Nonaesthetic Applications for Botulinum Toxin in Plastic Surgery

Matthew D. Freeman, M.D.; Ilana G. Margulies, M.D., M.S.; Paymon Sanati-Mehrizy, M.D.; Nikki Burish, M.D.; Peter J. Taub, M.D., M.S.

Disclosures

Plast Reconstr Surg. 2020;146(1):157-170. 

In This Article

Disorders

Pain-related Disorders

Chronic Migraine (Level of Evidence I to III). Chronic migraine is defined as headache on 15 days or more per month for greater than 3 months, of which 8 or more days meet the criteria for migraine with or without aura and/or respond to migraine-specific treatment, occurring in a patient with a history of at least five prior migraine attacks not attributed to another causative disorder or medication overuse.[15] Chronic migraine affects approximately 2 percent of the population, leading to reduced quality of life, increased analgesic misuse, increased health care costs, and increased missed work days.[16] Although migraine surgery has been found to be effective for chronic migraine,[17] onabotulinumtoxinA is a U.S. Food and Drug Administration–approved noninvasive treatment with efficacy supported by three large-scale studies.[18] The Phase 3 Research Evaluating Migraine Prophylaxis Therapy trial used a prospective, double-blinded, placebo-controlled study to conclude that onabotulinumtoxinA significantly improved all outcomes in chronic migraine, with improvement remaining at 56 weeks' follow-up.[19] The Chronic Migraine OnabotulinumToxin A Prolonged Efficacy Open Label study noted improvement after nine sessions, with favorable results at 24 months.[20] The ongoing Real-Life Use of Botulinum Toxin for the Symptomatic Treatment of Adults with Chronic Migraine, Measuring Health Care Resource Use, and Patient-Reported Outcomes Observed in Practice trial found long-term benefits of onabotulinumtoxinA injections during preliminary studies across 78 clinics in Europe and the United States.[21]

Although the therapeutic mechanism of botulinum toxin in preventing migraines is still being elucidated, it appears that it functions both at the injection site and at distant sites by means of axonal transport. Botulinum toxin inhibits the release of neurotransmitters and neuropeptides other than acetylcholine, and reduces release of substance P and calcitonin gene-related peptide, which likely causes the therapeutic effect in chronic migraine.[2] Botulinum toxin also modifies cell surface nociceptive receptors linked to chronic migraine.[2] Although botulinum toxin has been found to decrease frequency and intensity of migraines with minimal side effects in chronic migraine patients, episodic migraine and tension-type headache patients have not experienced the same results, and these conditions are currently not indications for botulinum toxin.[22–24]

The injection protocol in the Phase 3 Research Evaluating Migraine Prophylaxis Therapy trial involves a total of 155 to 195 U injected as 5-U aliquots across 31 to 39 intramuscular sites (Table 2). A retreatment schedule of every 12 weeks, up to five cycles, was well-tolerated.[18,19,25] Alternative protocols exist, including the use of a targeted peripheral nerve-directed approach with a decreased botulinum toxin type A dose, resulting in significant improvements in severity and duration of migraine headaches (Table 2).[26,27]

Osteoarthritis (Level of Evidence II to III). Patients with osteoarthritis often see hand surgeons because of pain that results from inflammation of the surrounding synovium, changes to the articular cartilaginous surface, and loss of joint space volume.[28] Inhibition of substance P, calcitonin gene-related peptide, and neurokinin A release may allow botulinum toxin to reduce osteoarthritis-related pain.[29] A systematic review showed a role for botulinum toxin in osteoarthritis treatment, but the reviewed studies were too heterogeneous, and the optimal injection method, dilution, and dosage need further investigation.[30] A recent meta-analysis of randomized controlled trials found a significant short-term joint pain reduction with intraarticular botulinum toxin injection, but again noted the need for study homogeneity and additional studies comparing botulinum toxin with conventional treatment modalities.[31]

Trigeminal and Postherpetic Neuralgia (Level of Evidence II to V). Trigeminal neuralgia is characterized by paroxysmal, sudden-onset episodes of severe pain in the distribution of the trigeminal nerve, usually unilaterally, with a variety of potential causes, although in many patients it is idiopathic.[32] Botulinum toxin use in trigeminal neuralgia was first reported for pain relief in intractable trigeminal neuralgia in 2002,[33] and its efficacy in reducing frequency and severity of episodes has been confirmed by a number of studies, including by means of meta-analysis, with single-dose regimens having effects comparable to multiple-dose regimens. Effective doses have ranged from 70 to 100 U botulinum toxin type A for single-dose regimens or 50 to 70 U botulinum toxin type A per treatment for repeated dose regimens.[34–36] Meta-analysis also revealed the efficacy of botulinum toxin in alleviating pain in refractory trigeminal neuralgia, although it emphasized the current lack of high-quality studies.[37]

Postherpetic neuralgia is a neuropathic pain condition that results from herpes zoster–induced peripheral nerve damage. Although topical or subcutaneous lidocaine and/or systemic therapy with tricyclic antidepressants or epileptic drugs has been found to be beneficial,[38] these therapies are limited by variable patient tolerance and adverse effects. Several reports and randomized controlled trials have found that up to 200 U of botulinum toxin type A injected subcutaneously throughout the affected area is beneficial in postherpetic neuralgia by decreasing pain, decreasing opioid use, and improving sleep time and quality.[39–42] However, additional long-term and more robust studies are needed to confirm these findings.

Temporomandibular Pain Disorders (Level of Evidence II to IV). Temporomandibular pain disorders, which can be divided into myofascial or arthrogenic, have a number of causes and affect up to 10 percent of the population.[43] Myofascial temporomandibular pain disorders respond well to pharmacologic therapy and behavioral changes, although refractory cases can be challenging to treat. Limited research into the use of botulinum toxin type A has yielded encouraging results with effective dosing ranging from repeated injections of 100 U to a single injection of 500 U of botulinum toxin type A into the masseter and/or temporalis muscle.[44,45] Additional case series found that 90 U of botulinum toxin type A injected into the masseter and temporalis decreased pain by at least 50 percent in 79 percent of patients.[46] Similar promising results were found with botulinum toxin type A use to correct disk displacement in arthrogenic temporomandibular pain disorders through lateral pterygoid muscle injection;[47,48] however, randomized prospective studies are needed to confirm the efficacy of botulinum toxin in temporomandibular pain disorders and determine optimal dosing.[49]

Skeletal Muscle Activity

Cervical Dystonia (Level of Evidence I). Cervical dystonia is the most common focal dystonia, characterized by involuntary head and neck posturing, potentially resulting in severe pain.[50] A 2017 meta-analysis showed significant improvement in severity, disability, and pain from a single injection session of botulinum toxin type A, but with increased risk for dysphagia (9 percent) and generalized weakness (10 percent).[50] A meta-analysis in 2016 showed similarly encouraging results for botulinum toxin type B.[51] All botulinum toxin products are now U.S. Food and Drug Administration approved for the treatment of cervical dystonia, with botulinum toxin type A used as first-line management (Table 3),[52,53] and botulinum toxin type B used for botulinum toxin type A–resistant patients.[54]

Hemifacial Spasm (Level of Evidence II to III). Hemifacial spasm, generally caused by vascular compression of the facial nerve near its brainstem origin, is characterized by facial nerve–mediated contractions of the face that can cause significant cosmetic and social disability.[55,56] Although few high-quality, randomized, placebo-controlled trials have been conducted for hemifacial spasm, numerous lower quality publications have supported the use of botulinum toxin as a first-line treatment. Success rates in those studies ranged from 76 to 100 percent, with effect lasting between 2.6 and 4 months. No systemic side effects were noted and minor side effects were transitory.[55] Although microvascular decompression of the facial nerve may be a curative procedure, studies comparing botulinum toxin versus surgical cohorts are lacking. Despite the lack of high-quality studies, hemifacial spasm is an on-label indication for botulinum toxin injection because of clinical experience.

Blepharospasm (Level of Evidence I). Blepharospasm is a dystonia affecting the orbicularis oculi muscle, causing excessive eyelid closure. It may be unilateral at onset, but usually progresses to bilateral involvement. Patient education, avoidance of causal agents (such as dopamine blockers), and avoidance of corneal injury have been fundamental in blepharospasm management.[57] Oral medications including benzodiazepines, baclofen, tetrabenazine, and clozapine have shown therapeutic effects because of their activities at gamma aminobutyric acid or dopaminergic receptors.[58] Facial nerve lysis and orbicularis myotomies were once used extensively but have been replaced by chemodenervation. Multiple clinical trials and two large evidence-based reviews have demonstrated that botulinum toxin is a safe and effective treatment choice (Figure 2).[59–61]

Figure 2.

Injection sites and protocol for botulinum toxin use in the treatment of blepharospasm. Current guidelines for treatment of blepharospasm include three injection sites in the orbicularis oculi: (A) lateral pretarsal orbicularis oculi of the upper lid; (B) medial pretarsal orbicularis oculi of the upper lid; (C) lateral pretarsal orbicularis oculi of the lower lid. Dosages at each site range from 1.25 to 2.5 U, with recommended dilutions of 100 U/8 ml to 100 U/4 ml. At repeated treatments, these doses may be increased up to twofold if necessary. To minimize the risk of brow ptosis, providers should avoid injection near the elevator palpebrae superioris. To minimize the risk of diplopia from inadvertent inferior oblique muscle injection, careful technique is warranted in the medial lower lid.

Benign Masseteric Hypertrophy (Level of Evidence III to IV). Benign masseteric hypertrophy is enlargement of the muscles responsible for mastication. The cause is unknown.[62] Although it is rarely a health risk, patients present with pain and/or aesthetic concerns. Conservative management can include oral muscle relaxants or intraoral splints to adjust occlusion. Although partial myomectomy is possible, intramuscular botulinum toxin injection causing selective loss of muscle function and decrease in muscle mass is an alternative treatment option (Figure 3).[63–65] Although studies have illustrated the efficacy of botulinum toxin in decreasing muscle volume and have established a tailored injection protocol based on masseter bulge type,[66–68] high-quality studies that evaluate the efficacy of botulinum toxin particularly in Western patient populations are needed.[62,64]

Figure 3.

Injection sites and protocol for botulinum toxin use in the treatment of masseter hypertrophy. First, draw a line from the corner of the angle of the lip to the lower part of the external auditory meatus. All injections should be kept below this line (horizontal line). Second, palpate the masseter muscle while asking the patient to clench their teeth tightly. Third, mark the anterior and posterior borders of the masseter muscle. Fourth, mark the following three points: point of maximum bulge (A), inferior point 1 cm lateral to anterior border of muscle (B), and inferior point 1 cm medial to the lateral border of the muscle (C). Fifth, depending on the bulk of the muscle, 5 to 15 U may be injected at each point, for a total of 15 to 45 U per side. The needle tip is introduced in a perpendicular fashion and is used to palpate the mandible and then retracted 1 to 2 mm before injection, thus avoiding the superficial facial musculature.

Bruxism (Level of Evidence II). A recent placebo-controlled pilot trial tested the safety and efficacy of onabotulinumtoxinA injections into the masseter and temporalis muscles in patients with symptomatic sleep bruxism.[69] Participants with sleep bruxism confirmed by polysomnography were injected with either onabotulinumtoxinA 200 U (60 U into each masseter and 40 U into each temporalis) or placebo. They were evaluated at 4- to 8-week time points by multiple questionnaires, polysomnographic data, and electromyographic recordings. None of the exploratory endpoints changed significantly, but total sleep time and number/duration of bruxing episodes favored the onabotulinumtoxinA group, indicating an improvement in sleep quality.

Synkinesia and Symmetrization of Nonaffected Face After Facial Palsy (Level of Evidence I to V). Synkinesia, which involves abnormal involuntary muscle activation that occurs with voluntary activation of a different muscle group, is most commonly caused by idiopathic Bell palsy and likely secondary to aberrant regeneration of axons with abnormal muscle activation.[70–72] The use of botulinum toxin in the 1980s for hemifacial spasm and blepharospasm was extrapolated to synkinesia in the 1990s, and it has been applied to several affected muscles, including platysma, orbicularis oculi, and depressor anguli oris.[73–75] The use of 40 to 120 U of botulinum toxin type A for eyelid synkinesia showed equivalent results for the 40-U subgroup, indicating that low-dose injections are effective.[76] Indeed, another study using 0.5 to 1.25 U of botulinum toxin type A per injection site for an average of 5.76 U total resulted in effective elimination of ocular synkinesis.[77] Furthermore, 64 percent of patients examined had complete resolution of their synkinesis with three or fewer treatments, raising the possibility of definitive management with botulinum toxin injections. Botulinum toxin use in synkinesia has also been found to improve patient-reported outcomes and blinded-physician evaluations, and may also improve responsiveness to adjunct treatment modalities such as neuromuscular retraining therapy.[78,79]

Patients with facial palsy with or without subsequent synkinesia commonly present with contralateral hyperkinesis or facial asymmetry involving the brow, periocular, and lateral oral commissure areas.[75] Contralateral botulinum toxin injection with or without physical therapy has been found to improve asymmetry and contralateral hyperkinesis even in patients with long-term facial paralysis.[80,81] For instance, Azuma et al. used 112.5 U of botulinum toxin type A to the contralateral face in synkinesia with mirror biofeedback therapy and observed significant, long-lasting improvements in facial symmetry.[82] Systematic review found botulinum toxin injection to improve facial asymmetry, particularly if used in combination with physical therapy, but noted the need for additional high-quality evidence.[83]

Exocrine Gland Hyperfunction

Sialorrhea (Level of Evidence I to IV). The use of botulinum toxin in the management of sialorrhea originally stemmed from observations in patients with botulism exhibiting severe dry mouth. Furthermore, studies on botulinum toxin injection for other indications have shown dry mouth as one of the more common side effects.[84] Although sialorrhea has a multitude of acute and chronic causes, botulinum toxin is usually indicated for chronic drooling caused by neurologic disorders such as cerebral palsy, amyotrophic lateral sclerosis, and Parkinson disease. A 2006 systematic review produced two randomized controlled trials that both showed a statistically significant improvement in sialorrhea.[84] A prospective, double-blind, crossover pilot study in amyotrophic lateral sclerosis and Parkinson disease patients showed that both types of botulinum toxin are effective for the treatment of sialorrhea.[85] A systematic review in 2011 regarding motoneuron disease did not identify additional experimental trials.[86] Another 2013 meta-analysis reinforced the need for further high-quality studies to compare botulinum toxin with surgical management and to determine the optimal dosage and injection location.[87]

Treatment of sialorrhea consists of botulinum toxin injection into the parotid and submandibular glands. Review of the literature identified one article with direct injection into the sublingual gland, which resulted in dysphagia in 50 percent of patients with no improvement in sialorrhea.[88–90] Injection into the parotid gland requires caution to minimize injection into the facial nerve. Injection regimens vary greatly in the literature, with ranges of reported injection sites (one to nine) and sites of injection (parotid gland versus subcutaneous to minimize risk of facial nerve palsy). Dosing per parotid gland is typically started at 30 U and can be up-titrated to 50 U.[88–90]

Axillary Hyperhidrosis (Level of Evidence I). Axillary hyperhidrosis is a result of sympathetic-mediated overactive eccrine glands and can cause significant social embarrassment.[91,92] Multiple randomized, double-blind, placebo-controlled studies have found botulinum toxin type A to be effective in reducing hyperhidrosis as reported by patients and as seen on ninhydrin-stained sheets.[93,94] However, botulinum toxin injection into the axilla is associated with significant pain. Multiple analgesic modalities have been attempted, such as icing before injection, topical anesthetics, and regional nerve blockade. A randomized placebo-controlled study investigating reconstituting onabotulinumtoxinA in lidocaine rather than normal saline showed improved pain during injection with similar improvement in symptoms.[95]

Identification of areas requiring treatment in axillary hyperhidrosis requires evaluation with the Minor iodine-starch test procedure. Patients should be instructed to shave their underarms and abstain from deodorant and antiperspirants for 24 hours before the procedure. The underarm is painted with iodine solution, and starch powder is applied once the iodine has dried. Regions of hyperhidrosis in the underarm will then develop a darkened appearance, marking the region for toxin injection. The recommended manufacturer's dosage for onabotulinumtoxinA in axillary hyperhidrosis is 50 U per axilla, typically diluted in 2 ml of solution. Aliquots of 0.1 to 0.2 ml are injected intradermally approximately 1 to 2 cm apart.[11]

Plantar/Palmar Hyperhidrosis (Level of Evidence II to IV). Although plantar/palmar hyperhidrosis is less common than hyperhidrosis of the axilla, it can cause significant social impairment, and act as a risk factor for skin infection and eczema.[96] Current treatments include aluminum chloride, oral medications such as clonidine, iontophoresis, and occasionally surgical sympathectomy; however, botulinum toxin injection (off-label) is a promising alternative. Although limited studies exist, both botulinum toxin type A and botulinum toxin type B have been found to be effective for palmar hyperhidrosis, and botulinum toxin type A has further been found to decrease plantar hyperhidrosis in adolescent patients, with minimal side effects.[96,97] Treatment complications include motor weakness and significant pain. In a placebo-controlled trial, three of 11 patients (27 percent) exhibited motor weakness lasting up to 5 weeks.[98] The treatment paradigm involves over 30 injections into the palm. Icing or wrist nerve blockade should be used.

The protocol for botulinum toxin injections for palmar/plantar hyperhidrosis is similar to that described for axillary hyperhidrosis. If avoiding the Minor iodine-starch test, a 1 × 1-cm grid is created on the palm or sole. A total of 100 U of botulinum toxin type A is then injected subcutaneously across the palm (150 U in the sole), with an attempt to evenly distribute the toxin across the grid.[99]

Frey Syndrome (Level of Evidence IV). Frey syndrome, characterized by gustatory sweating, results from injury to the auriculotemporal branch of the trigeminal nerve as it courses through the parotid gland. Innervation to the parotid to produce saliva is instead routed to the sweat glands of the scalp, causing sweating in the presence of gustatory stimuli. It is most common after surgery to the parotid gland.[100]

Botulinum toxin injections for Frey syndrome have been used since 1995. A systematic review in 2015 evaluating 22 published case studies showed that botulinum toxin type A was effective 98.5 percent of the time, with a complication incidence of 3.6 percent, which mostly consisted of dry mouth or transient muscular weakness in the area of injection.[100] Randomized, multicenter, placebo-controlled trials are needed to improve evidence quality. Although Frey syndrome is an off-label indication, botulinum toxin injections are considered first-line by many providers.

The Minor iodine-starch test can identify the cutaneous area requiring treatment. As in the management of hyperhidrosis, a 1 × 1-cm grid is marked, and 1 U of botulinum toxin is injected subcutaneously at each point. The total number of units required is dependent on each patient, with reported dosages between 16 and 80 U of botulinum toxin type A.[101,102]

Other Uses

Wound Healing (Level of Evidence II). Botulinum toxin injection for wound healing, keloids, and hypertrophic scarring has shown promising early results. A prospective randomized study found that facial wounds treated with botulinum toxin type A within 3 days of repair had significant scar improvement using a visual analogue scale as compared to those not treated with botulinum toxin type A.[103] However, when measures other than the visual analogue scale were used, no significant differences were noted. Other studies have shown some benefit but were too heterogeneous to support widespread use.[104] Potential mechanisms of action include chemodenervation of the muscles at the wound periphery, which allows healing in a tension-free environment, and reduction of transforming growth factor-β1, potentially a key mediator in hypertrophic scar development. Botulinum toxin for wound healing is currently an off-label indication.

Currently, no consensus exists on botulinum toxin dosing and injection patterns in the treatment of existing or anticipated scars. A recent prospective, double-blind, randomized, controlled trial used 10 U/cm of forehead scar at the time of closure as originally described by Gassner et al.[105,106] Timing of botulinum toxin injection also varies within the literature, including immediately before skin closure to greater than 1 week after surgery, with research suggesting that earlier injection is more effective.[107]

Raynaud Phenomenon (Level of Evidence II to IV). Raynaud phenomenon, classified as primary idiopathic or secondary disease, involves vasospastic episodes affecting cutaneous arterial inflow in localized areas including fingers and toes leading to pain, ischemia, ulceration, and potential amputation.[108] The efficacy of pharmacologic treatment for severe disease is variable, with some patients requiring sympathectomy for symptomatic relief. Botulinum toxin has been found to be an effective treatment option through an unclear mechanism, which may be related to its increase in vasodilation through sympathetic blockade.[109,110] A recent systematic review found a wide dosage range in prior reports from 12 to 300 U per hand primarily into digital neurovascular bundles and/or superficial palmar arch, and they largely showed improvements relating to digital temperature; pain; Disabilities of the Arm, Shoulder and Hand score; and ulcer healing.[111] Further efforts through clinical trials to produce high-quality evidence on botulinum toxin use in primary or secondary disease are ongoing.[112,113]

Abdominal Wall Reconstruction (Level of Evidence II to V). The efficacy of botulinum toxin in abdominal wall reconstruction was first evaluated in vivo, where botulinum toxin–mediated paralysis of abdominal wall muscles was found to increase intraabdominal volume and decrease pressure.[114] The clinical use of botulinum toxin in abdominal wall reconstruction has subsequently been evaluated in a number of studies, with a range of 200 to 500 U (minimum of 150 U if unilateral) injected into abdominal wall muscles showing overall efficacy in aiding closure of abdominal wall defects with or without component separation (Table 4).[115–127] A recent systematic review cited the need for randomized controlled trials to further evaluate efficacy, dose, and timing of administration, and to define criteria for optimal candidates.[121]

Prosthetic Breast Reconstruction and Augmentation (Level of Evidence II to IV). The use of botulinum toxin has been investigated for a number of purposes in prosthetic breast reconstruction, including to decrease postoperative pain, increase tissue expander volume expansion, and attenuate the development of capsular contracture; however, discordant study results exist. With respect to decreasing postoperative pain, 40 to 100 U of botulinum toxin type A injected into the pectoralis major with or without serratus anterior and rectus abdominis injections showed increased volume of expansion with decreased postoperative pain and narcotic use.[128,129] However, others showed that intraoperative injection of 100 U of botulinum toxin into the pectoralis muscle was not effective in decreasing postoperative pain.[130] Additional high-quality studies are needed to determine efficacy and evaluate optimal dosage.[131]

Botulinum toxin has also been found to be potentially therapeutic in capsular contracture in both in vivo and in vitro studies by preventing implant capsular formation though the inhibition of fibroblast differentiation by means of a transforming growth factor-β1/Smad–mediated mechanism.[132–134] Clinical investigation found that intraoperative injection of 100 U of botulinum toxin type A into the pectoralis major in breast augmentation resulted in a decreased incidence of capsular contracture and decreased thickness of the capsule.[135] Additional prospective studies are needed to further elucidate this therapeutic effect.[136]

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