Pain and biomechanical dysfunction are common presenting complaints to sports medicine physicians and can inhibit rehabilitation and recovery from injuries. The source of the pain and dysfunction can be difficult to determine, making management and treatment of underlying conditions challenging. Reduction or resolution of pain can optimize rehabilitation of biomechanical dysfunction improving human performance and patient well-being. Limited evidence suggests that botulinum neurotoxin (BoNT) is effective in treating a variety of painful musculoskeletal conditions. There are four commercially available pharmaceutical formulations of BoNT, each with individual potencies and FDA approved indications (1). This article discusses off-label musculoskeletal treatments with BoNT — providers should counsel patients accordingly. The purpose of this article is to review the literature and describe the efficacy of BoNT in various musculoskeletal conditions and degenerative pathologies.
BoNT-A and BoNT-B are available commercially. They are among seven toxins produced by the bacterium Clostridium botulinum. BoNT-A is the most commonly used formulation. However, there are three different types of BoNT-A available: onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA. Despite various formulations of BoNT, the mechanism of action remains the same. BoNT acts on both motor and sensory neurons. In motor neurons, BoNT reduces muscle activity by irreversibly binding to the motor endplate presynaptic receptors, inhibiting the release of acetylcholine, thereby producing muscle weakness. In sensory neurons, BoNT inhibits the release of pain modulators, such as substance P, glutamate, capsaicin-induced duration of anesthesia, TRPV1 pathway, and calcitonin gene-related peptide from peripheral neurons and central neurons. The clinical effects of BoNT on voluntary muscle contraction last approximately 3 months, while the autonomic effects are reported to last for nearly 6 months (2).
Chronic Exertional Compartment Syndrome
Chronic exertional compartment syndrome (CECS) is a debilitating disorder with a higher prevalence in active populations. The proposed pathophysiology is increased pressure in muscle compartments during exercise that can result in muscle tightness and pain, which can then advance to paresthesia, muscle weakness, and exercise intolerance. CECS predominantly involves the lower extremities, primarily affects active young adults, and negatively impacts running or other endurance activities. While the incidence of CECS in the general population is unknown, the incidence in the military population is 0.49 cases per 1000 patient-years (3–6). CECS is a clinical diagnosis, but intracompartmental pressure testing can be used as an adjunct to confirm the diagnosis. The characteristic presentation of CECS is muscle pain in the affected compartment at a specific time, distance, or intensity of exercise, which resolves minutes to hours after stopping the activity.
The current definitive treatment of CECS is surgical fasciotomy. However, according to a 2016 systematic review, surgical intervention for CECS was only successful in 66% of those affected, with 13% reporting complications from surgery, and 6% requiring a repeat surgical procedure (5). Similarly, a 2013 retrospective analysis of military members showed fasciotomy for CECS was successful in 55% of patients. Additionally, 28% of these patients were unable to return to full activity, 16% suffered surgical complications, and 6% required repeat fasciotomy (6). On average, studies show that successful fasciotomies require 13 wk before return to full activity (7–9).
Another treatment for CECS, gait retraining, is thought to reduce leg compartment pressures by altering running kinematics. A 2012 case series of 10 military members with CECS, who underwent a supervised gait retraining program emphasizing forefoot running, showed postintervention improvements in running distance, pain reduction, and performance at 6 wk and 54 wk of follow-up. This study also showed significant improvement in postintervention patient satisfaction scores (10). A 2015 prospective cohort study of 19 military members showed that home-based gait retraining for CECS patients was an effective alternative to supervised gait retraining while reducing time and resources (11). Despite high success rates in these limited case studies, real-world application of gait retraining has its limitations. Many patients struggle to make or sustain adaptations in their running style, especially when CECS pain limits their ability to run. Other patients have limited time for extensive rehabilitation or may already run with a mid or forefoot gait pattern.
A novel treatment for CECS is the administration of BoNT-A into muscles of the affected compartment(s). A 2013 case series studying BoNT-A injections for CECS demonstrates normalized intramuscular pressure up to 9 months postinjection in 87.5% (14/16) of the patients and exertional pain eliminated in 94% (15/16) of the patients. Eleven patients experienced transient dorsiflexion weakness that did not result in functional impairment, and one patient complained of new posterior leg pain unrelated to BoNT-A injections. No other adverse effects were reported in this study (3). A 2016 case report shows effective pain and paresthesia relief from CECS after one set of injections for a female recreational runner. In this report, the patient's symptoms resolved within 1 wk, and she was able to return to full activity within 4 wk. The patient had no return of symptoms, weakness, or other adverse effects during 14 months of follow-up (12).
An unpublished retrospective review of CECS patients treated with BoNT-A injections at the Ft. Belvoir Military Sports Medicine Clinic shows that 66% (19/29) of the patients returned to their desired activity level. Additionally, 20 patients were satisfied or somewhat satisfied with their treatment, and 12 patients continued to have sustained relief at the time of follow-up. However, seven patients experienced a recurrence of their symptoms with 7.8 months mean duration of improvement. Ninety-one percent (10/11) of patients who underwent both BoNT-A injections and fasciotomy reported a favorable response to BoNT-A before their surgery, suggesting that intramuscular BoNT-A injections for CECS might predict fasciotomy success.
Currently, based on these limited studies, BoNT-A is a safe and cost-effective alternative to fasciotomy for the treatment of CECS. In our practice, we use 25 U of onabotulinumtoxinA delivered with ultrasound guidance into the muscle belly at two locations in the proximal and distal thirds of the affected compartment(s) in the anterior, lateral, and deep posterior compartments, for a total of 50 U in each compartment. In the superficial posterior compartment, we inject 50 U of BoNT in the medial and lateral heads of the gastrocnemius and 50 U in the soleus muscle. We then begin gait retraining at approximately 3 wk posttreatment, and an ankle lace-up orthotic is utilized if the patient demonstrates weakness with ankle eversion or dorsiflexion. Our clinical experience matches the case series above that more than 50% of patients receiving BoNT-A return to their desired levels of activity without the need for surgical intervention.
Further studies are needed to identify therapeutic duration, maximally effective doses, the specific injection sites, and the side effects of BoNT-A to include whether there are secondary effects to the atrophy of the injected muscles. For instance, if BoNT-A causes demonstrable weakness with dorsiflexion or eversion, should patients wear an ankle lace-up orthotic during gait retraining to prophylactically protect them from an ankle sprain? A better understanding of the mechanism of action of BoNT-A in the treatment of CECS needs to be elucidated to determine whether its effects are related to pain relief, muscle blockade, or both. This determination would allow a better understanding of the condition and may lead to further treatment protocols. Additional work also is required to optimize gait retraining and rehabilitation programs to optimize return to full activity.
Plantar fasciopathy is the most common cause of plantar heel pain and leads to approximately 1 million office visits annually and 1% of all visits to orthopedic clinics (13). Pathophysiology of plantar fasciopathy is similar to tendinopathy with microscopic changes and thickening of the fibrous tissue of the plantar fascia near its origin at the medial calcaneal tuberosity. Risk factors for plantar fasciopathy appear to be multifactorial. Plantar fasciopathy is a clinical diagnosis with a characteristic presentation of medial heel pain exacerbated with weight-bearing activities in the morning, improvement with rest, and return with prolonged loading activities.
Plantar fascia pain can be self-limited, and many cases resolve within a year of onset (14). Treatment for plantar fasciopathy includes relative rest, stretching exercises for the plantar fascia and the calf muscles, eccentric loading exercises, intrinsic foot muscle exercises, insoles, and oral anti-inflammatory drugs. Additional options include musculoskeletal injection therapies, extracorporeal shock wave therapy (ESWT), and in refractory cases, surgical intervention (14). Surgical debridement is typically reserved for patients who have failed multiple previous conservative interventions. Plantar fascial surgery has a satisfaction rate of 50% but can have a recurrence rate of up to 25% (15).
In recent studies, BoNT-A is emerging as a potential therapy for plantar fasciopathies that have failed conservative management. A 2013 randomized, double-blinded trial studied 40 patients who had failed conservative management for 3 months. Patients either received 8 mg of dexamethasone superior to the plantar fascia or 250 U of BoNT-A. BoNT-A patients had injections of 100 U into the medial and lateral gastrocnemius muscle and 50 U in the soleus. The BoNT-A and dexamethasone groups received the same home stretching exercises. Compared with the steroid group, the BoNT-A group had significant improvement in pain and function scores between 2 and 6 months (16). A 2017 randomized controlled trial compared 100 U of incobotulinumtoxinA versus saline injected at the point of maximal tenderness on the affected side of 50 patients who failed 6 wk of conservative therapy. Both groups underwent identical physical therapy. The patients receiving BoNT-A experienced significantly better function and improved pain scores at 6 and 12 months postinjection (17). A 2016 meta-analysis of 22 randomized controlled trials compared intralesional BoNT-A, corticosteroids, platelet-rich plasma, dextrose prolotherapy, sham dry needling, and various amniotic derived preparations in patients with plantar fasciopathy. The meta-analysis found BoNT-A relieved pain in the first 6 months and improved functional disability in the first 2 months. Additionally, in this analysis, BoNT-A demonstrated no significant side effects (18).
Limited high-quality evidence suggests that BoNT-A is an effective and safe option to treat patients who failed conservative management of plantar fasciopathy. In our practice, a patient would have failed stretching, eccentric exercises, intrinsic foot muscles exercise, ESWT, prolotherapy, and possibly, platelet-rich plasma prior to considering BoNT-A. We would perform the procedure under ultrasound-guidance by injecting 50 U of onabotulinumtoxinA at the point of maximal tenderness below the plantar fascia proximally at the medial calcaneal tubercle. We also continue conservative management techniques after BoNT treatment to include stretching, eccentric exercises, and intrinsic foot muscles exercise. We have seen similar clinical responses to the studies presented with improved pain and function for 6 to 12 months. Further studies are needed to identify the most effective dose and type of BoNT, compare the various intrafascia versus extrafascia injection sites, and further investigate the side effects of BoNT treatment to include whether there are secondary effects to the atrophy of intrinsic foot muscles.
Osteoarthritis (OA) is one of the most common musculoskeletal disorders in adults, which can result in chronic disability. The etiology of OA is unknown. There are multiple extrinsic and intrinsic factors of OA to include biological and mechanical elements. OA treatments include nonpharmacologic, pharmacological, and surgical therapies, where the primary goal is improving pain and function. One pharmacological approach is utilizing intraarticular (IA) injection therapies, including corticosteroids, hyaluronic acid, prolotherapy, and platelet-rich plasma injections. There is limited level 1 evidence to suggest that BoNT-A provides an analgesic benefit to patients with refractory pain and dysfunction.
A 2016 randomized controlled trial of 44 patients who had failed conservative therapies compared 21 landmark-guided IA injections of 100 U of incobotulinumtoxinA with a control group of 20 patients who only received OA education; three patients were lost to follow-up. All patients had knee OA severity between two and three on the Kellgren-Lawrence (KL) Scale. The intervention group demonstrated significantly decreased VAS scores at 1 wk and 6 months (VAS scores pretreatment: 5.05 ± 1.12, reduced to 2.89 ± 1.04 at 1 wk; P < 0.001) and reduced to 3.45 ± 1.70 at 6 months (P < 0.001) (19). Limitations of this study include the lack of placebo or sham injection and the fact that the injections were landmark-based with no verification of where the medication was delivered.
A randomized, double-blinded controlled trial of 43 patients with moderate to severe shoulder arthritis randomized 21 patients to a group receiving 100 U IA BoNT-A with lidocaine and compared them with a placebo group of 22 patients receiving IA saline with lidocaine. This 1-month study found a single IA-BoNT-A injection of the shoulder had a statistically significant reduction in pain (VAS BoNT-A, −2.4 vs placebo group, −0.8; P = 0.014) and a small subset of 5 in the IA-BoNT-A group demonstrated improved quality of life on the short-form-36 improvement (P ≤ 0.035) (20). Limitations of this trial include study length of 1 month and the very small subset demonstrating improved quality of life.
A prospective, randomized, assessor-blinded trial of 75 patients with KL grade 2 symptomatic ankle OA randomized 38 patients to a group receiving 100 U BoNT-A into the symptomatic ankle compared with 37 patients in a group receiving hyaluronate injection plus 12 sessions of rehabilitation exercises. At 6 months, no significant differences were demonstrated in the ankle osteoarthritis scale, patient satisfaction, many pain and disability subscales (21). No difference in adverse events was reported between the two groups. The study is limited due to the absence of a control group, and only the hyaluronate injection group received rehabilitation exercises.
A 2018 systematic review of 18 level 1 to level 4 studies evaluated the safety and efficacy of alternatives to biological interventions in managing symptomatic knee osteoarthritis. This review included two studies, one was a 41-patient RCT with significant improvement of the patients' VAS scores at 1 wk and 6 months in the BoNT-A group when compared with the education-only group. The second was a nonrandomized, open-label study with 24 patient patients receiving 100 U of BoNT-A versus normal saline IA injections. The BoNT-A group had statistically significant improvement of Western Ontario and McMaster Universities Osteoarthritis Index scores at 3 months. The systematic review concluded that there is limited evidence that supports the use of BoNT (22). This study has significant limitations in the quality and quantity of studies reviewed and considerable heterogeneity in the studies included in the review.
There have been several meta-analyses looking at the efficacy of BoNT-A in general joint pain (23,24). A 2017 systematic review and meta-analysis assessed six randomized controlled trials with 326 patients for the benefit of IA injection of BoNT-A for chronic refractory joint pain regardless of joint or pathology. The study found a significant reduction in the weighted mean difference of pain scores 4 wk and 8 wk after an injection of IA BoNT-A. There also was a significant decreased in WOMAC scores between BoNT-A and the control group at 4 wk and 12 wk after the IA BoNT-A injection. No increased adverse events between BoNT-A and the control group. Limitations of this study include a small number of studies, variation in type and quantity of BoNT-A, varying joints and painful conditions, and the control group included corticosteroids and hyaluronate acid (23). A 2018 systematic review and meta-analysis of six randomized controlled trials of 382 patients evaluated the efficacy of IA injection of BoNT-A in patients with refractory joint pain. The study found that five trials had a statistically significant reduction of pain by one point on a numeric rating scale (NRS) at 2 months or less regardless of the dose of BoNT-A. Three studies showed a significant reduction in NRS at 2 months or less with the use of 100 U of IA-BoNT-A (24). These meta-analyses had overlapping studies due to the lack of randomized controlled trials meeting the search criteria. These meta-analyses reported no significant adverse events of IA BoNT (23,24).
High-quality evidence is limited, but our experience and the literature has shown that IA-BoNT-A may be an effective and safe method to treat refractory joint pain in osteoarthritis. In our experience, we first utilize conservative management techniques such as healthy weight maintenance, activity modification, and quadriceps and core strengthening exercises along with musculoskeletal injection therapies, such as hyaluronic acid, prolotherapy, and platelet-rich plasma. If the patient has refractory pain despite these treatments, we perform an ultrasound-guided IA knee injection of 50 U of onabotulinumtoxinA. We continue conservative treatment strategies with BoNT-A IA treatment to include activity modification, healthy weight maintenance, and strengthening exercises. In our patient population, we have had similar results of improved pain and dysfunction in patients with knee osteoarthritis for approximately 4 to 6 months. Further studies need to include larger and more diverse populations, evaluate various doses and types of BoNT, assess long-term outcomes at 12 months, avoid control groups that utilize other musculoskeletal injection therapies and evaluate the side effects of IA BoNT to include chondral toxicity.
Lateral epicondylosis is one of the most prevalent musculoskeletal disorders of the upper extremity. This condition is characterized by pain on or around the lateral elbow with or without intermittent radiation more proximally or distally to the lateral forearm and upper arm, respectively. The extensor carpi radialis brevis (ECRB), extensor digitorum, extensor digiti minimi, and extensor carpi ulnaris form the conjoined common extensor tendon that attaches to the anterolateral aspect of the lateral epicondyle. The ECRB is thought to be the most common tendon affected likely because it forms the deep and anterior aspect of the conjoined tendon crossing over the capitellum. The resulting pathophysiology is chronic tendinosis with disorganized tissues and neovascularization likely the results of abrasions during repetitive gripping or with elbow and wrist extension and flexion activities. Lateral epicondylosis is a clinical diagnosis, which can be elucidated by diagnostic imaging, such as ultrasound.
There are multiple conservative therapies to include activity modification, bracing, anti-inflammatory medications, and eccentric exercises. In refractory cases, the literature describes adjunct treatments to include ESWT, musculoskeletal injection therapies, and surgical intervention. BoNT-A injection generally has low-level evidence for treatment of lateral epicondylosis.
A 2018 systematic review and meta-analysis of six studies with 321 patients compared studies utilizing BoNT-A injected 1 cm to 6 cm distal to the lateral epicondyle to placebo or corticosteroids at three periods (2–4 wk, 8–12 wk, and 16 wk). The BoNT-A studies utilized either 60 U of abobotulinumtoxinA or 50 U of onabotulinumtoxinA. BoNT-A injections demonstrated a significant reduction in pain when compared with placebo throughout the 16 wk. Corticosteroid injections demonstrated more pain relief at 2 wk to 4 wk postinjection and equivalent pain relief throughout the 16 wk. A significant decrease in grip strength, as well as wrist and digit extension, was seen for the first 12 wk with BoNT-A (25).
A 2018 randomized double-blinded controlled trial of 60 patients with lateral epicondylosis refractory to treatment for greater than 6 months compared ECRB injection of 40 U BoNT-A at 5 cm distal to the epicondyle to an injection of saline as a placebo. Three months from the initial injection, 51.7% (15/29) of the BoNT-A group had greater than a 50% decrease in pain compared with 25% (7/28) of placebo patients. There also was a significant reduction in the visual analog scales for pain and quality of life in the BoNT-A group. The treatment group had a 17.2% rate of transitory paresis with the extension of the third finger (26). A 2019 study assessed the long-term effects of BoNT-A on lateral epicondylosis with a 1-year follow-up study. Fifty patients with clinical and ultrasonographic evidence of epicondylosis were treated with 40 U BoNT-A injected into the ECRB approximately 5 cm distal to the epicondyle. After the initial treatment, 44% of patient (22/50) had complete pain relief, and 40% of patients (20/50) requested a repeat BoNT-A due to recurrence of pain. Sixteen of those requesting a second injection, requested it at the 90-d follow up visit, compared with three at 180 d, and one at the 1-year follow-up visit. Of the 20 patients that received a repeat injection, 90% (18/20) received no further treatment. The study also demonstrated significant improvement (P < 0.05) in quality of life, painful and maximal gripping force, and repercussions on daily activities (27).
In refractory cases of lateral epicondylosis, BoNT-A has demonstrated promising results of pain relief and quality of life. Studies have shown a measurable weakness of the extensor digitorum, but no associated functional impairment. In our practice, we first consider all conservative treatments to include activity modification, bracing, anti-inflammatory medications, eccentric exercises, and musculoskeletal injection therapies, such as prolotherapy and platelet-rich plasma.
If the patient has failed these treatments, we inject 50 U of onabotulinumtoxinA with ultrasound guidance about 3 cm to 4 cm from the lateral epicondyle into the ECRB. We continue conservative management strategies after BoNT-A treatment to include activity modification, bracing, and eccentrics exercises. We have seen similar clinical responses to the studies presented with improved pain and function for 6 to 12 months. We continue conservative treatment strategies during this period with eccentric loading exercises and bracing. Further assessment is needed to enhance the quality of evidence for dosing, formulations, injection sites, side effects, and long-term outcomes.
Myofascial Pain Syndrome
Myofascial pain syndrome (MPS) is a common presenting clinical complaint of muscle pain caused by myofascial trigger points (MTPs). Even though it is a relatively common cause of chronic pain, there is a lack of accepted diagnostic criteria which leads to difficulty studying its epidemiology. MTPs can be found on physical examination by palpation of hyperirritable areas of taut bands of skeletal muscles that elicit referred pain when palpated. There are multiple treatments to include topical treatments, massage or stretching therapies, acupuncture, dry needling, and musculoskeletal injection therapies that include BoNT.
A 2014 Cochrane review of four studies with 244 patients comparing BoNT-A with placebo for the treatment of MPS found inconclusive evidence to support the use of BoNT-A for treatment of MPS (28). A 2015 randomized, double-blind, placebo-controlled study of 33 patients with 48 upper trapezius MTPs were randomized to 24 MTPs receiving 20 U of BoNT-A and 24 MTPs receiving a saline solution. The BoNT-A and placebo group had no statistically significant reduction in visual analog scale at 3- and 6-wk follow-ups, but there was a statistically significant reduction in pressure pain threshold at 6 wk without severe adverse events (29).
A 2016 systematic review and meta-analysis of 11 studies reviewed the efficacy of BoNT-A compared with placebo in the treatment of chronic head and neck MPS. The BoNT-A group demonstrated a significant reduction in pain at 2 months to 6 months, but not at 4 wk to 6 wk (30). A 2018 systematic review and meta-analysis of 33 studies compared the effectiveness of BoNT-A and local anesthetics on reduction in pain intensity in a patient with MPS for up to 24 wk. One article had a direct comparison, while 18 assessed local anesthetic and 16 addressed BoNT-A. BoNT-A results were inconsistent at mitigating pain at all follow-up periods. Local anesthetic injections were more effective than BoNT-A at reducing pain (31).
In refractory cases of MPS, BoNT-A demonstrated mixed results with no substantial evidence to suggest the use of BoNT-A over other therapies. In our practice, we utilize a series of musculoskeletal injections for MPS until complete symptom resolution. The injectates we use are lidocaine, marcaine, saline, and occasionally combine these treatments with triamcinolone. Further assessment is needed to enhance the quality of evidence for dosing, formulations, side effects, and long-term outcomes.
Off label use of BoNT-A in musculoskeletal disorders continues to expand in the literature. Appropriate patient selection and counseling are essential for off-label use of BoNT-A in musculoskeletal disorders to define treatment limitations and clear functional outcomes and goals. Currently, limited evidence supports the use of BoNT-A as a safe and effective CECS treatment. Literature illustrates promising pain relief and functional improvements in patients with plantar fasciopathy, osteoarthritis, and lateral epicondylosis. Evidence for the use of BoNT-A in MPS patients is inconclusive and, in most cases, is not superior to other injectates. Further research is required to provide stronger clinical recommendations for the use of BoNT in musculoskeletal conditions.
The views and opinions expressed in this article are those of the authors alone as individuals and do not reflect those of the Department of Defense, the United States Army, the United States Air Force, or the Uniformed Services University of the Health Sciences.
The authors declare no conflict of interest and do not have any financial disclosures.
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