Chemodenervation and Neurolysis

Overview and Description

Definition

Chemodenervation is the blockade of neuronal signaling at the neuromuscular junction using botulinum neurotoxin (BoNT). Chemical neurolysis is the application of a chemical agent directly to a nerve or motor point to intentionally interfere with nerve conduction through destruction of a portion of the nerve. Neurolysis is performed with either phenol (carbolic acid) or high concentrations of ethyl alcohol. Both of these procedures are typically performed to reduce spasticity or dystonia related to central nervous system disorders with the goal of achieving functional improvements. Effective use of chemodenervation and neurolysis can result in improvements in gait, independence, completion of ADLs, improved personal hygiene, reduction of caregiver burden, reduction of pain related to spasticity, improvement in self-image and mood, and prevention of contractures.

Mechanism of action

• Phenol and ethyl alcohol: Phenol and ethyl alcohol mediate their effect through nonselective denaturing of proteins upon application to a nerve.¹ This in turn interferes with nerve conduction and impairs innervation to muscles. Phenol for spasticity is typically used at concentrations between 5% and 7%, and ethyl alcohol in concentrations between 45% and 100%.
• BoNT: Botulinum toxin is produced by the anaerobic spore forming bacteria Clostridium botulinum; it has 7 serotypes, A through G. Only serotypes A and B are currently used in clinical practice.² There are currently four FDA approved formulations of BoNT. These include onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB. All BoNT formulations are composed of two subunits, a light chain and a heavy chain, and mediate their effect through blocking of neuromuscular transmission at the pre-synaptic terminal by inhibiting the release of acetylcholine-filled vesicles. BoNT-A formulations achieve this by cleaving SNAP-25, an integral part of the SNARE complex. BoNT-B cleaves synaptobrevin which similarly is a component of the SNARE complex. This results in partial chemical denervation and localized reduction in muscle activity. Transdermal BoNT works by chemically denervating sweat glands, providing local reduction in sweating.

Summary of Food and Drug Administration-Approved BTX Products^3,4,5,6

	Onabotulinum-toxinA	Abobotulinum-toxinA	Incobotulinum-toxinA	Rimabotulinum-toxinB
Cervical Dystonia	Yes	Yes	Yes	Yes
Glabellar lines	Yes	Yes	Yes
Blepharospasm	Yes*		Yes
Strabismus	Yes*
Axillary Hyperhidrosis	Yes
Upper extremity spasticity Adults	Yes	Yes	Yes
Lower extremity spasticity Adults	Yes	Yes
Chronic migraine	Yes
Overactive bladder	Yes
Detrusor overactivity	Yes**
Upper Limb Spasticity Pediatrics **	Yes	Yes	Yes***
Lower Limb Spasticity Pediatrics **	Yes	Yes
Sialorrhea			Yes****	Yes

Note:

• *OnabotulinumtoxinA can be used for treatment of blepharospasm and strabismus in patients 12 years and older.
• **Pediatric spasticity indications are for 2 years or older. Detrusor overactivity indicated for patients 5 years or older who have an inadequate or intolerant response to anticholinergics
• ***Excluding spasticity caused by cerebral palsy
• ****Chronic Sialorrhea in both adults and pediatric patients 2 years or older
• All other indications listed are approved for adult use only.
• Any other use is considered off-label.
• Phenol is not FDA approved, but is widely used for treatment of focal spasticity

Side Effects or Complications

• Phenol/Alcohol⁷
  • Complications include trauma to the injection site, tissue or vascular injury, muscle necrosis and fibrosis, risk of dysesthesias (most common when injection is to mixed motor and sensory nerves) and permanent weakness due to nerve damage. Systemic absorption is rare and can result in central nervous system effects, cardiovascular, pulmonary or renal compromise.
  • Caution should be taken in patients with advanced liver disease, as the liver metabolizes phenol.
  • Chronic phenol exposure may lead to renal toxicity, skin lesions, and gastrointestinal side effects.
• BoNT^3,4,5,6
  • Most common adverse reactions for spasticity management include pain at injection site, flu-like symptoms, neck pain and headache (related to chronic migraine treatment).
  • All botulinum toxin formulations have a black box warning regarding distant spread of the toxin which may occur days or weeks after injection. This may result in symptoms of swallowing or breathing difficulty and risk of death. Risk is greater in children and those with preexisting conditions which may place them at higher risk of dysphagia or respiratory compromise.

Both phenol and BoNT reduce hypertonia temporarily and need to be repeated periodically. Phenol is more technically difficult to perform and the effects typically last longer.

Relevance to Clinical Practice

Available or current treatment guidelines

• Botulinum Toxin and Chemical Neurolysis (with phenol or alcohol) may be considered isolated treatment options for focal spasticity but may also be considered in combination with one another and possibly with other treatment modalities for severe spasticity.⁸

Phenol

• Although no current guidelines exist, chemical neurolysis with phenol or alcohol can be used in conjunction with botulinum toxin when a large number of muscles are being targeted, therefore, allowing toxin use elsewhere. Historically, pure motor nerves were injected, however, more recently, mixed motor sensory nerves are targeted due to the relatively low cost and positive outcomes. ⁹ With the aid of ultrasound and electrical stimulation guidance, these injections attempt to isolate and deliberately injure the integrity of neural tissue, resulting in acute demyelination of the nerve, followed by a delayed destruction of nerve fibers at the motor branch of the mixed nerve.
• Phenol injectate must be prepared by a hospital pharmacy due to its unstable pharmacokinetics. It is unstable at room temperature and oxidizes in the presences of light and air. It is colorless and has a strong odor.¹
• Phenol can be prepared in a water, glycerin or lipid solution to the desired concentration, typically 5-7% for the treatment of spasticity.  At low concentrations, phenol tends to have a local anesthetic effect only. At higher concentrations above 3%, phenol acts as a neurolytic.
• Alcohol concentrations between 45-100% can be used for chemical neurolysis. Alcohol has a local anesthetic property at 5-10% concentrations.
• Electrical stimulation using a Teflon coated needle is used to localize a motor point to identify the peripheral nerve for neurolysis. The electric stimulation is decreased, and the needle is reoriented until the minimum current required (ideally 1-2mA at 1-2Hz) to obtain a muscle twitch is reached. This technique facilitates a close approximation to the nerve.
• Additionally, ultrasound guidance can be used to isolate peripheral nerves and to localize motor branches in mixed motor sensory nerves.
• Medication is then injected either at the nerve or at the motor point of the nerve as it enters the muscle.
• Phenols effects on spasticity are dose dependent, however, there is limited literature on guidance of phenol dosage per nerve. Maximum injected phenol solution for safe outcomes is generally agreed to be 1000mg– 1200mg (6% aqueous phenol solution = 60mg/mL).
• Systemic absorption of phenol in adults is thought to occur at dosages and concentrations much higher than what is traditionally used for chemical neurolysis.
• Although effects are generally immediate with higher concentrations; due to the local anesthetic effect of phenol, the therapeutic effect from neurolysis with lower concentrations may not be evaluated until after 24-28 hours and may take up to 3-7 days.
• Results can last weeks to months. Procedure can be repeated with a cumulative effect noted.
• Incidence of dysesthesias is 2% to 32% in adults and less than 5% in children; dysesthesias can last a few weeks. (more common when targeting mixed motor sensory nerves. Sensory nerves innervate quicker than motor nerves wolf et al 2000)
• Systemic analgesic treatment can be used to treat adverse effects of dysesthesias.
• Phenol and alcohol neurolysis are inexpensive and widely approved.

BoNT A and B¹⁰

• Dosing and Administration:
  • BoNT A serotypes:
    • OnabotulinumtoxinA (BOTOX®)
    • AbobotulinumtoxinA (Dysport®)
    • IncobotulinumtoxinA (Xeomin®)
  • BoNT B serotype:
    • rimabotulinumtoxinB (Myobloc®/Neurobloc®)
  • The various commercial formulations of botulinum toxin products are NOT interchangeable. Based on which serotype is used, the potency and duration of action may vary.11
    • Average onset varies 2-10 day
    • Average peak varies 2-8 weeks
    • Average duration varies 12-16 weeks
  • Side-effects secondary to systemic spread are possible when higher doses are used. Molecular size of botulinum toxin prevents it from crossing the blood brain barrier. The side-effect profile for onabotulinumtoxinA and incobotulinumtoxinA are similar; although, abobotulinumtoxinA seems to produce more local side-effects, which could be because of more diffusion or variations in conversion factors. BoNT type A has the potential for greater spread to nearby and remote muscles when compared to BoNT type B.12 BoNT type B has a lower pH value compared with the BoNT type A formulations, which could cause more injection site pain. BoNT type B also has a relatively stronger autonomic effect, such as dry mouth, corneal irritation, and accommodation difficulties.
  • Safety of use during pregnancy has not been established. Caution should be rendered when using BoNT in patients with neuromuscular conditions or neuromuscular junction disorders. Aminoglycosides may potentiate the efficacy of BoNT and should be avoided.
  • The FDA has approved dosing guidelines based on the botulinum toxin product, treatment type, age of patient, weight of patient and specific muscle targeted.
  • The FDA restricts repeat injections to every 90 days
  • The FDA recommends no more than 400 Units of OnabotulinumtoxinA. Dosing guidelines for FDA indicated muscles are listed below. All reconstitution should be with preservative free 0.9% normal saline.
    • OnabotulinumtoxinA A Dosing for Chronic Migraine Treatment³:
      • Approved for adult patients with chronic migraines, which is defined as, 15 or more migraines a month, with each lasting at least 4 hours a day.
      • Recommended dilution: 200 Units/4mL or 100 Units/2mL. Final concentration of 5 Units/0.1mL.

Facial Muscles	Recommended Dose/Number of Sites
Frontalis	20 Units divided in 4 sites
Corrugator	10 Units dived in 2 sites
Procerus	5 Units in 1 site
Occipitalis	30 Units divided in 6 sites
Temporalis	40 Units divided in 8 sites
Trapezius	30 Units divided in 6 sites
Cervical Paraspinals	20 Units divided in 4 Sites
Total Dose	155 Units per treatment session at 31 sites

• Onabotulinumtoxin A Dosing for Spasticity³:
  • Approved to treat adult patients with upper and lower limb spasticity, and pediatric patients (2-17 years of age) with upper and lower limb spasticity.
  • Recommended Dilution: 200 Units/4mL or 100 Units/2mL along with 0.9% Sodium Chloride solution.

Adult Upper Limb Muscles	Adult Recommended Dose/Number of Sites
Biceps Brachii	60- 200 Units divided in 2- 4 sites
Brachioradialis	45-75 Units divided in 1-2 sites
Brachialis	30-50 Units divided in 1-2 sites
Pronator Teres	15-25 Units in 1 site
Pronator Quadratus	10-50 Units in 1 site
Flexor Carpi Radialis	12.5 – 50 Units in 1 site
Flexor Carpi Ulnaris	12.5 – 50 Units in 1 site
Flexor Digitorum Profundus	30 – 50 Units in 1 site
Flexor Digitorum Sublimus	30 – 50 Units in 1 site
Lumbricals/Interossei	5-10 Units in 1 site
Adductor Pollicis	20 Units in 1 site
Flexor Pollicis Longus	20 Units in 1 site
Flexor Pollicis Brevis/Opponens Pollicis	5-25 Units in 1 site
Adult Lower Limb Muscles	Adult Recommended Dose/Number of Sites
Gastrocnemius – Medial Head	75 Units divided in 3 sites
Gastrocnemius – Lateral Head	75 Units divided in 3 sites
Soleus	75 Units divided in 3 sites
Tibialis Posterior	75 Units divided in 3 sites
Flexor Hallucis Longus	50 Units divided in 2 sites
Flexor Digitorum Longus	50 Units divided in 2 sites

Pediatric Upper Limb Muscles	Pediatric Recommended Dose/Number of Sites
Biceps Brachii	1.5 Units/kg to 3 Units/kg divided in 4 sites
Brachialis	1 Unit/kg to 2 Units/kg divided in 2 sites
Brachioradialis	0.5 Units/kg to 1 Unit/kg divided in 2 sites
Flexor Carpi Radialis	1 Unit/kg to 2 Units/kg divided in 2 sites
Flexor Carpi Ulnaris	1 Unit/kg to 2 Units/kg divided in 2 sites
Flexor Digitorum Profundus	0.5 Units/kg to 1 Unit/kg divided in 2 sites
Flexor Digitorum Sublimis	0.5 Units/kg to 1 Unit/kg divided in 2 sites

Pediatric Lower Limb Muscles	Pediatric Recommended Dose/Number of Sites
Gastrocnemius medial head	1 Unit/kg to 2 Units/kg divided in 2 sites
Gastrocnemius lateral head	1 Unit/kg to 2 Units/kg divided in 2 sites
Soleus	1 Unit/kg to 2 Units/kg divided in 2 sites
Tibialis Posterior	1 Unit/kg to 2 Units/kg divided in 2 sites

• OnabotulinumtoxinA Dosing for Cervical Dystonia:
  • Approved for adults and children 16 years of age or older.
  • Recommended dilution: 200 Units/2mL, 200 Units/4mL, 100 Units/1mL, or 100 Units/2mL along with 0.9% Sodium Chloride solution.

Type of Dystonia	Recommended Contralateral Muscles	Recommended Ipsilateral Muscles
Torticollis	Sternocleidomastoid	Splenius Capitis
	Trapezius	Splenius Cervicis
	Scalenes	Levator Scapulae
		Longissimus
Laterocollis		Levator Scapulae
		Trapezius
		Scalenes
		Sternocleidomastoid
		Splenius Capitis
		Splenius Cervicis
		Longissimus
Anterocollis	Sternocleidomastoid	Sternocleidomastoid
	Scalenes	Scalenes
Retrocollis	Levator Scapulae	Levator Scapulae
	Trapezius	Trapezius
	Longissimus Capitis Longissimus Cervicis	Longissimus Capitis LongissimusCervicis
	Splenius Capitis Splenius Cervicis	Splenius Capitis Splenius Cervicis
	Semispinalis Capitis	Semispinalis Capitis

Muscle	Recommended Dose
Splenius Capitis	15 – 100 units
Splenius Cervicis	20 – 60 Units
Sternocleidomastoid	15 – 100 Units
Scalene Complex	15 – 50 Units
Semispinalis Capitis	30 – 100 Units
Trapezius	20 – 100 Units
Longissimus	30 – 100 Units
Levator Scapulae	20 – 100 Units

• AbobotulinumtoxinA Dosing for Spasticity
  • Approved to treat adult and pediatric patients (2 to 17 years of age) with upper and lower limb spasticity
  • Recommended adult concentration 10 Units/0.1mL or 20 Units/0.1mL. Maximum total dose 1500 Units
  • Recommended pediatric concentration 20 Units/0.1mL or 50 Units/0.1mL. Maximum total upper limb dose 16 Units/kg or 640 Units, whichever is lower. Maximum unilateral lower limb dose 15 Units/kg or 1000 Units, whichever is lower. Maximum bilateral lower limb dose 30 Units/kg or 1000 Units, whichever is lower. Maximum total dose per treatment session 30 Units/kg or 1000 Units, whichever is lower.

Adult Upper Limb Muscles	Recommended Adult Dose Range	Number of Injection Sites
Flexor carpi radialis	100 Units to 200 Units	1 to 2
Flexor carpi ulnaris	100 Units to 200 Units	1 to 2
Flexor digitorum profundus	100 Units to 200 Units	1 to 2
Flexor digitorum superficialis	100 Units to 200 Units	1 to 2
Brachialis	200 Units to 400 Units	1 to 2
Brachioradialis	100 Units to 200 Units	1 to 2
Biceps Brachii	200 Units to 400 Units	1 to 2
Pronator Teres	100 Units to 200 Units	1

Adult Lower Limb Muscles	Recommended Adult Dose Range	Number of Injection Sites
Gastrocnemius medial head	100 Units to 150 Units	1
Gastrocnemius lateral head	100 Units to 150 Units	1
Soleus	330 Units to 500 Units	3
Tibialis posterior	200 Units to 300 Units	2
Flexor digitorum longus	130 Units to 200 Units	1 to 2
Flexor halluces longus	70 Units to 200 Units	1

Pediatric Upper Limb Muscles	Recommended Pediatric Dose Range	Number of Injection Sites
Brachialis	3 Units/kg to 6 Units/kg	1 to 2
Brachioradialis	1/5 Units/kg to 3 Units/kg	1
Biceps brachii	3 Units/kg to 6 Units/kg	1 to 2
Pronator teres	1 Units/kg to 2 Units/kg	1
Pronator quadratus	0.5 Units/kg to 1 Unit/kg	1
Flexor carpi radialis	2 Units/kg to 4 Units/kg	1 to 2
Flexor carpi ulnaris	1.5 Units/kg to 3 Units/kg	1
Flexor digitorum profundus	1 Unit/kg to 2 Units/kg	1
Flexor digitorum superficialis	1.5 Units/kg to 3 Units/kg	1 to 4

Pediatric Lower Limb Muscles	Recommended Pediatric Dose Range	Number of Injection Sites
Gastrocnemius	6 Units/kg to 9 Units/kg	1 to 4
Soleus	4 Units/kg to 6 Units/kg	1 to 2

• AbobotulinumtoxinA dosing for Cervical Dystonia in Adults
  • 500 Units to 1000 Units with recommended concentration of 50 Units/0.1ml or 25 Units/0.1ml
• IncobotulinumtoxinA dosing for Upper Limb Spasticity in Adults and Pediatrics
  • Maximum recommended dose in pediatrics is 8 Units/kg up to a maximum of 200 units per single upper limb or 16 Units/kg up to maximum of 400 units for bilateral upper limbs

Adult Upper Limb Muscles	Recommended Adult Dose Range	Number of Injection Sites
Flexor digitorum superficialis	25 Units to 100 Units	2
Flexor digitorum profundus	25 Units to 100 Units	2
Flexor carpi radialis	25 Units to 100 Units	1 to 2
Flexor carpi ulnaris	20 Units to 100 Units	1 to 2
Brachioradialis	25 Units to 100 Units	1 to 3
Biceps	50 Units to 200 Units	1 to 4
Brachialis	25 Units to 100 Units	1 to 2
Pronator quadratus	10 Units to 50 Units	1
Pronator teres	25 Units to 75 Units	1 to 2
Flexor pollicis longus	10 Units to 50 Units	1
Adductor pollicis	5 Units to 30 Units	1
Flexor pollicis brevis/Opponens pollicis	5 Units to 30 Units	1

Pediatric Upper Limb Muscles	Recommended Pediatric Dose Range	Number of Injection Sites
Brachioradialis	1 to 2 Units/kg, max 50 Units	1 to 2
Biceps	2 to 3 Units/kg, max 75 Untis	1 to 3
Brachialis	1 to 2 Units/kg, max 50 Units	1 to 2
Flexor carpi radialis	1 Unit/kg, max 25 Units	1
Flexor carpi ulnaris	1 Unit/kg, max 25 Units	1
Pronator quadratus	0.5 Units/kg, max 12.5 Units	1
Pronator teres	1 to 2 Units/kg, max 50 Units	1 to 2
Flexor digitorum superficialis	1 Unit/kg, max 25 Units	1
Flexor digitorum profundus	1 Unit/kg, max 25 Units	1
Flexor pollicis longus	1 Unit/kg, max 25 Units	1
Adductor pollicis	0.5Units/kg, max 12.5 Units	1
Flexor pollicis brevis/opponens pollicis	0.5 Units/kg, max 12.5 Units	1

• IncobotulinumtoxinA dosing for Cervical Dystonia
  • 120 Units initial dose, usually injected into the sternocleidomastoid, levator scapulae, splenius capitis, scalenus, and/or the trapezius muscle(s) though this list is not exhaustive. Dose and number of injection sites in each treated muscle should be individualized based on number and location of muscle to be treated, degree of spasticity/dystonia, muscle mass, body weight, and response to previous botulinum toxin injections.
• RimabotulinumtoxinB dosing for Cervical Dystonia
  • Dosing for patients with prior history of tolerating botulinum toxin injections is 2500 to 5000 Units divided among affected muscles. Those without prior history of tolerating botulinum toxin injections should receive a lower initial dose.

Creating a Treatment Plan

• Prior to the utilization of botulinum toxin products, a thorough discussion between patient, caregiver and provider regarding goals of treatment should be addressed.
• Common goals of treatment:
  • Pain reduction, spasticity reduction, improvement in caregiver burden, improvement in activities of daily living and functional mobility, improvement in range of motion, contracture prevention, skin breakdown prevention, improvement in gait mechanics, improvement in positioning and posture, prevention of joint destruction and skin breakdown, and improvement in hygiene.
• When beginning treatment with botulinum toxin products, the FDA recommends initiation with the lowest approved dosing.
• It is beneficial to have close follow up with the patient to monitor therapeutic effectiveness and determine whether patient and caregiver goals were achieved. Based on these discussions, future treatments may be tailored on an individual patient basis.
• If treatments are insufficient, consider increasing dose or dilution, changing injection technique, or adding phenol neurolysis. If these measures are ineffective, then oral treatment or surgical interventions might be considered.

Localization Techniques

• BoNT injections are most effective when injected close to motor points.
• The effects of BoNT can decrease significantly when given as little as 1 cm away from the motor point.
• To increase the accuracy of localization, the following methods are commonly used: anatomic localization using palpation, electromyography (EMG) guidance, electrical stimulation (ES), sonography (US), and computerized tomography/fluoroscopy guidance (less commonly used).
• Anatomic Localization:
  • Based on common anatomic landmarks, palpation is used to localize the target muscle.
  • Pro: No extra equipment is required. Very user-friendly technique. Fast and easy technique for superficial and easily located musculature. Patient can assist by voluntary contracting the specific muscle targeted. Least time consuming.
  • Con: This technique is the least precise. There is low reliability that the provider is in the correct musculature, especially for deeper muscles. In addition, it may be difficult with this technique to access deeper musculature.
• EMG guidance:
  • Motor unit potentials (MUAPs) that are close to the needle tip are identified either by morphology or acoustic properties. Crisp, full-sized MUAPs confirm needle tip near the contracting muscle fibers.
  • Pro: Studies demonstrate EMG guidance is an effective way to inject closest to the motor end-plate, which is the target goal.
  • Con: EMG guidance only indicates the needle being in an active muscle and not a specific muscle. In addition, EMG guidance is not appropriate if there is difficulty obtaining active or passive muscle activation.
• Electrical Stimulation:
  • When ES is used for guidance, the needle electrode is introduced into the desired muscle, and the muscle is stimulated. BoNT is injected once contraction of only the desired muscle is noted. With ES, proximity of the needle tip to the motor endplate zones is confirmed, and the ability of BoNT to diffuse in the muscle is relied on.
  • Pro: ES is an effective way to inject closest to the motor end-plate, which is the target goal.
  • Con: ES is more time consuming and painful due to stimulation of the muscle. In addition, providers require more experience and training to effectively utilize this methodology. You do not want to use this method if contraction of muscle won’t result in obvious joint movement.
• Sonography or ultrasound (US) guidance:
  • Real-time visualization of the target muscle makes US a very helpful guide when targeting muscles.
  • Pro: US guidance allows for painless tracking of the musculature, precision and accuracy of superficial and deep muscles. This technique allows for avoidance of neuro-vasculature. In addition, a fine, thin needle can be utilized to minimize pain.
  • Con: Highly dependent on operator’s skill and training. The needle, although in the muscle, may not be close to the motor endplates. This method is more time consuming as well.
• Computerized tomography/Fluoroscopic Guidance:
  • Rarely used for identifying muscles because of cost and time limitations.

Cutting Edge/ Unique Concepts/ Emerging Issues

Antigenicity to botulinum toxin formulations should be considered with a primary or secondary nonresponse. Botulinum toxin consists of foreign proteins, thus, antibodies can be formed against these proteins. First generation formulations of BoNT (onabotulinumtoxinA and abobotulinumtoxinA) contain accessory clostridial proteins and are more associated with development of antigenicity than second generation formulations of BoNT that do not contain these proteins (incobotulinumtoxinA).¹³ Risk factors for antibody production include the amount of toxin used at each visit and short treatment intervals. Antibodies can be detected serologically or by assessing paralysis after unilateral frontalis or extensor digitorum brevis injections. If antigenicity develops to one formulation of BoNT, alternative formulations can be tried.

Botulinum toxin is increasingly used to treat off label conditions, such as:

• Bruxism: Injecting the masseters and/or the temporalis with BoNT type A has been shown to be effective in reducing pain and discomfort associated with primary bruxism in adults. Doses of BoNT type A varied among studies and ranged from a total of 14 U to 60 U per masseter and/or 20 U to 40 U per temporalis.­¹⁴
• Gastrointestinal Disorders: BoNT type A injected into both the internal and external sphincters helps reduce rectal sphincter spasms. Doses up to 80 U have been considered safe. Injection into the anal sphincters can also improve resolution of chronic anal fissures. BoNT has also been used to treat achalasia and esophageal spasms.
• Nociceptive Pain: The ability of botulinum toxin to inhibit neuropeptide release from nociceptors, thereby blocking central and peripheral pain sensitization processes, can be utilized to treat several pain conditions such as low back pain, piriformis syndrome, myofascial pain, chronic pelvic pain, painful bladder syndrome, and plantar fasciitis. ¹⁵
• Neuropathic Pain Conditions: Favorable results have been reported with subcutaneous injection of botulinum toxin into areas associated with post-herpetic neuralgia, post-traumatic neuralgia, peripheral nerve lesions, diabetic neuropathy, neuropathic pain associated with spinal cord injury, and trigeminal neuralgia.¹⁶
• Residual Limb hyperhidrosis: The use of intradermal botulinum toxin has been used in case reports to treat focal areas of increased perspiration in the amputated limb. ¹⁷
• Hidradenitis suppurativa: The use of botulinum toxin has been shown in case reports to alleviate pain, slow the progression and resolve abscess formation. ¹⁸
• Scoliosis: The use of botulinum toxin for adolescents with idiopathic scoliosis has shown promising results in regards to improving Cobb angle measurements at 6 weeks following injection into the iliopsoas muscle on the concave side of the curve. Similar studies have looked at this in patients with cerebral palsy, however, no radiographic or clinical improvement was noted. ^19,20
• Oral Secretion Control: The use of various botulinum toxins in the setting of sialorrhea have been used in both adults and pediatrics for salivary control. Additionally, it has been used off label in those undergoing non-invasive ventilation to optimize secretion control and prevent complications such as aspiration.­­^{22, 23}
• Pediatric Indications: Botulinum toxin will often be used in the pediatric population for indications that have been approved for treatment in adults. There is ongoing research to obtain approval for these indications in the pediatric population.  

Phenol toxin off-label uses include:

• Currently there are no consensus guidelines for phenol neurolytic injections.
• Phenol can be used for persistent and intractable pain conditions. A diagnostic local anesthetic block on the desired nerve should be performed prior to neurolysis. If the desired effect is obtained, the patient may benefit from neurolysis.

In addition to the various off label uses for chemodenervation, consideration should be taken for adjunct treatments when managing spasticity. Botulinum toxin treatment is often used in conjunction with various modalities and interventions including orthotics, serial casting, electrical stimulation, or other advanced technology such as robotics.

Gaps in Knowledge/ Evidence Base

Although BoNT has been widely approved for the above listed diagnoses, more class I studies are needed to determine safety and efficacy for the treatment of spasticity and other off-label uses. There is increasing evidence that dosages above FDA recommendations may provide improvement in spasticity with post stroke spasticity²¹ with minimal adverse effects, however, functional outcome data is limiting. These higher dosages are often used off label and are in need of continued evaluation. Additionally, many muscles are injected off label in order to comprehensively treat spasticity. Further studies are needed to optimize dosing, injection guidance, injection distribution, and dilution in order to enhance functional outcome measures. There is a particular lack of studies to understand appropriate indications and safe dosing ranges in the pediatric population. Further studies are also needed to better understand how to best convert patients from one formulation of botulinum toxin to another. Further studies are additionally needed to develop consensus guidelines for the use of phenol neurolytic injections.

References

1. D’Souza RS, Warner NS. Phenol Nerve Block. [Updated 2022 Apr 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK525978/
2. Samizadeh S, De Boulle K. Botulinum neurotoxin formulations: overcoming the confusion. Clin Cosmet Investig Dermatol. 2018;11:273-287. https://doi.org/10.2147/CCID.S156851
3. https://www.botoxmedical.com/
4. https://www.dysporthcp.com/ 
5. https://www.xeomin.com/
6. https://www.myobloc.com/
7. Gaid, M., Phenol Nerve Block for the Management of Lower Limb Spasticity. 2012, ACNR.
8. Elovic EP, Esquenazi A, Alter KE, Lin JL, Alfaro A, Kaelin DL. Chemodenervation andnerve blocks in the diagnosis and management of spasticity and muscle overactivity. PM R. 2009 Sep;1(9):842-51. doi: 10.1016/j.pmrj.2009.08.001. PMID: 19769919.
9. Karri, J. (2019). Phenol Neurolysis for Management of Focal Spasticity in the Distal Upper Extremity. PM R. doi: 10.1002/pmrj.12217
10. Bentivoglio AR, Del Grande A, Petracca M, Ialongo T, Ricciardi L. Clinical differences between botulinum neurotoxin type A and B. Toxicon. 2015 Dec 1;107(Pt A):77-84. doi: 10.1016/j.toxicon.2015.08.001. Epub 2015 Aug 7. PMID: 26260691.
11. Brin, M.F.; James, C.; Maltman, J. Botulinum toxin type A products are not interchangeable: A review of the evidence. Biol. Targets Ther. 2014, 8, 227.
12. Borodic, G.E.; Joseph, M.; Fay, L.; Cozzolino, D.; Ferrante, R.J. Botulinum A toxin for the treatment of spasmodic torticollis: Dysphagia and regional toxin spread. Head Neck 1990, 12, 392–399.
13. Carr, W.W., Jain, N. & Sublett, J.W. Immunogenicity of Botulinum Toxin Formulations: Potential Therapeutic Implications. Adv Ther 38, 5046–5064 (2021). https://doi.org/10.1007/s12325-021-01882-9
14. Sendra LA, Montez C, Vianna KC, Barboza EP. Clinical Outcomes of Botulinum Toxin Type A Injections in the Management of Primary Bruxism in Adults: A Systematic Review. Journal of Prosthetic Dentistry. 2021 July 126(1): 33-40 https://doi.org/10.1016/j.prosdent.2020.06.002
15. Safarpour, Yasaman. “Botulinum Toxin Treatment Of Pain Syndromes –An Evidence Based Review”. Toxicon, vol 1, no. 147, 2018, pp. 120-128., Accessed 15 Oct 2019.
16. Lippi L, de Sire A, Folli A, D’Abrosca F, Grana E, Baricich A, Carda S, Invernizzi M. Multidimensional Effectiveness of Botulinum Toxin in Neuropathic Pain: A Systematic Review of Randomized Clinical Trials. Toxins. 2022; 14(5):308. https://doi.org/10.3390/toxins14050308
17. Hansen, C., & Godfrey, B. (2016). Residual Limb Hyperhidrosis Managed by Botulinum Toxin Injections, Enhanced by the Iodine-Starch Test: A Case Report. PM&R, 9(4), 415-418.
18. Shi, W. et al, Successful treatment of stage III hidradenitis suppurativa with botulinum toxin A. BMJ Case Rep 2019: 12
19. Wong, C., Gosvig, K., & Sonne-Holm, S. (2017). The role of the paravertebral muscles in adolescent idiopathic scoliosis evaluated by temporary paralysis. Scoliosis And Spinal Disorders, 12(1).
20. Wong, C., Pedersen, S., Kristensen, B., Gosvig, K., & Sonne-Holm, S. (2015). The Effect of Botulinum Toxin A Injections in the Spine Muscles for Cerebral Palsy Scoliosis, Examined in a Prospective, Randomized Triple-blinded Study. SPINE, 40(23), E1205-E1211.
21. Baricich, A., Picelli, A., Santamato, A., Carda, S., de Sire, A., & Smania, N. et al. (2018). Safety Profile of High-Dose Botulinum Toxin Type A in Post-Stroke Spasticity Treatment. Clinical Drug Investigation, 38(11), 991-1000.
22. Ann Otol Rhinol Laryngol. (2008) Botulinum toxin injection to the salivary glands for the treatment of sialorrhea with chronic aspiration. Annals of Otology, Rhinology, & Laryngology  Feb;117(2):118-22. doi: 10.1177/000348940811700209
23. Harbottle J, et al. Developing an intrasalivary gland botox service for patients receiving long-term non-invasive ventilation at home: a single-centre experience BMJ Open Resp Res 2022;9:e001188. doi:10.1136/bmjresp-2021-001188

Bibliography

Bach K, Simman R. The Multispecialty Toxin: A Literature Review of Botulinum Toxin. Plast Reconstr Surg Glob Open. 2022 Apr 6;10(4):e4228. doi: 10.1097/GOX.0000000000004228. PMID: 35402123; PMCID: PMC8987218.

Berweck S, Schroeder AS, Fietzek UM, Heinen F. Sonography-guided injection of botulinum toxin in children with cerebral palsy. Lancet. Vol 363. England; 2004:249-250.

Bodine-Fowler SC, Allsing S, Botte MJ. Time course of muscle atrophy and recovery following a phenol-induced nerve block. Muscle Nerve. 1996;19:497-504.

Camargo CH, Cattai L, Teive HA. Pain Relief in Cervical Dystonia with Botulinum Toxin Treatment. Toxins (Basel). 2015;7(6):2321-2335.

Comella CL, Buchman AS, Tanner CM, Brown-Toms NC, Goetz CG. Botulinum toxin injection for spasmodic torticollis: increased magnitude of benefit with electromyographic assistance. Neurology. 1992;42(4):878-882.

Grigoriu AI, Dinomais M, Remy-Neris O, Brochard S. Impact of Injection-Guiding Techniques on the Effectiveness of Botulinum Toxin for the Treatment of Focal Spasticity and Dystonia: A Systematic Review. Arch Phys Med Rehabil. 2015;96(11):2067-2078.e2061.

Elovic, E., Esquenazi, A., Alter, K., Lin, J., Alfaro, A., & Kaelin, D. (2009). Chemodenervation and Nerve Blocks in the Diagnosis and Management of Spasticity and Muscle Overactivity. PM&R, 1(9), 842-851

Escaldi, S., Neurolysis: A Brief Review for a Fading Art. Phys Med Rehabil Clin N Am, 2018; 29(3): p. 519-527.Gracies, J.M., et al., Traditional pharmacological treatments for spasticity. Part I: Local treatments. Muscle Nerve Suppl, 1997. 6: p. S61-91.

Kocabas, H. (2010). Comparison of phenol and alcohol neurolysis of tibial nerve motor branches to the gastrocnemius muscle for treatment of spastic foot after stroke: a randomized controlled pilot study. Eur J Phys Rehabil Med, 46(1), 5-10.

Kwon JY, Hwang JH, Kim JS. Botulinum toxin a injection into calf muscles for treatment of spastic equinus in cerebral palsy: a controlled trial comparing sonography and electric stimulation-guided injection techniques: a preliminary report. Am J Phys Med Rehabil. 2010;89(4):279-286.

Lee SA, Choi JY, Oh BM. The effect of CT-guided botulinum toxin injection on cervical dystonia, confirmed by nine-month follow-up using 18F-FDG PET/CT : A case report. Am J Phys Med Rehabil. 2019.

Lim EC, Seet RC. Botulinum toxin: description of injection techniques and examination of controversies surrounding toxin diffusion. Acta Neurol Scand. 2008;117(2):73-84.

Morel C, Hauret I, Andant N, Bonnin A, Pereira B, Coudeyre E. Efficacy of two injection-site localisation techniques for botulinum toxin injections: a single-blind, crossover, randomised trial protocol among adults with hemiplegia due to stroke. BMJ Open. 2016;6(11):e011751.

Picelli A, Bonetti P, Fontana C, et al. Accuracy of botulinum toxin type A injection into the gastrocnemius muscle of adults with spastic equinus: manual needle placement and electrical stimulation guidance compared using ultrasonography. J Rehabil Med. 2012;44(5):450-452.

Picelli A, Lobba D, Midiri A, et al. Botulinum toxin injection into the forearm muscles for wrist and fingers spastic overactivity in adults with chronic stroke: a randomized controlled trial comparing three injection techniques. Clin Rehabil. 2014;28(3):232-242.

Picelli A, Tamburin S, Bonetti P, et al. Botulinum toxin type A injection into the gastrocnemius muscle for spastic equinus in adults with stroke: a randomized controlled trial comparing manual needle placement, electrical stimulation and ultrasonography-guided injection techniques. Am J Phys Med Rehabil. 2012;91(11):957-964.

Rappl T, Parvizi D, Friedl H, et al. Onset and duration of effect of incobotulinumtoxinA, onabotulinumtoxinA, and abobotulinumtoxinA in the treatment of glabellar frown lines: a randomized, double-blind study. Clin Cosmet Investig Dermatol. 2013;6:211-219.

Thompson, A.J., et al., Clinical management of spasticity, in J Neurol Neurosurg Psychiatry. 2005: England. p. 459-63.

Walker HW, Lee MY, Bahroo LB, Hedera P, Charles D. Botulinum toxin injection techniques for the management of adult spasticity. PMR. 2015;7(4):417-427.

Walker KJ, McGrattan K, Aas-Eng K, Smith AF. Ultrasound guidance for peripheral nerve blockade. Cochrane Database Syst Rev. 2009(4):Cd006459.

Walker TJ, Dayan SH. Comparison and overview of currently available neurotoxins. J Clin Aesthet Dermatol. 2014;7(2):31-39.

Original Version of the Topic

Supreet Deshpande, MD, Mark E. Gormley Jr. Neurolysis. 9/20/2013

Previous Revision(s) of the Topic

Natasha L Romanoski, DO, Kevin Moser, MD, Neyha Cherin, DO. Neurolysis. 11/29/2019

Author Disclosure

Natasha L Romanoski, DO
IPSEN, Honorarium, Consulting

Kevin Moser, MD
Nothing to Disclose

Neyha Cherin, DO
Nothing to Disclose