Efficacy and Safety of Intra-Articular Botulinum Toxin A Injection for Knee Osteoarthritis: A Systematic Review, Meta-Analysis, and Meta-Regression of Clinical Trials : JBJS Open Access

Journal Logo

Advanced Search
Scientific Articles

Efficacy and Safety of Intra-Articular Botulinum Toxin A Injection for Knee Osteoarthritis

A Systematic Review, Meta-Analysis, and Meta-Regression of Clinical Trials

Ismiarto, Yoyos Dias MD, PhD1,a; Prasetiyo, Gregorius Thomas MD2

Author Information

1Division of Pediatric Orthopaedic Surgery, Department of Orthopaedics and Traumatology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia

2Department of Orthopaedics and Traumatology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia

aEmail for corresponding author: [email protected]; [email protected]

Investigation performed at the Universitas Padjadjaran, Bandung, Indonesia

Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (https://links.lww.com/JBJSOA/A460).

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

JBJS Open Access 8(1):e22.00121, January-March 2023. | DOI: 10.2106/JBJS.OA.22.00121
  • Open
  • SDC
  • Disclosures

Abstract

Osteoarthritis (OA) is a chronic degenerative joint disease that is commonly encountered in daily practice in older individuals and causes prolonged pain, decreased function, and disability1. In 2015, the World Health Organization estimated that 9.6% of men and 18% of women >60 years old around the world had symptomatic OA2. The prevalence of OA is predicted to reach 25% of the world population in 2040, resulting in a prominent socioeconomic burden in the next few decades3.

Also known as degenerative arthritis, this multifactorial disease is characterized by progressive joint degradation leading to permanent cartilage damage, subchondral bone sclerosis, and synovial inflammation4. The knees, which are the largest synovial joints in the human body, account for almost four-fifths of the total burden of OA worldwide, and the prevalence of knee OA increases with increasing patient obesity and age5. The pathological process in knee OA that results in pain, stiffness, and mobility limitations involves structural changes in and around the knee joint, especially cartilage damage and osteophyte formation, that affect knee function and result in inflammatory symptoms6.

Several modalities for treating knee OA are available, beginning with conservative management (e.g., physical exercise and weight control) and pharmacological treatment (e.g., acetaminophen) and ending with total knee replacement7. Historically, cyclooxygenase inhibitors such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) have been the drugs most frequently used for OA. However, long-term use of these drugs can result in gastrointestinal, renal, cardiovascular, and hematological adverse events8. If a patient does not respond to oral medications, then intra-articular injections may be considered9. It is hypothesized that topical treatment will result in fewer systemic adverse events, and injecting the drugs directly into the joint is expected to produce an immediate effect on the joint9. Intra-articular administration of several agents has been studied, and intra-articular therapy was often more effective than NSAIDs and other systemic pharmacological agents10. Initially, intra-articular injection of corticosteroids was introduced as an alternative to systemic administration. More recently, intra-articular viscosupplementation with hyaluronic acid and regenerative treatments were introduced10.

Although initially intended to be used as a treatment for strabismus, botulinum toxin A is now widely used for various purposes, and in-depth research has been performed11. Botulinum toxin A can cause muscle paralysis by inhibiting the production of acetylcholine at the neuromuscular junction11. Inhibitory effects on neuropeptide secretion and suppression of inflammation by botulinum toxin A have also been shown to possibly produce an analgesic effect in several studies12. Previous meta-analyses published in 2017 and 2018 demonstrated that intra-articular injections of botulinum toxin A may improve pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores better than placebo in adult patients with refractory joint pain13,14. However, the evidence regarding the efficacy and safety of intra-articular botulinum toxin A injections for knee OA remains unclear. The aim of the present systematic review and meta-analysis was therefore to perform an up-to-date evaluation of the efficacy and safety of botulinum toxin A for the management of knee OA.

Materials and Methods

Eligibility Criteria

The inclusion criteria for this study, reported on the basis of the PICOS formulation, were as follows. Participants: patients diagnosed with knee OA of any grade. Intervention: intra-articular injection at the knee joint using a 100 to 200-IU dose of botulinum toxin A. Comparison: injections containing placebo such as 0.9% saline solution or education only without any injections. Outcomes: reductions (from baseline) in early visual analog scale (VAS) pain (at ≤4 weeks), late VAS pain (at >4 weeks), early WOMAC (at ≤4 weeks), and late WOMAC scores (at >4 weeks), and any adverse events resulting from the intervention. Studies: randomized clinical trials.

The following were exclusion criteria: (1) studies of children (<18 years old); (2) studies of pregnant women; (3) studies without a control or comparison group; (4) observational (cohort, case-control, cross-sectional) studies, case series, and case reports; (5) non-primary studies (review articles, correspondence, editorials); and (6) studies not available in the English language.

Literature Search and Study Selection

Four databases (Europe PMC [PubMed Central], Scopus, PubMed, and ClinicalTrials.gov) were searched for English-language articles until September 10, 2022, with the following keywords: “(knee osteoarthritis OR OA knee OR gonarthrosis OR genu osteoarthritis OR OA genu) AND (botulinum toxin OR botox OR BTX OR BoNT OR dysport) AND (clinical trials OR randomized trials OR RCT).” Additional details regarding the search strategies used with each study database are shown in Appendix Supplementary Table 1. Screening of titles and abstracts was carried out independently by 2 reviewers to identify eligible studies. The reference lists of the eligible studies were also evaluated for additional potentially relevant articles. All duplicates were removed. The same 2 reviewers then evaluated the remaining full-text articles for eligibility on the basis of the inclusion and exclusion criteria; any discrepancies were resolved through discussion. The results were compiled in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline15.

Data Extraction

Two reviewers extracted the author names, year of publication, study design, outcomes of interest, and the following sample characteristics: sample size, age, gender, body mass index (BMI), Kellgren-Lawrence grade, and dose of botulinum toxin.

The following outcomes of interest were analyzed: reductions (from baseline) in early and late VAS pain and WOMAC scores, and any adverse events resulting from the intervention. Early and late time intervals were defined as ≤4 and >4 weeks after surgery, respectively. The early reduction was thus defined as the score reported up to 4 weeks after the injection minus the score at baseline, and the late reduction was defined as the score at >4 weeks minus the baseline score. A VAS with a score ranging from 0 (no pain) to 10 (unbearable pain) has been shown to be a valid and reliable measure for pain16. The WOMAC index is a disease-specific, self-administered instrument for patients with OA of the knee or hip17. The score has 3 dimensions (with a total of 24 individual scenarios) that measure pain (5 scenarios), stiffness (2 scenarios), and physical function (17 scenarios). These results are scored on scales of 0 to 20 for pain, 0 to 8 for stiffness, and 0 to 68 for physical function. A higher score on a scale indicates greater pain, stiffness, or physical dysfunction.

Risk-of-Bias Assessment

Two reviewers assessed the risk of bias in each included clinical trial using the Risk of Bias version 2 (RoB v2) tool from the Cochrane Collaboration11,18. This tool assesses 5 domains: the randomization process, deviations from the intended intervention, missing outcome data, measurement of the outcomes, and selection of the reported results. The results for these 5 domains classify the risk of bias in a randomized clinical trial (RCT) as low if all domains are rated as having a low risk of bias, as having some concern if ≥1 domains have some concern regarding bias, and as high if ≥1 domains have a high risk of bias11,18.

Statistical Analysis

Outcomes consisting of continuous variables were analyzed using the inverse-variance method to obtain the standardized mean difference (SMD) and accompanying 95% confidence interval (CI). Random-effect modeling was used, as heterogeneity due to differences in the botulinum toxin dose and in the OA grading among the included studies was expected. Heterogeneity was assessed using the I2 (inconsistency) value; ≤25%, 26% to 50%, and >50% were categorized as low, moderate, and high heterogeneity, respectively11. Data that had been reported as the median and interquartile range or as the median, minimum, and maximum were converted to the mean and standard deviation (SD) using the formula from Wan et al.19. Meta-regression with a random-effect model using the restricted maximum likelihood was performed for age, gender, BMI, and Kellgren-Lawrence grade to assess the effect of the interaction between botulinum toxin A injection and each of these prespecified variables on the outcomes of interest. Funnel plots were utilized to provide a qualitative assessment of the risk of publication bias.

Source of Funding

This study did not receive any external funding.

Results

Study Selection and Characteristics

A total of 537 studies were found in the PubMed, Scopus, Europe PMC, and ClinicalTrials.gov databases. After removing duplicates and screening on the basis of the titles and abstracts, 517 articles were eliminated, and the remaining 20 articles underwent full-text review to assess their eligibility. Fourteen of the 20 articles were eliminated because the population was not specifically patients with knee OA (5 articles), other well-known therapeutic agents such as corticosteroids or hyaluronic acid were used in the comparison group (5 articles), the study did not have a control group (1 article), or the study was not an RCT (3 articles). The remaining 6 studies20-25, with a total of 446 patients with knee OA, were analyzed (Fig. 1). Of these 6 RCTs, 3 had a double-blinded design, 2 had a single-blinded design, and the remaining article did not provide sufficient information to determine whether it was a single-blinded or open-label (unblinded) RCT. The number of participants in the included studies ranged from 40 to 132. Most of the participants in the included studies had Kellgren-Lawrence grade-II or III knee OA. All of the included studies used 100 to 200 IU of botulinum toxin A injected intra-articularly into the knee joint, usually with ultrasound guidance. Details regarding the characteristics of each included study are shown in Table I.

F1
Fig. 1:
PRISMA diagram showing the selection of studies for inclusion in the systematic review and meta-analysis.
TABLE I - Characteristic of the Included Studies*
Study Design Population Intervention Comparison
Sample Size Age† (yr) Male BMI† (kg/m 2 ) Kellgren–Lawrence Grade
Arendt-Nielsen 20 (2017) Double-blinded RCT 121 62.3 ± 8.6 48.7% 28 ± 3.9 9.1% I, 62% II, 28.9% III 200 IU botulinum toxin A, single dose into patellofemoral space using ultrasound guidance Placebo (2 mL of 0.9% saline solution)
Bao 21 (2018) Single-blinded RCT 40 65.8 ± 3.5 47.5% NA 65% II, 32.5% III, 2.5% IV 100 IU botulinum toxin A, single dose into suprapatellar bursa using ultrasound guidance Placebo (2.5 mL of 0.9% saline solution)
Hsieh 22 (2016) Prospective RCT 41 67.9 ± 6.8 39% 27.4 ± 3.7 2.4% I, 29.3% II, 63.4% III, 4.9% IV 100 IU botulinum toxin A, single dose at junction of upper one-third and lower two-thirds of patella without ultrasound guidance Education only
Mahowald 23 (2009) Single-blinded RCT 42 NA NA NA NA 100 IU botulinum toxin A + lidocaine, single dose Placebo (saline solution + lidocaine)
McAlindon 24 (2018) Double-blinded RCT 132 60.8 ± 7.9 41.6% 31 ± 6.1 56% II, 44% III 200 IU botulinum toxin A, single dose injected intra-articularly using ultrasound guidance Placebo (2 mL of 0.9% saline solution)
Mendes 25 (2019) Double-blinded RCT 70 63.5 ± 6.7 7.1% 30.4 ± 5 55.7% II, 44.3% III 100 IU botulinum toxin A, single dose 2 cm from superolateral angle of patella Placebo (2 mL of 0.9% saline solution)
*BMI = body mass index, RCT = randomized clinical trial, NA = not available.
†The values are given as the mean ± standard deviation.

Study Quality

The RoB v2 tool categorized 4 of the 6 included trials as having a low risk of bias in all 5 domains. The remaining 2 trials had some concerns regarding the risk of bias because the outcome measurement information was not clear enough to establish that it was collected in a blinded fashion and thus free from the possibility of manipulation (Table II).

TABLE II - Risk-of-Bias Assessment of the Included Studies*
Study Randomization Process Deviations from Intended Interventions Missing Outcome Data Measurement of the Outcome Selection of the Reported Result Overall
Arendt-Nielsen 20 (2017) Low risk Low risk Low risk Low risk Low risk Low risk
Bao 21 (2018) Low risk Low risk Low risk Low risk Low risk Low risk
Hsieh 22 (2016) Low risk Low risk Low risk Some concerns Low risk Some concerns
Mahowald 23 (2009) Low risk Low risk Low risk Some concerns Low risk Some concerns
McAlindon 24 (2018) Low risk Low risk Low risk Low risk Low risk Low risk
Mendes 25 (2019) Low risk Low risk Low risk Low risk Low risk Low risk
*Using the RoB v2 tool.

Botulinum Toxin Versus Control

Reduction in Early VAS Pain

Six studies (n = 446 patients with knee OA) reported on early VAS pain. The pooled analysis showed that intra-articular injection of botulinum toxin A was associated with a greater reduction in the VAS pain score from baseline to ≤4 weeks postoperatively than in the control group (SMD, −0.63 [95% CI, −1.08 to −0.18], p = 0.007, I2 = 79%, random-effect modeling) (Fig. 2-A).

F2
Fig. 2:
Forest plots showing the comparison between intra-articular injection of botulinum toxin A (Botox A) and placebo in patients with knee OA: reduction in VAS pain scores at early time points (Fig. 2-A), reduction in VAS pain scores at late time points (Fig. 2-B), reduction in WOMAC scores at early time points (Fig. 2-C), and reduction in WOMAC scores at late time points (Fig. 2-D). df = degrees of freedom and IV = inverse variance.

Reduction in Late VAS Pain

Five studies (n = 404 patients with knee OA) reported on late VAS pain. The pooled analysis showed that intra-articular botulinum toxin A injection was associated with a greater reduction in the VAS pain score from baseline to >4 weeks postoperatively than in the control group (SMD, −0.57 [95% CI, −1.07 to −0.08], p = 0.02, I2 = 81%, random-effect modeling) (Fig. 2-B).

Reduction in Early WOMAC

Five studies (n = 325 patients with knee OA) reported on the early WOMAC score. The pooled analysis showed that intra-articular botulinum toxin A injection was associated with a greater reduction in the WOMAC score from baseline to ≤4 weeks postoperatively than in the placebo group (SMD, −0.84 [95% CI, −1.61 to −0.06], p = 0.03, I2 = 90%, random-effect modeling) (Fig. 2-C).

Reduction in Late WOMAC

Six studies (n = 446 patients with knee OA) reported on the late WOMAC score. The pooled analysis showed that intra-articular botulinum toxin A injection was associated with a greater reduction in the WOMAC score from baseline to >4 weeks postoperatively than in the control group (SMD, −1.12 [95% CI, −1.91 to −0.32], p = 0.006, I2 = 93%, random-effect modeling) (Fig. 2-D).

Adverse Events

Four of the 6 studies reported safety outcomes for intra-articular botulinum toxin A injection. In 1 study24, the most commonly reported adverse events were arthralgia (20.9%), joint swelling (9.3%), hypertension (7%), and nasopharyngitis (4.7%); however, there were no significant differences in these adverse events compared with the control group. The remaining 3 studies20,23,25 reported no adverse events associated with the intra-articular botulinum toxin A injection.

Meta-Regression

Meta-regression was used to identify factors that influenced the relationship between intra-articular botulinum toxin A injection and each outcome of interest. Variability in those outcomes in patients with knee OA receiving botulinum toxin A treatment can be explained by patient factors that are known to be predictors of the outcomes of treatment (see Appendix Supplementary Table 2). The meta-regression analysis revealed that the association between intra-articular botulinum toxin A injection and the reduction in the VAS pain score at ≤4 weeks in patients with knee OA was significantly influenced by age (beta coefficient = −0.2046 [95% CI, −0.3332 to −0.0760], p = 0.0018) (see Appendix Supplementary Fig.1-A) but was not influenced by gender (p = 0.4383), BMI (p = 0.1382), or Kellgren-Lawrence grade (p = 0.2267) (see Appendix SupplementaryFigs. 1-B, 1-C, and 1-D). The reduction in the VAS pain score at >4 weeks was also significantly influenced by age (beta = −0.1858 [95% CI, −0.3570 to −0.0145], p = 0.0335) (see Appendix Supplementary Fig. 2-A) and BMI (beta = 0.1759 [95% CI, 0.0321 to 0.3196], p = 0.0165) (see Appendix Supplementary Fig. 2-B) but not by gender (p = 0.3584) or Kellgren-Lawrence grade (p = 0.9226) (see Appendix Supplementary Figs. 2-C and 2-D).

The meta-regression analysis also revealed that the association between intra-articular botulinum toxin A injection and the reduction in the WOMAC score at ≤4 weeks was not significantly influenced by age (p = 0.2186), gender (p = 0.3442), or Kellgren-Lawrence grade (p = 0.7861) in patients with knee OA (see Appendix Supplementary Figs. 3-A, 3-B, and 3-C). The influence of BMI on this outcome of interest could not be analyzed because of insufficient data in the included studies. The reduction in the WOMAC score at >4 weeks was significantly influenced by BMI (beta = 0.1968 [95% CI, 0.0534 to 0.3401], p = 0.0071) (see Appendix Supplementary Fig. 4-A) but not by age (p = 0.3522), gender (p = 0.4919), or Kellgren-Lawrence grade (p = 0.5332) (see Appendix Supplementary Figs. 4-B, 4-C, and 4-D).

Publication Bias

Because publication bias in reviews of ≤10 studies is hampered by the resulting lack of power, making the results less reliable26,27, it was not assessed in the current analysis of 6 studies.

Discussion

The pooled analyses in this study revealed that intra-articular injection of botulinum toxin A (at a dose of 100 to 200 IU) was associated with greater reductions, compared with the control group, in the VAS pain score at ≤4 weeks, VAS pain score at >4 weeks, WOMAC score at ≤4 weeks, and WOMAC score at >4 weeks in patients with knee OA. The relationships of intra-articular botulinum toxin A injection with reductions in VAS pain scores at early and late time points were significantly influenced by age, and the latter was also influenced by BMI. The meta-regression analysis indicated that BMI significantly influenced the relationship between botulinum toxin A injection and the reduction in the WOMAC score at late time points. In addition to its effectiveness in improving pain, intra-articular administration of botulinum toxin A in patients with knee OA was also relatively safe; no serious adverse events or mortality were reported.

Numerous recent studies have indicated that OA has an inflammatory component, rather than being simply a non-inflammatory degenerative joint disease28,29. Inflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α, chemokines, and other inflammatory mediators produced by the synovium and chondrocytes can be detected in the synovial fluid of patients with OA28,29. Joint structures contain Aδ, Aβ, and C nerve fibers whose excitation threshold becomes lower in cases of injury and inflammation. Aδ fibers may be sensitized by TNF-α, while C fibers may be sensitized by TNF-α, IL-6, IL-1β, or IL-17A, in response to innocuous or noxious mechanical stimuli30,31. Neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) also play an important role in pain generation at locations outside the spine through sensitization of nerves and nociceptors (peripheral sensitization)32. Chronic joint inflammation is also associated with hyperexcitability of spinal nociceptive neurons (central sensitization)33,34.

Botulinum toxin A may counteract and inhibit these peripheral and central sensitization processes, thereby modulating the pain resulting from OA. Release of substance P from dorsal-root ganglion neurons and stimulated release of CGRP from trigeminal ganglion neurons have been shown to be inhibited by the administration of botulinum toxin A35,36. Studies have also shown that botulinum toxin A may reduce the expression of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, dampening the inflammatory process and reducing pain propagation resulting from peripheral stimuli35,37,38. These reductions in peripheral sensitization and afferent input to the spinal cord from peripheral nerve endings may indirectly decrease the central sensitization process. Botulinum toxin A may also be transported along the axon in a retrograde manner and modulate neuronal activity in the central nervous system through stimulation of inhibitory gamma-amino butyric acid (GABA)-A receptors and μ opioid receptors in the spinal cord12,39,40. All of these properties of botulinum toxin A may explain why administration of this toxin is able to reduce pain in patients with knee OA.

This study has several limitations. First, available data regarding botulinum toxin injection for the management of knee OA are limited, and our results are therefore based on a relatively small number of clinical trials. Second, notable heterogeneity was seen in some of the outcomes of interest in the study, which can have resulted from differences in the botulinum toxin A dosage and in the proportions of Kellgren-Lawrence grades of knee OA. Third, several of the clinical trials included in this study have some concern regarding bias, primarily because of a lack of blinding during measurement of the outcomes. Finally, the total cost of using intra-articular botulinum toxin A injection for knee OA could not be analyzed because cost data were lacking in the included studies. The high cost of botulinum toxin injection11 is a major concern regarding this potential treatment for knee OA.

In conclusion, this systematic review and meta-analysis suggests that intra-articular injection of botulinum toxin A may improve OA symptoms better than placebo does in patients with knee OA, as evidenced by greater reductions in both the VAS pain and WOMAC scores. Larger, well-conducted RCTs are warranted to confirm the results of this study.

Appendix

Supporting material provided by the authors is posted with the online version of this article as a data supplement at jbjs.org (https://links.lww.com/JBJSOA/A461).

References

1. Buckwalter JA, Saltzman C, Brown T. The impact of osteoarthritis: implications for research. Clin Orthop Relat Res. 2004 Oct;(427)(Suppl):S6-15.
2. Zhang Y, Niu J. Editorial: Shifting Gears in Osteoarthritis Research Toward Symptomatic Osteoarthritis. Arthritis Rheumatol. 2016 Aug;68(8):1797-800.
3. Hootman JM, Helmick CG, Barbour KE, Theis KA, Boring MA. Updated Projected Prevalence of Self-Reported Doctor-Diagnosed Arthritis and Arthritis-Attributable Activity Limitation Among US Adults, 2015-2040. Arthritis Rheumatol. 2016 Jul;68(7):1582-7.
4. Herrero-Beaumont G, Roman-Blas JA, Castañeda S, Jimenez SA. Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics. Semin Arthritis Rheum. 2009 Oct;39(2):71-80.
5. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016 Oct 8;388(10053):1545-602.
6. Dell’Isola A, Allan R, Smith SL, Marreiros SS, Steultjens M. Identification of clinical phenotypes in knee osteoarthritis: a systematic review of the literature. BMC Musculoskelet Disord. 2016 Oct 12;17(1):425.
7. Nelson AE, Allen KD, Golightly YM, Goode AP, Jordan JM. A systematic review of recommendations and guidelines for the management of osteoarthritis: The chronic osteoarthritis management initiative of the U.S. Bone and Joint Initiative. Semin Arthritis Rheum. 2014 Jun;43(6):701-12.
8. Jevsevar DS. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013 Sep;21(9):571-6.
9. Testa G, Giardina SMC, Culmone A, Vescio A, Turchetta M, Cannavò S, Pavone V. Intra-Articular Injections in Knee Osteoarthritis: A Review of Literature. J Funct Morphol Kinesiol. 2021 Feb 3;6(1):15.
10. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015 Jan 6;162(1):46-54.
11. Lie H, Lukito PP, Sudirman T, Purnama AA, Sutedja R, Setiawan A, Jeo WS, Irawan A, Satriya W, Koerniawan HS, Hariyanto TI. Utility of botulinum toxin injection for post-operative pain management after conventional hemorrhoidectomy: a systematic review and meta-analysis of clinical trials. Scand J Gastroenterol. 2022 Sep 1:1-7.
12. Kumar R. Therapeutic use of botulinum toxin in pain treatment. Neuronal Signal. 2018 Aug 31;2(3):NS20180058.
13. Courseau M, Salle PV, Ranoux D, de Pouilly Lachatre A. Efficacy of Intra-Articular Botulinum Toxin in Osteoarticular Joint Pain: A Meta-Analysis of Randomized Controlled Trials. Clin J Pain. 2018 Apr;34(4):383-9.
14. Wu T, Song HX, Dong Y, Ye Y, Li JH. Intra-articular injections of botulinum toxin A for refractory joint pain: a systematic review and meta-analysis. Clin Rehabil. 2017 Apr;31(4):435-43.
15. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;372(71):n71.
16. Haefeli M, Elfering A. Pain assessment. Eur Spine J. 2006 Jan;15(Suppl 1)(Suppl 1):S17-24.
17. Roos EM, Klässbo M, Lohmander LS. WOMAC osteoarthritis index. Reliability, validity, and responsiveness in patients with arthroscopically assessed osteoarthritis. Western Ontario and MacMaster Universities. Scand J Rheumatol. 1999;28(4):210-5.
18. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM, Emberson JR, Hernán MA, Hopewell S, Hróbjartsson A, Junqueira DR, Jüni P, Kirkham JJ, Lasserson T, Li T, McAleenan A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K, White IR, Whiting PF, Higgins JPT. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898.
19. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014 Dec 19;14:135.
20. Arendt-Nielsen L, Jiang GL, DeGryse R, Turkel CC. Intra-articular onabotulinumtoxinA in osteoarthritis knee pain: effect on human mechanistic pain biomarkers and clinical pain. Scand J Rheumatol. 2017 Jul;46(4):303-16.
21. Bao X, Tan JW, Flyzik M, Ma XC, Liu H, Liu HY. Effect of therapeutic exercise on knee osteoarthritis after intra-articular injection of botulinum toxin type A, hyaluronate or saline: A randomized controlled trial. J Rehabil Med. 2018 Jun 15;50(6):534-41.
22. Hsieh LF, Wu CW, Chou CC, Yang SW, Wu SH, Lin YJ, Hsu WC. Effects of Botulinum Toxin Landmark-Guided Intra-articular Injection in Subjects With Knee Osteoarthritis. PM R. 2016 Dec;8(12):1127-35.
23. Mahowald ML, Krug HE, Singh JA, Dykstra D. Intra-articular Botulinum Toxin Type A: a new approach to treat arthritis joint pain. Toxicon. 2009 Oct;54(5):658-67.
24. McAlindon TE, Schmidt U, Bugarin D, Abrams S, Geib T, DeGryse RE, Kim K, Schnitzer TJ. Efficacy and safety of single-dose onabotulinumtoxinA in the treatment of symptoms of osteoarthritis of the knee: results of a placebo-controlled, double-blind study. Osteoarthritis Cartilage. 2018 Oct;26(10):1291-9.
25. Mendes JG, Natour J, Nunes-Tamashiro JC, Toffolo SR, Rosenfeld A, Furtado RNV. Comparison between intra-articular Botulinum toxin type A, corticosteroid, and saline in knee osteoarthritis: a randomized controlled trial. Clin Rehabil. 2019 Jun;33(6):1015-26.
26. Thornton A, Lee P. Publication bias in meta-analysis: its causes and consequences. J Clin Epidemiol. 2000 Feb;53(2):207-16.
27. Terrin N, Schmid CH, Lau J, Olkin I. Adjusting for publication bias in the presence of heterogeneity. Stat Med. 2003 Jul 15;22(13):2113-26.
28. Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol. 2011 Sep;23(5):471-8.
29. Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. 2010 Nov;6(11):625-35.
30. Richter F, Natura G, Löser S, Schmidt K, Viisanen H, Schaible HG. Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. Arthritis Rheum. 2010 Dec;62(12):3806-14.
31. Syx D, Tran PB, Miller RE, Malfait AM. Peripheral Mechanisms Contributing to Osteoarthritis Pain. Curr Rheumatol Rep. 2018 Feb 26;20(2):9.
32. Schaible HG, Schmelz M, Tegeder I. Pathophysiology and treatment of pain in joint disease. Adv Drug Deliv Rev. 2006 May 20;58(2):323-42.
33. Hassan H, Walsh DA. Central pain processing in osteoarthritis: implications for treatment. Pain Manag. 2014 Jan;4(1):45-56.
34. Lluch E, Torres R, Nijs J, Van Oosterwijck J. Evidence for central sensitization in patients with osteoarthritis pain: a systematic literature review. Eur J Pain. 2014 Nov;18(10):1367-75.
35. Lora VR, Clemente-Napimoga JT, Abdalla HB, Macedo CG, Canales GT, Barbosa CM. Botulinum toxin type A reduces inflammatory hypernociception induced by arthritis in the temporomadibular joint of rats. Toxicon. 2017 Apr;129:52-7.
36. Arezzo JC. Possible mechanisms for the effects of botulinum toxin on pain. Clin J Pain. 2002 Nov-Dec;18(6)(Suppl):S125-32.
37. Ham HJ, Yeo IJ, Jeon SH, Lim JH, Yoo SS, Son DJ, Jang SS, Lee H, Shin SJ, Han SB, Yun JS, Hong JT. Botulinum Toxin A Ameliorates Neuroinflammation in the MPTP and 6-OHDA-Induced Parkinson’s Disease Models. Biomol Ther (Seoul). 2022 Jan 1;30(1):90-7.
38. Fang B, Xie Y, Shan S, Zhou J. Botulinum Toxin Type A Attenuates Hypertrophic Scars Formation by Preventing Macrophage M1 Polarization. Plast Reconstr Surg Glob Open. 2019 Sep 10;7(8 Suppl):118.
39. Drinovac V, Bach-Rojecky L, Lacković Z. Association of antinociceptive action of botulinum toxin type A with GABA-A receptor. J Neural Transm (Vienna). 2014 Jun;121(6):665-9.
40. Drinovac V, Bach-Rojecky L, Matak I, Lacković Z. Involvement of μ-opioid receptors in antinociceptive action of botulinum toxin type A. Neuropharmacology. 2013 Jul;70:331-7.

Supplemental Digital Content

Copyright © 2023 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.