Botulinum Toxins for Treatment of Pain in Orthopedic Disorders

(1)

Botulinum Toxin Treatment Program, Yale School of Medicine, New Haven, CT, USA

Abstract

Chronic pain is a major issue in many orthopedic disorders. With the discovery of analgesic effects of botulinum neurotoxins (BoNTs), there is an emerging interest in exploring the potential role for BoNTs in relieving orthopedic pain.

In this chapter, the data on BoNT therapy in four orthopedic disorders for which placebo-controlled studies are available are presented. These disorders consist of chronic lateral epicondylitis, painful local arthritis, refractory pain after total knee arthroplasty, and anterior knee pain related to vastus lateralis imbalance. Using the recommendations of the Assessment Subcommittee of the American Academy of Neurology, an evidence-based level of efficacy is defined for each condition.

The level of evidence for chronic lateral epicondylitis is B (probably effective) based on one class I and two class II studies. It is level C (possibly effective) for both refractory pain after total knee arthroplasty and local painful arthritis and anterior knee pain related to vastus lateralis imbalance (each with one class II study). While these positive data are encouraging, better designed, high-quality, and controlled studies (class I and II) are needed for optimal definition of the analgesic role of botulinum neurotoxins in orthopedic disorders.

Keywords

Lateral epicondylitisTennis elbowAnterior knee painPatellofemoral syndromeOsteoarthritisArthritisBotulinum toxinBotulinum neurotoxinOnabotulinumtoxinAAbobotulinumtoxinAIncobotulinumtoxinARimabotulinumtoxinB

Introduction

Over the past 15 years, a variety of communications have drawn attention to the usefulness of botulinum neurotoxin (BoNT) therapy in orthopedic conditions with refractory pain. In this chapter, we will discuss four such disorders in which blinded, placebo-controlled studies and case series have suggested the efficacy of BoNTs. These consist of chronic lateral epicondylitis, refractory pain after total knee arthroplasty (TKA), chronic joint pain related to arthritis, and anterior knee pain with vastus lateralis imbalance.

Chronic Lateral Epicondylitis

Lateral epicondylitis (LE) is a clinical condition characterized by pain in the elbow related to overuse of the joint commonly noted among athletes (tennis elbow) or heavy workers (Ahmad et al. 2013). Currently, it is believed that degeneration of the extensor tendons is responsible for the clinical symptoms (Nishl and Ashman 2003), although the role of inflammation is still debated despite paucity of pathological evidence. The concept of tendinopathy and tendon degeneration is supported by ultrasound examination of the affected joints (Connel et al. 2001). Lateral epicondylitis is a common disorder with a prevalence of 4–7/1,000 patients per year (Hamilton 1986; Verhaar 1994). In clinical practice, patients with acute LE recover within 12 months (83 % in one observation—Smidt et al. 2002). The small percentage that evolves into the chronic form (CLE) is often resistant to pharmacotherapy. Treatment of CLE includes avoiding exposure of the affected elbow to heavy load, bracing, physical therapy, pharmacotherapy, and surgery. Pharmacotherapy encompasses commonly used analgesic medications: cyclooxygenase inhibitors, nonsteroidal anti-inflammatory drugs, GABAergic analgesics (gabapentin and pregabalin), and, in more severe cases, opioid analgesics. Injection therapy introduces steroid and no-steroid drugs into the painful region. Krogh et al. (2013) recently reviewed the world literature on injection therapy for CLE. Of the 141 clinical trials (RTC), 17 studies were chosen for final meta-analysis: 10 corticosteroids, 4 botulinum toxins, 3 autologous blood, 2 PRP, and 1 each for hyaluronic acid, prolotherapy, polidocanol, and glycosaminoglycan polysulfate. Although most of these studies strongly suggested efficacy, the authors concluded that presence of high state of bias rendered interpretation of the data difficult in most of the studies; a number of factors such as assessor or patient blinding, allocation concealment, selection or attrition reporting, and company’s interest were the areas of concern.

Botulinum Neurotoxin Studies in CLE

Of the five reported RTCs in CLE, four were blinded and placebo controlled and one was a blinded but a comparator study.

Placebo-Controlled Studies

Wong et al. (2005) evaluated the efficacy of abobotulinumtoxinA (aboA) in 60 subjects (49 women) with CLE in a double-blind, placebo-controlled study. The primary outcome was reduction of pain in VAS (0–100 mm) at weeks 4 and 12. Handgrip strength was the secondary outcome. The toxin group received 60 units of aboA diluted in 1 cc of normal saline. The injections (saline or toxin) were administered “deeply into the subcutaneous tissue and muscle,” 1 cm from the lateral epicondyle, and were aimed toward the tender spot.

The mean VAS scores for the botulinum group at baseline and at 4 weeks were 65.5 and 25.3 mm, respectively. For the placebo group, the VAS scores were 66.2 and 50.5 mm at the same time points, denoting a significant improvement in favor of the toxin (p < 0.001). At week 12, the mean VAS scores were 23.5 mm for the botulinum group and 43.5 mm for the placebo group, again supporting an analgesic effect for aboA (p = 0.006). The grip strength decreased slightly in both groups, but the difference between the two groups was not statistically significant. At 4 weeks, four patients on aboA experienced paralysis of finger extension.

In another blinded and controlled study, Hayton et al. (2005) compared the effect of abobotulinumtoxinA (50 units) with saline in 40 patients with CLE who had failed to respond to steroid therapy. The injections were intramuscular and performed 5 cm distal to the maximum point of tenderness at the lateral epicondyle, in line with the middle of the wrist. Investigators assessed pain with the visual analog scale, the quality of life with short-form SF12, and handgrip with Jamar dynamometer before injection and 3 months after injection. They found no difference between the toxin and the placebo with the aforementioned assessments at 3 months.

Placzek et al. (2007) conducted a multicenter, double-blinded, placebo-controlled RTC in 130 patients with CLE. The toxin group received 60 units of abobotulinumtoxinA diluted in 0.6 cc of saline (0.9 %). The control group received the same volume of saline. The solution (toxin or saline) was injected 3–4 cm distal to the tender epicondyle and at two locations reflecting different depths after partial withdrawal of the needle following injection of one half of the solution. The level of pain was assessed by VAS at baseline (before injection) and at 2, 6, 12, and 18 weeks. Patients’ and physician’s satisfaction were measured on a score of 0 (substantially worse) to 4 (substantially better) at the same time points. The strength of finger extension was also measured by a vigorimeter in all patients. Injection of aboA resulted in significant improvement of pain at all weeks after injection (2, 6, 12, and 18—p < 0.05) (Table 14.1).

Table 14.1

Comparison of clinical pain scores between groups

Visit	Score^a
Visit	Botulinum	Placebo	p value^b
Injection	8.43 ± 0.24 (68)	8.55 ± 0.21 (62)	0.920
Week 2	5.24 ± 0.38 (68)	6.85 ± 0.35 (61)	0.003
Week 6	4.53 ± 0.37 (68)	5.69 ± 0.37 (61)	0.020
Week 12	3.76 ± 0.36 (68)	5.02 ± 0.41 (61)	0.023
Week 18	2.88 ± 0.35 (68)	4.29 ± 0.41 (57)	0.009

From Placzek et al. (2007). Printed with permission from the Journal of Bone and Joint Surgery

^aThe values are given as the mean clinical pain score and the standard error of the mean with the number of patients in parentheses

^bThe level of significance of the difference between the botulinum and placebo groups as assessed with the Mann–Whitney U test

Espandar et al. (2010) conducted a randomized placebo-controlled study of 48 patients with chronic refractory lateral epicondylitis. The patients in the toxin group received 60 units of abobotulinumtoxinA, and the control group received the same volume of normal saline. The site of injection was chosen based on prior studies on cadavers (Liu et al. 1997), 33 % of the arm length below the lateral epicondyle. In most individuals, the posterior interosseous nerve innervates the extensor carpi ulnaris and extensor digitorum at this point. The primary outcome was intensity of pain at rest measured by VAS (0–100 mm) at 4, 8, and 16 weeks after injection. Secondary outcomes included intensity of pain during maximum pinch, maximum handgrip, and grip strength. The aboA group showed significant reduction of pain at rest compared to the placebo group at 4 weeks (14.1 mm), at 8 weeks (11.5 mm), and at 16 weeks (12.6 mm) (p = 0.01). Among the secondary outcomes, the intensity of pain during the maximum pinch was also decreased significantly in the aboA group compared to controls (p = 0.004). All patients in the toxin group developed some weakness of finer extensors which resolved by week 8. In one patient, weakness of the third and fourth fingers which had developed at week 4 resolved by week 16.

Comparator Study

Lin et al. (2010) compared the effect of 50 units of onabotulinumtoxinA (onaA) with steroid injection (40 mg of triamcinolone acetonide) in a small double-blind study of 16 patients with CLE. The onaA and triamcinolone were injected into the extensor carpi radialis brevis near the common origin of the wrist and finger extensors of the affected elbow. The level of pain, handgrip, and quality of life were assessed with VAS, dynamometer, and the World Health Organization’s brief questionnaire at baseline, 4, 8, and 12 weeks. Both onabotulinumtoxinA and triamcinolone improved pain at 4, 8, and 12 weeks. At 4 weeks, the analgesic effect of triamcinolone was greater than aboA (0.02), but as time went on, there was a trend for onaA to have more analgesic effect. The strength of handgrip was mildly diminished in the onaA group. No other side effects were noted. BoNT studies in CLE are summarized in Table 14.2.

Table 14.2

Blinded studies of BoNT-A in chronic lateral epicondylitis

Study	Class	# of pts	Type	Toxin	Dose (u)	PO at week(s)	SO	Results
Wong et al. (2005)	II	60	DBPC	AboA	60	VAS: 12	Handgrip	p < 0.001 (VAS)
Hayton et al. (2005)	II	40	DBPC	AboA	50	VAS	SF12, handgrip	NS
Placzek et al. (2007)	I	130	DBPC	AboA	60	VAS: 2, 6, 12, 16	PPS	p < 0.05—VAS all weeks, PPS p < 0.05
Espandar et al. (2010)	II	48	DBPC	AboA	60	VAS: 4, 8, 16 MP, MG		p = 0.01 (VAS) p = 0.04 (MP)
Lin et al. (2010)	II	16	Comp	OnaA and triamcinolone	50	VAS: 4, 8, 12		p = 0.02 (VAS) week 4 triamcinolone > onaA