Research on injections for ankle pain

Marc Darrow, MD, JD.

In our practice we see many people with chronic ankle sprain who have a medical history including numerous ankle arthroscopic procedures. They will usually contact out office looking for options to their next surgery which would be an ankle fusion or a total ankle replacement. Why? Because chronic ankle instability is very common and unfortunately prone to re-injury or recurrent problems. Usually, someone being told they need one more surgery will lead these people to more exhaustively research alternatives. This includes the various types of ankle injections.

A July 2020 paper (1) compared various medicine injection treatments for ankle pain caused by osteochondral lesions (loss of cartilage leading to a bone on bone situation) and osteoarthritis. The injection treatments included were hyaluronic acid, Platelet-rich plasma (PRP), saline, methylprednisolone (steroid), botulinum toxin type A, mesenchymal stem cells (MSCs), and prolotherapy.

This was a review study where researchers combined studies and the study data to form an opinion on which of these treatments would work best. The problem with the results of this study? There were not enough studies of good evidence in direct comparisons of ALL the treatments for the researchers to review to give any opinion.

Also in 2020, (2) research lead by Harvard Medical School wrote: “Injection therapy may provide pain relief and improvement in the clinical condition but they do not come without certain limitations including potential failure. In the event that injections are not beneficial for the discussed syndromes, evaluation for surgical intervention may need to be obtained. While there appears to be positive outcomes due to injection-based treatment in small-scale trials, further studies are needed to evaluate the positive effects of injection-based treatment for chronic foot and ankle pain.”

A 2022 paper (3) followed up on this research to suggest: “The best evidence is currently available for viscosupplementation but the study situation for the use of platelet-rich plasma (PRP) is still not sufficiently comprehensive and there are only a few case reports on the use of mesenchymal stem cells.”

The different types of ankle pain injections – which shot works? Evidence is inconclusive.

While we then cannot offer a direct comparison of the treatments, we can review the research in this article where there is a direct comparison and give a broad over view of these treatments for ankle joint pain.

A May 2022 study (4) did offer this observation: “blood, cell-based, and injectable therapies such as PRP, platelet poor plasma biomatrix loaded with mesenchymal stromal cells, concentrated bone marrow aspirate, hyaluronic acid, and stem or stromal cell therapy including mesenchymal stem cell allografts, and adipose tissue-derived stem cells, and micronized adipose tissue injections” can be considered: “Promising and established treatment modalities.”

A September 2021 paper (5) added: “. . . some studies have investigated intra-articular injections for ankle osteoarthritis, and there is some evidence to suggest that hyaluronic acid or PRP may be effective in the short term for ankle osteoarthritis. Additionally, positive effects were observed in limited cases through the intra-articular injection of mesenchymal stem cells, but no high-quality evidence has been reported. In conclusion, the relative efficacy of injectable orthobiological therapies is far from a definitive recommendation, and robust comparative trials are needed.”

Botox injections for ankle pain vs hyaluronic acid injection – which shot works best?

In a study published in the Journal of foot and ankle research (6) investigators compared the effectiveness of intraarticular Botulinum toxin type A and intraarticular hyaluronate plus rehabilitation exercise in patients with ankle osteoarthritis over a 6 month period.

  • Seventy-five patients with symptomatic ankle osteoarthritis grade 2 were randomized to receive either a single 100-unit Botulinum toxin type A injection into the target ankle or a single hyaluronate injection plus 12 sessions of rehabilitation exercise (30 minutes/day, 3 times/week for 4 weeks).
  • There were no significant between-group differences in pain, disability and functional scores.
  • Conclusions: Treatment with intraarticular Botulinum toxin type A or hyaluronate injection plus rehabilitation exercise was associated with improvements in pain, physical function and balance in patients with ankle osteoarthritis. These effects were rapid at 2 weeks and might last for at least 6 months. There was no difference in effectiveness between the two interventions.

There are many studies which favor the Botox injections in cases of Cerebral Palsy, post-stroke when there is neurological deficit, or in helping patients who had severe burns to their legs. The Botox helps with movement. At our practice, we do not treat these conditions.

Ankle Injections

 

Hyaluronic acid injections for ankle pain and ankle arthritis

I often tell patients who come in with a lot of effusion (swelling) in a joint, that their effusion, that large amount of joint fluid, is hyaluronic acid. So why would you put in more hyaluronic acid with an injection of it? It’s already causing pain. In the early part of my practice I use to give hyaluronic acid injections. I did not get very good results with the health of the joints I was treating.

A September 2020 study (7) also examined the effectiveness of hyaluronic acid injections in varying stages of ankle arthritis. Here is what the paper said:

“Nonoperative measures are often used as first line treatment in ankle osteoarthritis. One of these measures consists of hyaluronic acid injections in the affected ankle joint, but efficiency of this treatment is uncertain. The purpose of the study was to evaluate the effect on Self-reported Foot and Ankle Score, visual analog (pain) scale score at rest, and visual analog (pain) scale score at activity 6 months after a single dose of hyaluronic acid in patients with ankle osteoarthritis.

Fifteen 15 patients were included for analysis. Median Self-reported Foot and Ankle Score remained unchanged (no improvement), whereas visual analog score at activity went from and visual analog score at rest showed small improvement. Subgroup analysis on arthrosis grade (grade I-II and III-IV) showed no statistically significant changes for all variables even though patients with grade III-IV degenerative arthritis seemed to benefit more from the treatment.

The results indicate that a single injection of hyaluronic acid is insufficient to produce at clinically relevant response after 6 months.”

A 2017 paper (8) documented that although few studies are present in the literature about the use of local viscosupplementation in ankle osteoarthritis, viscosupplementation’s potential use for ankle osteoarthritis has been suggested and recommended. The researchers write: “Although randomized trials showed scores improvement also in placebo-treated patients, current evidence suggests that viscosupplementation for treatment of ankle osteoarthritis is a safe and effective method. More randomized controlled trials with a large number of patients that compare not only the different types, dosages and frequency of Hyaluronic acid injection, but also the effectiveness of Hyaluronic acid versus corticosteroids infiltrations and Hyaluronic acid injection versus other types of conservative treatment are still needed.”


Cortisone Injections for ankle pain

Remarkably there is very little research on the effectiveness of cortisone for ankle pain. A study from October 2018 (9) recorded these observations:

  • “Intra-articular injections are commonly used to treat knee arthritis pain; however, whether their efficacy generalizes to ankle arthritis remains debatable.”

When these researchers compared cortisone to hyaluronic acid, PRP, and stem cell injections, they found the effects of cortisone may only be short term and the “Evidence from small trials favors hyaluronic acid and PRP injections for the treatment of pain associated with ankle osteoarthritis.” At the time of this study, the researchers could not find enough research on stem cell therapy to make a recommendation for ankle injury I cover this below.

A 2022 paper relied on a 2008 study (10) to suggest corticosteroid could “provide short-term symptomatic relief lasting between 4 and 8 weeks. According to the available body of evidence, they should be reserved for persistent pain in higher-grade osteoarthritis with a maximum of three or four injections a year, because of the damaging effect to the joint cartilage.”(11)

Platelet Rich Plasma Injections for ankle pain

PRP treatments involve collecting a small amount of your blood and spinning it in a centrifuge to separate the platelets from the red cells. The collected platelets are then injected back into the injured area to stimulate healing and regeneration.

A February 2021 study (12) tested how effective and safe a single intraarticular injection of platelet-rich plasma was for patients with ankle arthritis.

  • Thirty-nine patients with symptomatic ankle osteoarthritis were assessed.
  • These patients had ankle osteoarthritis for at least six months
  • The patients received a single injection of PRP (3 mL) into symptomatic ankles.

The goal of the study was to see how these patients did at six months after the single shot.

  • Results: Significantly improvement in the pain and function scores were noted at 1-, 3-, and 6-month follow-ups.
  • Acetaminophen consumption dropped significantly and no serious adverse events occurred.
  • The study showed promise for a single intraarticular injection of PRP in the treatment of ankle ankle arthritis.

Conflicting results

A May 2023 review study (20) assessed the efficacy of PRP for ankle osteoarthritis treatment. Three studies from meta-analysis and two individual studies were included, which consisted of one random control study and four before-after comparison studies. In guarded outcomes, the authors found compared to before treatment, PRP significantly reduced VAS (Visual Analogue Scale, Pain scale of 0 – 10 patient reported outcomes) with a summary that “PRP may beneficially improve pain and functional scores for ankle osteoarthritis in a short-term period.”  However they also note: “Treatments of ankle ankle osteoarthritis with various PRP preparations seemed to be effective, in terms of pain and function, when compared with before treatment. With very low quality of evidences, high costs, and diverging settings, PRP is weakly recommended for ankle osteoarthritis as an alternative or adjunct therapy after failed conservative treatment. Its benefits would be attained approximately 12 weeks after injection with acceptable minor complications.”

An August 2023 review study (21) of prior peer review research suggested “Intra-articular PRP injections, compared with placebo injections, did not significantly improve ankle symptoms and function over the course of 52 weeks in patients with ankle osteoarthritis. The results of this study do not support the use of PRP injections for posttraumatic ankle osteoarthritis, which is common in athletes.” The authors however cautioned that “. . . the studies reviewed had considerable methodological limitations (such as small sample sizes, few placebo-controlled studies, and other risk-of-bias concerns) and therefore low level of evidence, which necessitates caution when interpreting these results.”

A May 2023 systematic review (22) “revealed that PRP applied alone or combined with other treatments was safe and effective for the talar cartilage repair in patients with osteoarthritis or talus cartilage injury. There were almost no reports of adverse events related to PRP intervention. As an adjunct to talar-cartilage-related surgery, PRP could improve postoperative function and pain intensity more than saline, HA and (other treatments).

An August 2023 study (23) assessed four previously published studies with a total of 127 patients, (about 56 years old, 60 men and 67 women).

  • Short-term follow-up results suggested significant improvement of the American Orthopaedic Foot and Ankle Society (AOFAS) score in the PRP injection group compared to the control group.
  • Consistently, there was a statistical difference in AOFAS score between PRP injection and control groups in the final follow-up (more than 6 months).
  • Furthermore, we found a significant reduction in VAS scores in the PRP groups at both the short-term follow-up and the more than six months follow-up
  • The improvement of AOFAS and VAS scores at more than six months follow-up reached the minimal clinically important difference (MCID).

Conclusion: “This meta-analysis supports the safety of PRP intra-articular injection for ankle osteoarthritis.” The authors did note a concern that improvements in the outcomes scores in the PRP group at short-term follow-up do not exceed the MCID to be clinically significant and it should be noted that PRP injection provides significant improvement  more than six months follow-up.”

Comparing PRP and Prolotherapy in treating ankle arthritis pain

In 1997 I began practicing regenerative medicine for musculoskeletal problems by offering Prolotherapy. Prolotherapy is the injection of a simple sugar (dextrose). I found the newer, far more effective techniques of Stem Cell Therapy and Platelet-Rich Plasma (PRP) Therapy are actually more advanced versions of Prolotherapy, which is short for “proliferation therapy” (the proliferation of new cells following the injection of a substance that will stimulate new tissue growth).

A little more than 10 years later I started to use PRP or platelet rich plasma therapy. PRP treatments involve collecting a small amount of your blood and spinning it in a centrifuge to separate the platelets from the red cells. The platelets contain healing agents, or “growth factors.”  The collected platelets are then injected back into the injured area to stimulate healing and regeneration. The platelets contain healing agents, or “growth factors.” Even though I found both these treatments effective and used both treatments on myself, I began to favor using PRP because of the clinical evidence we were seeing of its superior healing power.

A July 2019 study (13) compared PRP and Prolotherapy. Here is what the study reported:

“Osteochondral lesions of talus are among the most common ankle problems. Platelet-rich plasma (PRP) and prolotherapy are 2 successful injection-based techniques for treatment of chronic musculoskeletal problems. The aim of the present study was to compare PRP and prolotherapy injections for the management of osteochondral lesions of talus.”

This was a retrospective cohort study of 49 patients with osteochondral lesions of talus symptoms of more than 6 months who had been refractory (not responsive) to 3 months of treatment using (other) conservative methods.

The patients were divided into 2 groups:

Prolotherapy injections – 27 patients got the dextrose Prolotherapy shots and 22 received the PRP injections.

The patients were given 3 injections of 4 mL solution into periarticular and intra-articular ankle joint spaces.

After treatment, patients were evaluated via Visual Analogue Scale (VAS), American Orthopedic Foot and Ankle Society Score (AOFAS), and Ankle Osteoarthritis Scale (AOS) at baseline and 21 days, 90 days, 180 days, and 360-day follow-up periods.

RESULTS: Both PRP and Prolotherapy treatments resulted in greater improvement in pain and ankle functions at follow-up periods extending to 1 year and there was no difference between the groups for the outcomes at follow-up periods. Excellent or good outcomes were reported by 88.8% of the patients in Prolotherapy group and 90.9% of the patients in PRP group.

Bone marrow stem cell injections for ankle pain

Dr. Marc Darrow performing Non-Surgical Ankle Treatment

I have a more comprehensive article on this site Alternatives to ankle fusion and ankle replacement surgery.

Here is a summary of that article:

December 2016 research in the Journal of experimental orthopaedics from doctors at the Steadman Philippon Research Institute (14) reviewed the research in the treatment of ankle osteoarthritis with bone marrow derived stem cells.

  • The goal of this study was to review outcomes of bone marrow aspirate concentrate (bone marrow derived stem cells) for the treatment of chondral (cartilage) defects and osteoarthritis of the talus of the ankle. The researchers noted that there is not much research (at the time of this paper’s writing). . . Nonetheless, the evidence available showed varying degrees of beneficial results of bone marrow derived stem cell therapy for the treatment of ankle cartilage defects (arthritis). The researchers hypothesized that bone marrow aspirate concentrate may be useful in regeneration of tissue, enhancing the quality of cartilage repair. As a result, BMAC promotes a potentially healthy environment for hyaline cartilage growth and repair. The health of cartilage is one of the goals of this type of medicine.

Research cited:

  • A 2009 study published in Clinical Orthopaedics and Related Research, reported that 94 % of patients returned to low impact sports activity at an average 4.4 months after bone marrow aspirate transplantation and 77 % of patients returned to high impact sports activity at an average 11.3 months. (15)
  • The same researchers in 2013 reported that 73 % of the 36 patients playing sports before surgery were able to return to sports. They also reported that 22 % of these 36 patients were able to return to sport, but at a lower level than before surgery. (16)
  • A 2011 study reported that 95 % of patients who had undergone bone marrow concentrate treatments returned to their pre-symptom level of sporting activity at an average 13 weeks.(17)

A heavily cited and received 2015 study showed that stem cell treatments were able to regrow cartilage in ankles significant enough to improve function and pain levels in selected patients. Walking distances were shown to dramatically improve in the patient group.(18)

In a post-surgical study from December 2018, (19) researchers found the injection of bone marrow mesenchymal stem cells could improve the repair process of the osteonecrosis.

In our office we evaluate every patient to offer a recommendation as to which healing program would be most beneficial to them. We do this after an assessment of their ankle pain, history of ankle instability and ankle sprain, level of arthritis, overall condition of the ankle joint and the realistic expectation which treatment may best address the cartilage, tendon, tendonitis or ligament injury the patient may suffer from.

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Ankle pain and avascular necrosis of the talus

Ankle Fusion and Ankle Replacement Surgery and possible alternative treatments

 

Citations for this article:

1 Boffa A, Previtali D, Frattura GD, Vannini F, Candrian C, Filardo G. Evidence on ankle injections for osteochondral lesions and osteoarthritis: a systematic review and meta-analysis. International Orthopaedics. 2020 Jul 9:1-5.
2 Urits I, Smoots D, Franscioni H, Patel A, Fackler N, Wiley S, Berger AA, Kassem H, Urman RD, Manchikanti L, Abd-Elsayed A. Injection techniques for common chronic pain conditions of the foot: a comprehensive review. Pain and therapy. 2020 Jun;9(1):145-60.
3 Jerosch J. Conservative treatment options for arthritis of the ankle: What is possible, what is effective?. Der Unfallchirurg. 2022 Jan 18.
4 Danilkowicz R, Murawski C, Pelligrini M, Walther M, Valderrabano V, Angthon C, Adams S. Nonoperative and Operative Soft-Tissue and Cartilage Regeneration and Orthopaedic Biologics of the Foot and Ankle: An Orthoregeneration Network (ON) Foundation Review. Arthroscopy: The Journal of Arthroscopic & Related Surgery. 2022 May 21.
5 Tejero S, Prada-Chamorro E, González-Martín D, García-Guirao A, Galhoum A, Valderrabano V, Herrera-Pérez M. Conservative Treatment of Ankle Osteoarthritis. Journal of Clinical Medicine. 2021 Jan;10(19):4561.
6 Sun SF, Hsu CW, Lin HS, Chou YJ, Chen JY, Wang JL. Efficacy of intraarticular botulinum toxin A and intraarticular hyaluronate plus rehabilitation exercise in patients with unilateral ankle osteoarthritis: a randomized controlled trial. Journal of foot and ankle research. 2014 Dec 1;7(1):9.
7 Jantzen C, Ebskov LB, Andersen KH, Benyahia M, Rasmussen PB, Johansen JK. The Effect of a Single Hyaluronic Acid Injection in Ankle Arthritis-A Prospective Cohort Study. The Journal of Foot and Ankle Surgery. 2020 May 29.
8 Papalia R, Albo E, Russo F, Tecame A, Torre G, Sterzi S, Bressi F, Denaro V. The use of hyaluronic acid in the treatment of ankle osteoarthritis: a review of the evidence. Journal of Biological Regulators and Homeostatic Agents. 2017 Dec 27;31(4 Suppl 2):91-102.
9 Vannabouathong C, Del Fabbro G, Sales B, Smith C, Li CS, Yardley D, Bhandari M, Petrisor BA. Intra-articular injections in the treatment of symptoms from ankle arthritis: a systematic review. Foot & ankle international. 2018 Oct;39(10):1141-50.
10 Ward ST, Williams PL, Purkayastha S. Intra-articular corticosteroid injections in the foot and ankle: a prospective 1-year follow-up investigation. The Journal of foot and ankle surgery. 2008 Mar 1;47(2):138-44.
11 Herrera-Pérez M, Valderrabano V, Godoy-Santos AL, de César Netto C, González-Martín D, Tejero S. Ankle osteoarthritis: comprehensive review and treatment algorithm proposal. EFORT Open Reviews. 2022 Jul 1;7(7):448-59.
12 Sun SF, Hsu CW, Lin GC, Lin HS, Chou YJ, Wu SY, Huang HY. Efficacy and safety of a single intra-articular injection of platelet-rich plasma on pain and physical function in patients with ankle osteoarthritis—a prospective study. The Journal of Foot and Ankle Surgery. 2021 Jul 1;60(4):676-82.
13 Akpancar S, Gül D. Comparison of platelet rich plasma and prolotherapy in the management of osteochondral lesions of the talus: A retrospective cohort study. Medical science monitor: international medical journal of experimental and clinical research. 2019;25:5640.
14 Chahla J, Cinque ME, Schon JM, et al. Bone marrow aspirate concentrate for the treatment of osteochondral lesions of the talus: a systematic review of outcomesJournal of Experimental Orthopaedics. 2016;3:33. doi:10.1186/s40634-016-0069-x.
15 Giannini S, Buda R, Battaglia M, Cavallo M, Ruffilli A, Ramponi L, Pagliazzi G, Vannini F. One-step repair in talar osteochondral lesions: 4-year clinical results and t2-mapping capability in outcome prediction. The American journal of sports medicine. 2013 Mar;41(3):511-8.
16 Giannini S, Buda R, Battaglia M, Cavallo M, Ruffilli A, Ramponi L, Pagliazzi G, Vannini F. One-step repair in talar osteochondral lesions: 4-year clinical results and t2-mapping capability in outcome prediction. The American Journal of Sports Medicine. 2013 Mar;41(3):511-8.
17 Kennedy JG, Murawski CD. The Treatment of Osteochondral Lesions of the Talus with Autologous Osteochondral Transplantation and Bone Marrow Aspirate Concentrate: Surgical TechniqueCartilage. 2011 Oct;2(4):327-36. doi: 10.1177/1947603511400726. PMID: 26069591; PMCID: PMC4297142.
18 Emadedin M, Ghorbani Liastani M, Fazeli R, et al.Long-Term Follow-up of Intra-articular Injection of Autologous Mesenchymal Stem Cells in Patients with Knee, Ankle, or Hip Osteoarthritis. Arch Iran Med. 2015 Jun;18(6):336-44. doi: 015186/AIM.003.
19 Hernigou P, Dubory A, Lachaniette CH, Khaled I, Chevallier N, Rouard H. Stem cell therapy in early post-traumatic talus osteonecrosis. International orthopaedics. 2018 Dec 1;42(12):2949-56.1767–2107
20 Laohajaroensombat S, Prusmetikul S, Rattanasiri S, Thakkinstian A, Woratanarat P. Platelet-rich plasma injection for the treatment of ankle osteoarthritis: a systematic review and meta-analysis. Journal of Orthopaedic Surgery and Research. 2023 May 19;18(1):373.
21 Paget LD, Reurink G, de Vos RJ, Weir A, Moen MH, Bierma-Zeinstra SM, Stufkens SA, Goedegebuure S, Krips R, Maas M, Meuffels DE. Platelet-rich plasma injections for the treatment of ankle osteoarthritis. The American Journal of Sports Medicine. 2023 Aug;51(10):2625-34.
22 Peng J, Wang Q, Xu Y, He H. Platelet-rich plasma treatment for talar cartilage repair: a systematic review and meta-analysis. BMC Musculoskeletal Disorders. 2023 Dec;24(1):1-1.
23 Ding SL, Ji LF, Zhang MZ, Xiong W, Sun CY, Han ZY, Wang C. Safety and efficacy of intra-articular injection of platelet-rich plasma for the treatment of ankle osteoarthritis: a systematic review and meta-analysis. International Orthopaedics. 2023 Mar 21:1-2.

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