 U temporalis); NRS reduced from 5 to 2 (Kwon and Park 2020). • **PREEMPT** I and **PREEMPT** II (Phase III Research Evaluating Migraine Prophylaxis Therapy) studies – 2010. • 1384 patients. • Min. intramuscular dose of 155U on ONA-BoNTA (max 195U) Kępczyńska & Domitrz 2022, Aurora et al., 2010, Diener et al., 2010 • 31 injection sites across 7 H&N muscles. • Main results estb. ONA-BoNTA is **safe, well tolerated & effective** in prophylactic tx of **chronic migraine**. | Area of Injection | Recommended Dose | | :--- | :--- | | Frontalis | 20 units (4 sites) | | Corrugator | 10 units (2 sites) | | Procerus | 5 units (1 site) | | Occipitalis | 30 units (6 sites) + 10 units in 2 sites (follow the pain areas—optional injections) | | Temporalis | 40 units (8 sites) + 10 units in 2 sites (follow the pain areas—optional injections) | | Trapezius | 30 units (6 sites) + 20 units in 4 sites (follow the pain areas—optional injections) | | Cervical paraspinal muscle group | 20 units (4 sites) | | | | | :--- | :--- | | | **Summary: 155–195 units** | OnabotulinumtoxinA dosing in chronic migraine according to protocol PRREMPT Kępczyńska K, Domitrz I. Botulinum toxin—a current place in the treatment of chronic migraine and other primary headaches. *Toxins*. 2022 Sep 5;14(9):619. Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, Diener HC, Brin MF. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. *Cephalalgia*. 2010 Jul;30(7):793-803. Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, Silberstein SD, Brin MF. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. *Cephalalgia*. 2010 Jul;30(7):804-14.  #### PREEMPT Protocol for Chronic Migraine Phase III studies established that OnabotulinumtoxinA (ONA-BoNTA) is safe and effective for prophylactic treatment. **Dosing Summary:** 155–195 units across 31 injection sites. **Injection Areas and Recommended Doses:** - **Frontalis:** 20 units (4 sites) - **Corrugator:** 10 units (2 sites) - **Procerus:** 5 units (1 site) - **Occipitalis:** 30–40 units (6–8 sites) - **Temporalis:** 40–50 units (8–10 sites) - **Trapezius:** 30–50 units (6–10 sites) - **Cervical Paraspinal Group:** 20 units (4 sites) A table titled 'OnabotulinumtoxinA dosing in chronic migraine according to protocol PRREMPT'. The table lists the 'Area of Injection' (Frontalis, Corrugator, Procerus, Occipitalis, Temporalis, Trapezius, Cervical paraspinal muscle group) and the corresponding 'Recommended Dose' in units per site. It concludes with a summary row indicating a total range of 155–195 units. # Summary- BoNT-A use in orofacial pain conditions | Orofacial Pain Type | Efficacy Summary | Clinical Notes | Injection Sites | |---|---|---|---| | Trigeminal Neuralgia (TN) | BoNT-A is a viable addition to the treatment options of patients with TN. There is a need to establish proper dosing | Considered when standard treatments (e.g., carbamazepine) fail or are not tolerated; the advantage of a one-time injection is obvious | Trigger areas (e.g., gums). Intradermal or submucosal along painful trigeminal branches; avoid deep muscular injection | | Post-Traumatic Trigeminal Neuropathy (PTTN) | Limited evidence; data is based on small trials and case reports, or preclinical experiments | Some patients benefit, but animal experiments demonstrated the central antinociceptive effect of BoNT-A on peripheral neuropathic pain | Near affected peripheral nerve (e.g., mental foramen region); avoid causing motor dysfunction | | Myofascial Orofacial Pain (TMD/MOP) | Conflicting data with moderate to low certainty. However, long-term efficacy cannot be ignored | Some benefit in refractory cases; similar effect to anesthetics; not superior to placebo in many trials | Masseter, temporalis, medial pterygoid, and neck muscles based on trigger point’s location | | Facial Migraine (Chronic Neurovascular Orofacial Pain) | A key prophylactic therapy for chronic migraine, but a lack of studies in facial migraine | Approved for chronic migraine; limited data in facial variants but rationale supported by trigeminovascular mechanisms | Forehead, scalp, or subdermal facial areas avoiding mimic muscles to prevent asymmetry | --- Sharav Y, Benoliel R, Haviv Y. Botulinum Toxin-A, Generating a Hypothesis for Orofacial Pain Therapy. Toxins. 2025 Aug 4;17(8):389. --- * Further well-designed placebo-controlled, double-blind RCTs are required. * Dosing protocols to be established.  #### Efficacy and Injection Site Matrix | Orofacial Pain Type | Efficacy Summary | Clinical Notes | Injection Sites | | :--- | :--- | :--- | :--- | | **Trigeminal Neuralgia** | Viable addition to treatment options. | Used when standard meds fail; one-time injection advantage. | Trigger areas (gums), intradermal/submucosal. | | **Post-Traumatic Neuropathy** | Limited evidence; small trials/case reports. | Some benefit in peripheral neuropathic pain. | Near affected peripheral nerve (e.g., mental foramen). | | **Myofascial Pain (TMD)** | Conflicting data; moderate to low certainty. | Benefit in refractory cases; similar to anesthetics. | Masseter, temporalis, medial pterygoid. | | **Facial Migraine** | Key prophylactic therapy for chronic migraine. | Supported by trigeminovascular mechanisms. | Forehead, scalp, or subdermal facial areas. | Table: Summary of BoNT-A use in orofacial pain conditions. Columns include 'Orofacial Pain Type', 'Efficacy Summary', 'Clinical Notes', and 'Injection Sites'. Rows detail treatments for Trigeminal Neuralgia (TN), Post-Traumatic Trigeminal Neuropathy (PTTN), Myofascial Orofacial Pain (TMD/MOP), and Facial Migraine, providing specific efficacy data, clinical context, and anatomical injection targets for each. # Adverse effects * Large margin of safety. * Usually mild . * Tend to occur 1–2 weeks after injection and are usually transient. **Scheinberg 2009** * Localised pain/ tenderness. **Fu et al., 2010, Scheinberg 2009** * Bruising/ haemorrhage. **Fu et al., 2010, Scheinberg 2009** * Hyperesthesia. **Fu et al., 2010, Scheinberg 2009** * Local weakness/ transient facial weakness/ asymmetry. **Scheinberg 2009** * Headache and flu-like symptoms. **Chen et al 2015** Scheinberg A. Clinical use of botulinum toxin. Aust Prescr 2009;32:39-42 Fu KY, Chen HM, Sun ZP, Zhang ZK, Ma XC. Long-term efficacy of botulinum toxin type A for the treatment of habitual dislocation of the temporomandibular joint. British Journal of Oral and Maxillofacial Surgery. 2010 Jun 1;48(4):281-4. Chen YW, Chiu YW, Chen CY, Chuang SK. Botulinum toxin therapy for temporomandibular joint disorders: a systematic review of randomized controlled trials. International journal of oral and maxillofacial surgery. 2015 Aug 1;44(8):1018-26. #### Common Side Effects Adverse effects are usually mild, transient, and occur 1–2 weeks post-injection. - Localized pain, tenderness, or bruising. - Hemorrhage at the injection site. - Hyperesthesia. - Localized muscle weakness, transient facial weakness, or asymmetry. - Headache and flu-like symptoms. # Complications - **Dysphagia, nasal speech, painful chewing, nasal regurgitation, and dysarthria.** [subside within **2–4 weeks**]. Fu et al., 2010. - **Rare:** skin rash, pruritus and allergic reaction. Scheinberg 2009 - **Possible detrimental effects on mandibular bone in preclinical animals & humans.** Correlation of bone loss with dosage & frequency of administration remains unknown. Moussa et al., 2024 - In rabbit models: With BTX paralysis of the masseter, the resulting underloading was sufficient to cause notable and persistent bone loss at the TMJ. Rafferty et al., 2012 - Overdose: symptoms of botulism, including ptosis, diplopia, deterioration in swallowing and speech, generalised weakness and respiratory failure. Scheinberg 2009 - **Neutralising antibodies to BTX**-can lead to loss of treatment effect. Okeson 2019. - **Higher doses and shorter interval (< 3months).** Jabbari B., 2022, Rahman et al., 2022, ebs.tga.gov.au - **Longer duration receiving BTX-A (>10yrs)** Rahman et al., 2022 Scheinberg A. Clinical use of botulinum toxin. Aust Prescr 2009;32:39-42 Rafferty KL, Liu ZJ, Ye W, Navarrete AL, Nguyen TT, Salamati A, Herring SW. Botulinum toxin in masticatory muscles: short-and long-term effects on muscle, bone, and craniofacial function in adult rabbits. Bone. 2012 Mar 1;50(3):651-62. Moussa MS, Bachour D, Komarova SV. Adverse effect of botulinum toxin‐A injections on mandibular bone: A systematic review and meta‐analysis. Journal of oral rehabilitation. 2024 Feb;51(2):404-15. Fu KY, Chen HM, Sun ZP, Zhang ZK, Ma XC. Long-term efficacy of botulinum toxin type A for the treatment of habitual dislocation of the temporomandibular joint. British Journal of Oral and Maxillofacial Surgery. 2010 Jun 1;48(4):281-4. Okeson JP. Management of temporomandibular disorders and occlusion. 8th ed. St. Louis: Elsevier; 2019. #### Functional and Systemic Complications - **Transient Impairments:** Dysphagia, nasal speech, painful chewing, nasal regurgitation, and dysarthria (typically subside within 2–4 weeks). - **Rare Reactions:** Skin rash, pruritus, and allergic reactions. - **Overdose (Botulism symptoms):** Ptosis, diplopia, respiratory failure, and generalized weakness. #### Long-Term Risks - **Mandibular Bone Loss:** Preclinical studies show persistent bone loss at the TMJ and mandible due to muscle underloading; correlation with human dosage is still being studied. - **Immunogenicity:** Development of neutralizing antibodies can lead to loss of treatment effect. - **Risk Factors:** Higher doses, short intervals (< 3 months), and long-term use (> 10 years). - Hypersensitivity to the active substance or any of the ingredients. (**ebs.tga.gov.au**, *Scheinberg 2009*) - Infection or inflammation at the proposed injection sites. (**ebs.tga.gov.au**, *Scheinberg 2009*) - Generalised disorder of muscle activity (eg. myasthenia gravis, Lambert-Eaton Syndrome). (**ebs.tga.gov.au**, *Scheinberg 2009*) - Pregnancy/ breastfeeding. (*Scheinberg 2009*) - Theoretical drug interactions - may interact with medications that affect neuromuscular transmission including aminoglycosides or curare-like compounds. (*Scheinberg 2009*) - Toxin preparations contain albumin, which carries a theoretical risk for transmission of viral or prion diseases. (*Scheinberg 2009*) **Scheinberg A. Clinical use of botulinum toxin. Aust Prescr 2009;32:39-42** **Therapeutic Goods Administration. Australian Public Assessment Report (AusPAR) for Xeomin [Internet]. Canberra: TGA; 2024. Available from: https://www.tga.gov.au** **Therapeutic Goods Administration. Product Information: BO #### Absolute and Relative Contraindications - Hypersensitivity to the active substance or any ingredients (e.g., albumin). - Infection or inflammation at the proposed injection site. - Generalized disorders of muscle activity (e.g., Myasthenia Gravis, Lambert-Eaton Syndrome). - Pregnancy and breastfeeding. #### Drug Interactions and Safety Notes - **Neuromuscular Transmission:** Potential interactions with aminoglycosides or curare-like compounds. - **Biological Risk:** Toxin preparations contain albumin, carrying a theoretical risk for transmission of viral or prion diseases. **Thank You** Thank You <div style="background-color:#006293; padding:10px 0; margin-bottom:20px; color:white;"> <h1 style="margin:0; text-align:center;">References</h1> </div> - Sim WS. Application of botulinum toxin in pain management. The Korean journal of pain. 2011 Mar 31;24(1):1-6. - Carr WW, Jain N, Sublett JW. 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[^1]: Original PDF page 1: [[L30 Botulinum toxin for orofacial pain.pdf#page=1|L30 Botulinum toxin for orofacial pain, p.1]] [^2]: Original PDF page 2: [[L30 Botulinum toxin for orofacial pain.pdf#page=2|L30 Botulinum toxin for orofacial pain, p.2]] [^3]: Original PDF page 3: [[L30 Botulinum toxin for orofacial pain.pdf#page=3|L30 Botulinum toxin for orofacial pain, p.3]] [^4]: Original PDF page 4: [[L30 Botulinum toxin for orofacial pain.pdf#page=4|L30 Botulinum toxin for orofacial pain, p.4]] [^5]: Original PDF page 5: [[L30 Botulinum toxin for orofacial pain.pdf#page=5|L30 Botulinum toxin for orofacial pain, p.5]] [^6]: Original PDF page 6: [[L30 Botulinum toxin for orofacial pain.pdf#page=6|L30 Botulinum toxin for orofacial pain, p.6]] [^7]: Original PDF page 7: [[L30 Botulinum toxin for orofacial pain.pdf#page=7|L30 Botulinum toxin for orofacial pain, p.7]] [^8]: Original PDF page 8: [[L30 Botulinum toxin for orofacial pain.pdf#page=8|L30 Botulinum toxin for orofacial pain, p.8]] [^9]: Original PDF page 9: [[L30 Botulinum toxin for orofacial pain.pdf#page=9|L30 Botulinum toxin for orofacial pain, p.9]] [^10]: Original PDF page 10: [[L30 Botulinum toxin for orofacial pain.pdf#page=10|L30 Botulinum toxin for orofacial pain, p.10]] [^11]: Original PDF page 11: [[L30 Botulinum toxin for orofacial pain.pdf#page=11|L30 Botulinum toxin for orofacial pain, p.11]] [^12]: Original PDF page 12: [[L30 Botulinum toxin for orofacial pain.pdf#page=12|L30 Botulinum toxin for orofacial pain, p.12]] [^13]: Original PDF page 13: [[L30 Botulinum toxin for orofacial pain.pdf#page=13|L30 Botulinum toxin for orofacial pain, p.13]] [^14]: Original PDF page 14: [[L30 Botulinum toxin for orofacial pain.pdf#page=14|L30 Botulinum toxin for orofacial pain, p.14]] [^15]: Original PDF page 15: [[L30 Botulinum toxin for orofacial pain.pdf#page=15|L30 Botulinum toxin for orofacial pain, p.15]] [^16]: Original PDF page 16: [[L30 Botulinum toxin for orofacial pain.pdf#page=16|L30 Botulinum toxin for orofacial pain, p.16]] [^17]: Original PDF page 17: [[L30 Botulinum toxin for orofacial pain.pdf#page=17|L30 Botulinum toxin for orofacial pain, p.17]] [^18]: Original PDF page 18: [[L30 Botulinum toxin for orofacial pain.pdf#page=18|L30 Botulinum toxin for orofacial pain, p.18]] [^19]: Original PDF page 19: [[L30 Botulinum toxin for orofacial pain.pdf#page=19|L30 Botulinum toxin for orofacial pain, p.19]] [^20]: Original PDF page 20: [[L30 Botulinum toxin for orofacial pain.pdf#page=20|L30 Botulinum toxin for orofacial pain, p.20]] [^21]: Original PDF page 21: [[L30 Botulinum toxin for orofacial pain.pdf#page=21|L30 Botulinum toxin for orofacial pain, p.21]] [^22]: Original PDF page 22: [[L30 Botulinum toxin for orofacial pain.pdf#page=22|L30 Botulinum toxin for orofacial pain, p.22]] [^23]: Original PDF page 23: [[L30 Botulinum toxin for orofacial pain.pdf#page=23|L30 Botulinum toxin for orofacial pain, p.23]] [^24]: Original PDF page 24: [[L30 Botulinum toxin for orofacial pain.pdf#page=24|L30 Botulinum toxin for orofacial pain, p.24]] [^25]: Original PDF page 25: [[L30 Botulinum toxin for orofacial pain.pdf#page=25|L30 Botulinum toxin for orofacial pain, p.25]] [^26]: Original PDF page 26: [[L30 Botulinum toxin for orofacial pain.pdf#page=26|L30 Botulinum toxin for orofacial pain, p.26]] [^27]: Original PDF page 27: [[L30 Botulinum toxin for orofacial pain.pdf#page=27|L30 Botulinum toxin for orofacial pain, p.27]] [^28]: Original PDF page 28: [[L30 Botulinum toxin for orofacial pain.pdf#page=28|L30 Botulinum toxin for orofacial pain, p.28]] [^29]: Original PDF page 29: [[L30 Botulinum toxin for orofacial pain.pdf#page=29|L30 Botulinum toxin for orofacial pain, p.29]] [^30]: Original PDF page 30: [[L30 Botulinum toxin for orofacial pain.pdf#page=30|L30 Botulinum toxin for orofacial pain, p.30]] [^31]: Original PDF page 31: [[L30 Botulinum toxin for orofacial pain.pdf#page=31|L30 Botulinum toxin for orofacial pain, p.31]] [^32]: Original PDF page 32: [[L30 Botulinum toxin for orofacial pain.pdf#page=32|L30 Botulinum toxin for orofacial pain, p.32]] [^33]: Original PDF page 33: [[L30 Botulinum toxin for orofacial pain.pdf#page=33|L30 Botulinum toxin for orofacial pain, p.33]] [^34]: Original PDF page 34: [[L30 Botulinum toxin for orofacial pain.pdf#page=34|L30 Botulinum toxin for orofacial pain, p.34]] [^35]: Original PDF page 35: [[L30 Botulinum toxin for orofacial pain.pdf#page=35|L30 Botulinum toxin for orofacial pain, p.35]]