L30 Botox

Botulinum Toxin for Orofacial Pain¹

Dr Lasanthini Weerakkody
Oral Medicine Specialist

Table of Contents²

• Overview
• Mechanism of action
• BoNT Preparations
• Indications
  • Practical applications & protocols
• Adverse effects
• Complications
• Contraindications

Overview of Botulinum Toxin

Structural Composition of Botulinum Toxin (BoNT)³

BoNT-A Supramolecular Complex (~760-kDa Assembly)

• Core Neurotoxin (150 kDa): The active component
  • The core neurotoxin consists of two polypeptide chains: a heavy chain and a light chain.
  • The protein is stable in acid but decomposes to yield the 150 kDa neurotoxin in a physiological state.
• Nontoxic Proteins (Complexing Proteins):
  • Hemagglutinin (HA) Proteins
  • Nonhemagglutinin (NHA) Protein

Bacterial Origin

==Botulinum toxin is a neurotoxin produced by the anaerobic rod-shaped bacterium Clostridium botulinum.==

Classification and Commercial Brands

• BoNT/A: Botox, Dysport, Xeomin
• BoNT/B: NeuroBloc, Myobloc

Regulatory Approval

These agents are approved by the FDA and TGA for various medical and cosmetic uses.

• BoNT/E: Currently under clinical trials.
• 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

Mechanism of Action⁴

Physiological Pathway⁵

1. Normal Motor Neuron Function: Acetylcholine (ACh) release leads to muscle contraction.
   • By preventing acetylcholine release, the toxin limits the firing of the postsynaptic nerve, thereby reducing muscle contraction and glandular secretion.
2. Pain Transmission: ACh and other neurotransmitters (Substance P, CGRP, Glutamate) contribute to pain signaling and central/peripheral sensitization.

Cellular Mechanism of Action

1. Binding: The toxin binds to specific receptors on the presynaptic surface of cholinergic neurons.
2. Endocytosis: Botulinum toxin is taken up by the nerve terminus
3. Separation: It separates into its heavy and light polypeptide chains.
4. 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.
5. Inhibition: The SNARE complex fails to form, preventing the fusion of synaptic vesicles with the terminal membrane.
6. Inhibition: The SNARE complex fails to form, preventing the fusion of synaptic vesicles with the terminal membrane
7. Effect: Exocytosis of ACh into the synaptic cleft is blocked, resulting in temporary localized muscle relaxation (typically lasting ~3 months)..
8. Effect: Exocytosis of ACh into the synaptic cleft is blocked, resulting in temporary paralysis of targeted muscle fibers (typically lasting

Analgesic Mechanism

Beyond motor neurons, BoNT may act on sensory nerves and nociceptors. It is suggested to inhibit the release of pain-mediating neurotransmitters such as Substance P, glutamate, and CGRP. ~3

Info

Over time, the nerve terminal regenerates SNARE proteins and forms new synaptic contacts, restoring muscle function. months).

Botulinum Toxin Preparations and Excipients

Composition of BoNT Preparations⁶

• 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.
  • Human serum albumin, sodium chloride, lactose, or sucrose are added to prevent product inactivation during storage.

Therapeutic Formulations and Brands

Classification of Therapeutic Preparations⁷

• BoNT/A + NAPs (Neurotoxin Associated Proteins):
  • Botox®
  • Dysport®
• Isolated BoNT/A (Pure Neurotoxin):
  • Xeomin® - Xeomin is derived from the same strain as Botox but undergoes further purification to remove NAPs.
• BoNT/B + NAPs:
  • Myobloc®

TGA Registered Agents in Australia⁸

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

Potency and Conversion Factors

Potency Measurement⁹

• Biologic activity is measured in Mouse Units (MU).

Mouse Units (MU)

One unit is defined as the amount of toxin required to cause death in 50% of a group of mice. Because manufacturers use different testing methods, units are not directly interchangeable between brands.

• 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.

Clinical Administration and Protocols

Preparation and Dilution¹⁰

• Vials are typically diluted with 0.5–5 mL of saline prior to injection.
• Most BoNT-A preparations are freeze-dried or vacuum-dried powders requiring reconstitution with sterile saline, whereas Myobloc (Type B) is available as a ready-to-use solution.
• Higher dilution increases the spread of the toxin.
• Most require specific temperature regimens, though Xeomin can be stored at room temperature.

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
• A 30-gauge needle is typically used for injection.

First-Line Therapy

BoNT is considered first-line therapy for head and neck movement disorders.

Clinical Indications for Orofacial Pain¹¹

Applications in Orofacial Pain and Dysfunction¹²

• Head and Neck Movement Disorders
• Temporomandibular Disorders (TMD)
• Neuropathic Orofacial Pain (OFP)
• Headache Disorders
• Other Conditions:
  • Facial paralysis
  • Sialorrhea
  • Head and neck cancer complications

Oromandibular Dystonia

Injection Sites and Approaches¹³

• Masseter and Temporalis Muscles: Standard injection sites for dystonia management.
  • Masseter: Injected at three points. Care must be taken to avoid the parotid gland.
  • Temporalis: Usually injected at three sites simultaneously with the masseter.
• Medial Pterygoid Muscle: Can be accessed via intraoral or extraoral approaches. - Intraoral: Palpated in relation to the occlusal plane (EMG recommended). - Extraoral: Needle inserted 10mm anterior to the mandibular angle.
• Lateral Pterygoid Muscle: Can be accessed via intraoral or extraoral approaches. - Intraoral: Entry at the mucobuccal fold near the upper second molar. - Extraoral: Needle inserted through the mandibular notch below the zygomatic arch.

Temporomandibular Disorders¹⁴

Muscular Temporomandibular Disorders

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.

Articular Temporomandibular Disorders

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. - Follow-up: Studies reporting no recurrence for up to two years.

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.

Bruxism and Clenching

Clinical Outcomes in Bruxism¹⁵

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.

Evidence Summary for TMD and Bruxism¹⁶

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 Orofacial Pain¹⁷

Neuropathic OFP

Trigeminal Neuralgia

Efficacy in Classical Trigeminal Neuralgia (TN)

• Third-Division TN: Injected submucosally or subcutaneously into trigger zones.
• Second-Division TN: Injected into the sphenopalatine ganglion.
  • V2 Injections: Sometimes made into the sphenopalatine ganglion using CAD-CAM needle guides.
• 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 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.

Persistent Idiopathic Dentoalveolar Pain

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.

Burning Mouth Syndrome

Clinical Data for Burning Mouth Syndrome¹⁸

• 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.

Case Study Summaries¹⁹

• 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).

Chronic Migraine Prophylaxis

PREEMPT Protocol for Chronic Migraine²⁰

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)

FDA Approval and Frequency

Approved by the FDA in 2010 based on the PREEMPT 1 and 2 trials. The protocol is recommended at least three times over 12 months.

Summary of Efficacy and Injection Sites

Efficacy and Injection Site Matrix²¹

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.

Evidence Levels and Protocols

• Trigeminal Neuralgia/Neuropathic Pain: Limited but showing efficacy in studies.
• TMD: Limited; effective for muscular/myofascial subtypes but not necessarily superior to conservative treatment.
• Migraine: Established safety and efficacy via PREEMPT protocol.

Safety and Contraindications

Adverse Effects

Common Side Effects²²

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.

Immune Response

Flu-like symptoms following injection are typically an immune response to the toxin.

Complications and Long Term Risks

Functional and Systemic Complications²³

• 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.
• Inadvertent spread of the toxin can be the underlying cause of functional complications like dysphagia or nasal speech.

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.
  • Human studies, in addition to animal studies, suggest potential mandibular or TMJ bone loss due to muscle paralysis.
• 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).

Contraindications and Drug Interactions²⁴

Absolute and Relative Contraindications²⁵

• 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.

• Treatment Failure: May be due to preparation errors, poor muscle selection, or insufficient dosage, in addition to antibody formation.

Thank You

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25. Original PDF page 30: L30 Botulinum toxin for orofacial pain, p.30 ↩

26. Original PDF page 32: L30 Botulinum toxin for orofacial pain, p.32 ↩

27. Original PDF page 33: L30 Botulinum toxin for orofacial pain, p.33 ↩

28. Original PDF page 34: L30 Botulinum toxin for orofacial pain, p.34 ↩

29. Original PDF page 35: L30 Botulinum toxin for orofacial pain, p.35 ↩