Mechanism of Action

Botulinum toxin prevents the release of the neurotransmitter acetylcholine into the neuromuscular junction. The toxins bind to cholinergic neurons and prevent acetylcholine-containing vesicles from fusing with the synaptic membrane, inhibiting muscular activity. Traditionally, pain relief has been attributed to a reduction in muscle hyperactivity. Recent studies have suggested that there is a direct analgesic effect based on BTX action on neurotransmitters other than acetylcholine, including substance P and glutamate.

Clinically, muscle weakness occurs after 2 to 5 days and lasts for about 2 to 3 months before starting to wear off. The duration of effect varies among patients, and subjective effects may be seen up to 6 months. There is a correlation between the amount of BTX used and duration of action, though even with higher doses the duration appears to plateau at about 3 months.

Dosing of Botulinum Toxin

The potency of commercially available BTX is determined by in vivo mouse assays. One unit of BTX is defined as the intraperitoneal amount of toxin lethal to 50% (LD ₅₀ ) of Swiss Webster mice. ^, Units are not comparable or interchangeable between different commercial formulations. For example, 20 units of onabotulinumtoxin A (ONA) (Botox) does not have the same potency as 20 units of abobotulinumtoxin A (ABO) (Dysport) or rimabotulinumtoxinB (RIMA) (Myobloc). The dose required to effectively weaken a muscle varies with the density of neuromuscular junction in any given muscle and the pathology being treated. Toxicity can occur, and recommendations for a safe total body dose are 12 units/kg for ONA and 30 units/kg for ABO.

Reconstitution of Botulinum Toxin

Botulinum toxin typically is available in a vacuum-dried crystalline form. The toxin appears as a barely visible thin crystalline complex at the bottom of the vial ( Figs. 11.1 and 11.2 ) and must be reconstituted with sterile preservative-free normal saline (0.9% sodium chloride injection). RimabotulinumtoxinB (Myobloc) does not require reconstitution. These authors routinely use a dilution of 2 mL preservative-free saline per 100 units of onabotulinumtoxin A, though for small muscles concentration of 1 mL normal saline per 100 units has been used. For ABO, 1.5 mL normal saline per 300 units or 2.5 mL per 500 units is used.

Vial Containing Onabotulinumtoxin A.

© 2020 Allergan. Used with permission. All rights reserved.

Posterior view of a vial of onabotulinumtoxin A illustrating that the toxin is in dried crystalline form which is a barely visible thin complex at the bottom of the vial.

© 2020 Allergan. Used with permission. All rights reserved.

For reconstitution, saline should be slowly injected into the BTX vial, checking that vacuum is present in the vial to ensure sterility; the vacuum can then be released by disconnecting the syringe from the needle. The botulinum toxin is gently mixed with the saline by moving vial side to side prior to drawing up the botulinum toxin solution. Reconstituted BTX should be refrigerated, but there is some concern that BTX may lose potency if stored.

Techniques for Administration

To maximize clinical effectiveness of BTX, the toxin must be injected into the fascial compartment of the muscle, and the dose must be sufficient to neutralize the neuromuscular junction. Localization of the target muscle can be aided using electrical stimulation. Ultrasound (US), fluoroscopy, and computed tomography (CT) can also ensure accurate placement of the BTX ( Table 11.1 ). The number of injection sites should take into account the spread of medication, with animal studies showing that the toxin diffuses 30 to 45 mm from the injection site.

Myofascial Pain Syndrome (Trigger Points)

The exact pathogenesis of myofascial pain is unknown, and diagnostic criteria have varied across the literature. Myofascial pain is characterized by “trigger points,” defined as “a hyperirritable spot in skeletal muscle that is associated with a hypersensitive palpable nodule in a taut band. The spot is tender when pressed and can give rise to characteristic referred pain, motor dysfunction, and autonomic phenomena.” While the mechanism of BTX on myofascial pain is unclear, one theory is that BTX interrupts the pathologic muscle contraction allowing the muscle to relax. BTX may be an alternative treatment for recalcitrant trigger points that have not responded to dry needling or anesthetic injections. Despite not clearly understanding the pathology, multiple studies have reported improved pain following BTX-A injections, including three randomized controlled trials (RCTS) comparing BTX-A injection to injection of saline and one RCT comparing BTX-A injection to dry needling. Five RCTs found no significant difference between a single BTX injection and placebo. In one study, some subjects were asymptomatic after a second injection, and an additional RCT has shown significant improvement with a second dose, suggesting possible benefit with sequential injections. Studies comparing BTX to local anesthetic or methylprednisolone have had heterogeneous results, some suggesting the injectates are equally beneficial. ^{, ,}

Most studies used palpation for localization, injecting into the most tender area. A local twitch response can help confirm the trigger point. Electromyography (EMG) guidance and fluoroscopic guidance have also been used. ^, All studies except one used BTX-A, with onabotulinumtoxin A dosages ranging from 10 to 100 units per injection site, up to 300 units total, and ABO dosages ranging from 40 to 120 units per site, 480 units total ( Table 11.2 ). A randomized open-label prospective study comparing ABO doses of 60, 80, and 120 units for lower back trigger points found no dose–response relationship. A retrospective chart review compared BTX-A and BTX-B for myofascial pain and found BTX-A had a significantly greater mean reduction in pain scores and longer duration of relief.

The current body of literature provides no strong evidence to recommend or reject this treatment modality. RCTs comparing BTX to saline placebo injection are complicated by the fact that the saline is an active control. Further investigation is needed to determine the most efficacious BTX dosing and injection techniques.

Chronic Exertional Compartment Syndrome

Chronic exertional compartment syndrome (CECS) is caused by a reversible increase in the pressure within a fascial compartment. CECS most often involves the anterior and lateral compartments of the leg, leading to decreased tissue perfusion during periods of exertion. The symptoms quickly resolve with rest. The diagnosis is confirmed by checking the compartment pressures at rest and after exercise with needle manometry.

Initial treatment is typically nonoperative, and chemodenervation with BTX has been reported. Robust research including RCTs is still lacking. In one case series with 16 patients, BTX-A was used to treat CECS involving the anterior compartments (targeting tibialis anterior, extensor hallucis longs, extensor digitorum longs) and lateral compartments (targeting peroneus brevis and longus muscles). Subjects showed a significant decrease in intra-compartmental pressures for up to 9 months. Three other case reports, including a case of CECS involving the forearm, have shown sustained benefit at end of follow-up period at 10 to 15 months post treatment. ^, Some loss of muscle strength was noted as a potential side effect, though in all cases, post-treatment weakness resolved over the course of months.

Plantar Fasciitis

Plantar fasciitis has been associated with hyperpronation and mechanical overload resulting in excessive tension on the fascia. Nonoperative management of plantar fasciitis includes nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroid injections, and physical therapy. Corticosteroids have been a mainstay of treatment, but studies have shown similar or superior results with BTX injections. The plantar fascia is not composed of muscle, but palpation- or EMG-guided botulinum toxin injections have targeted the adjacent abductor hallucis and flexor digitorum brevis (FDB) muscles or the gastrocnemius and soleus with significant pain relief. Ultrasound (US)- and landmark-guided injections directly into the plantar fascia have also been used, resulting in significant pain relief.

BTX-A to treat plantar fasciitis has been studied in multiple RCTs comparing BTX-A to placebo, ^, three of which showed significant improvement in pain compared to placebo, one finding no difference in treatment groups. Studies have also compared BTX to steroids (concluding no difference in pain relief between treatment groups) and extracorporeal shock wave (ECSW) therapy (suggesting the ECSW group had greater pain relief). Studies showed benefit from single BTX-A injection lasting from follow-up at 8 weeks up to 12 months. ^, The dose of BTX-A has ranged from 50 units up to 250 units, with the most common dose being 70 units divided between the FDB muscle and abductor hallucis muscle. ^,

Lateral Epicondylitis

Lateral epicondylitis is often an overuse injury leading to degenerative changes of the common extensor tendon. Standard treatment involves antiinflammatories, physical therapy, bracing, and corticosteroid injections. Corticosteroid injections have shown a short-term improvement in pain, but one study showed worse clinical outcomes with cortisone compared to placebo at the 1-year follow-up. ^, Botulinum toxin for lateral epicondylitis was initially reported in case studies and an early prospective study. ^, Since then, four randomized placebo-controlled trials have been performed which support BTX-A injection as beneficial treatment for lateral epicondylitis, though three studies have not shown significant superiority in pain relief in the BTX treatment group compared to placebo or steroids. ^,

BTX is thought to ease the tension on the enthesis site, allowing the tendon to heal. BTX-A doses have ranged from 20 to 50 units onabotulinumtoxin A ^, and 40 to 60 units ABO ^, with the extensor carpi radialis brevis most commonly targeted using EMG guidance, ^{, ,} palpation guidance, or electric stimulation ( Table 11.3 ). EMG and palpation guidance have been used to target the extensor digitorum communis. ^, Other studies have injected the most tender spot using landmark guidance, ^{, ,} with one recent study using US to inject 10 to 30 units incobotulinumtoxin A to specific symptomatic forearm extensor muscles. Sustained benefit after a single injection has been seen up to 18 months in one study.

The most significant adverse effect is weakness of finger and wrist extensors, with studies showing mild paresis lasting from 2 to 16 weeks. This weakness may not be tolerated by patients whose work requires intricate hand movements.

Osteoarthritis

OA is the most common type of arthritis. There are no treatments to cure or reverse the disease process, and various therapeutic and lifestyle interventions have been proposed for the management of symptomatic OA. In recent years, there has been a growing interest in new applications of BTX. A 2018 meta-analysis showed IA BTX has beneficial and significant short-term effects in decreasing refractory joint pain, but a nonsignificant improvement at 6 months. BTX has been studied in ankle, knee, hip, and shoulder OA, with the majority of studies examining the impact of BTX on knee OA. RCTs have compared BTX to a 0.9% normal saline control, ^, hyaluronate injection, corticosteroid injection, and education. Most studies showed that pain and quality-of-life parameters improved with IA BTX, but not all studies found IA BTX to be superior to placebo, ^, steroids, or hyaluronic acid.

The evidence for IA BTX is limited, and the clinical value is unclear. The severity of OA, type and dose of BTX, location of injection, and number of injections may impact results. One study showed benefit of BTX in Kellgren-Lawrence stage III OA, but no improvement in stage IV OA. For the knee, shoulder, and ankle OA, ONA (100 units) was the most common botulinum toxin and dose used ( Table 11.4 ), with doses ranging from as low as 25 units for ankle and knee OA ^{, ,} to 300 units for knee OA. Higher doses of BTX may be less effective, with one study showing benefit with 100 units, but that 200 units of IA BTX had no effect. ^,

The IA application of BTX is novel, but the evidence is still limited. Most studies have been uncontrolled, single center, and with a small sample size and short-term follow-up. Studies have varied in BTX brand and dosing, number of injections, and protocols (i.e., multiple injections, co-administration with other injectates). In addition, not all IA pathology has been treated with IA BTX. Hip OA has been treated with BTX injected into the adductor longus and magnus muscle to reduce pressure on the femoral head and acetabulum ^, and patellofemoral pain syndrome treated with BTX injection into the vastus lateralis muscle. ^, More studies are needed to better define BTX’s role in managing IA pathology.

Thoracic Outlet Syndrome

TOS is due to compression of the neurovascular bundle in the neck. Compression can occur at the interscalene triangle, costoclavicular space, or retropectoralis minor space. Patients can present with neurogenic or vascular symptoms. Neurogenic TOS resulting in irritation of the brachial plexus trunk or cords accounts for the majority of all TOS cases. Botulinum toxin has been used for the management of TOS, weakening the muscles that impinge the brachial plexus. Successful treatment of neurogenic and arterial TOS ^, has been reported. BTX was superior to corticosteroid in a prospective longitudinal study, but the majority of studies are case reports ^{, ,} or retrospective. ^{, ,} Only one randomized double-blind controlled trial exists, which found no clinically or statistically significant difference between BTX and the normal saline control at 6 months. The use of imaging can help minimize complications from the inadvertent spread of toxin. There is no statistically significant difference in complication rate or outcomes with a combination of US and EMG versus fluoroscopy with EMG. Studies have targeted the anterior scalene, ^{, , , ,} middle scalene, ^, trapezius, subclavius, ^, and pectoralis minor ^, muscles. The majority of studies used onabotulinumtoxin A, with doses ranging from 15 to 100 units depending on the number of muscles being targeted ( Table 11.5 ). ^a

a References 94, 95, 97, 99, 101, 102.

TABLE 11.5

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