http://informahealthcare.com/psm ISSN: 0091-3847 (print) Phys Sportsmed, 2015; Early Online: 1–5 DOI: 10.1080/00913847.2015.1017440
REVIEW
Current concepts on the use of corticosteroid injections for knee osteoarthritis Tsun Yee Law 1, Chau Nguyen1, Rachel M. Frank2, Samuel Rosas1 and Frank McCormick3 The Physician and Sportsmedicine Downloaded from informahealthcare.com by Kainan University on 04/28/15 For personal use only.
1
Holy Cross Orthopedic Institute, Fort Lauderdale, FL, USA, 2Rush University Medical Center, Chicago, IL, USA, and 3LESS Institute, Miami, FL, USA
Abstract
Keywords
Intraarticular corticosteroid injections are commonly used by the primary care providers and orthopedic surgeons to treat knee pain associated with osteoarthritis (OA). There is a spectrum of options for treating knee OA, ranging from ice therapy to partial or total knee replacement surgery. In mid-range treatment spectrum are different kinds of injections, with the most widely used being corticosteroid and hyaluronic acid. In addition, there are different types of corticosteroids used and also commonly mixed with different local anesthetics. The purpose of this paper is address current concepts on the use of corticosteroid steroid therapy for the treatment of knee OA.
Corticosteroids, intraarticular, knee, osteoarthritis, injection
Introduction Currently, there are 51.8 million adults diagnosed with arthritis, amounting to 22% of the active adult population [1]. Knee osteoarthritis (OA) is one of the leading causes of disability in United States and worldwide [2]. There is a spectrum of options for treating knee OA, ranging from ice therapy to partial or total knee replacement surgery. In mid-range treatment spectrum are different kinds of injections, with the most widely used being corticosteroid and hyaluronic acid (HA). The purpose of this paper is address current concepts on the use of corticosteroid therapy for the treatment of knee OA. Mechanism of action of glucocorticoids in OA The complete mitigation of the inflammatory cascade in OA is not completely understood; however there is some literature to explain how cortisone reduces inflammation. Glucocorticoids reduce the proinflammatory effects of arachidonic acid by acting directly on nuclear steroid receptors which alter the synthesis of mRNA and proteins leading to changes in T-cell and B-cell functions, decreases in the levels of cytokines and enzymes, and inhibition of phospholipase A2 [3]. OA has a number of effects on the juxta-articular bone such as bone remodeling, subchondral bone sclerosis, subchondral cysts, and increased osteoblastic and osteoclastic activities [4]. Increased levels of cytokines, in general, have been found in subchondral OA bone, specifically IL-6 and TNF-a have been implicated in bone formation as well as inflammation of the synovium [4]. Further, it has been suggested that
History Received 23 October 2014 Accepted 6 February 2015 Published online 23 February 2015
the increased amounts of arachidonic acid found in bone marrow fat is the possible starting point of the bone growth by acting as a positive feedback mechanism [4]. The amount of TNF-a and IL-6 will diminish over a short period of time since the proinflammatory effects of arachidonic acid will no longer be expressed due to the repression process induced by steroids [4,5].
Effectiveness of intraarticular steroid injections Intraarticular (IA) corticosteroid therapy may provide shortterm pain relief in patients with knee OA, with low risk of adverse effects [6-8]. A systematic review of IA steroid injections for knee OA concluded that the beneficial effect of treatment commenced 1 week after injection and could last for 3–4 weeks [8,9]. A separate meta-analysis corroborated these results, noting short-term benefits of up to 2 weeks after injection and also reporting some longer-term benefit of up to 16 to 24 weeks [2]. A Cochrane systematic review conducted by Bellamy et al. further evaluated the efficacy of IA corticosteroids in the treatment of knee OA [6]. The review included results of 28 trials comparing IA corticosteroid to IA placebo. In brief, IA corticosteroids were shown to be more effective than placebo in pain reduction and patient global self-assessment at 1 and at 2–3 weeks post-injection [6]. Beyond 4–24 weeks post-injection, there were no significant changes in efficacy of IA corticosteroid [6]. The authors concluded that the beneficial effects of IA corticosteroid appear rapid but may be of short duration (1–3 weeks) [6]. An additional systematic review by
Correspondence: Tsun Yee Law, MD, Holy Cross Hospital, Orthopedic Research Institute, 5597 N. Dixie Highway, Fort Lauderdale, FL 33334, USA. E-mail: [email protected] 2015 Informa UK Ltd.
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Hepper et al. also determined that the duration of effect may be short and only consistently lasts for 1 week [10].
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Potential side effects of cortisone injections A general concern expressed among the medical research community is whether long-term use of IA steroids would cause any deleterious effects on joints or tissues [11-15]. One study attempted to addressed these concerns by comparing clinical and radiographic outcomes in a group of 68 patients treated with repeated IA knee injections of triamcinolone acetonide 40 mg (Kenalog) with a control group of 34 patients receiving saline injection into the knee; both IA steroid and saline injections were given every 3 months over the course of 2 years [14]. The authors demonstrated no differences in joint space width between the two groups at both 1 and 2 years of treatment. There was a greater improvement in range of motion and pain control in the corticosteroid group compared to the saline group at the end of the first year. Further, there was a significant improvement in knee pain and stiffness in the corticosteroid group over the 2 years; these results were not demonstrated in the control group. This trial provides some evidence for the long-term effectiveness and safety of IA corticosteroid injections, with no acceleration of the progression of OA noted in the treatment group. While complications of IA corticosteroid treatment are infrequent, the most commonly reported unwanted side effects include atrophy of the skin at the injection site, facial flush, and post-injection flare (soreness and inflammation following the injection) [12]. The facial flush is more commonly seen ~ 16 hours after IA injection of triamcinolone and it lasts on average 36 hours [16]. The post-injection steroid flare is thought to be due to injecting the crystalline nature of deposteroids which causes a crystal-induced synovitis [17]. This typically will occur within the first 24–36 hours post-injection and is usually self-limited [18]. Systemic side effects such as infection, increased blood glucose, hypercortisolism, and others are rarely seen, although careful planning and precautions such as utilizing gloves should be taken to avoid them. However, there is some evidence in the literature that shows an acute 2- to 3-day rise in blood glucose in patients with diabetes after a single IA corticosteroid injection of methylprednisolone or betamethasone in the knee [19]. While there is only a limited amount of literature regarding dose and systemic effects, it has been suggested that a dose > 40 mg has no added benefit and therefore limiting the dose accordingly will lower the risk of systemic side effects [20]. Preclinical studies suggest certain corticosteroids and associated anesthetics can be harmful to the viability of cartilageproducing cells known as chondrocytes [9,21,22]. Tendon rupture, predominantly the Achilles tendon, is another serious possible adverse effect of IA corticosteroid use that the literature does not currently adequately address but is a possible concern [23]. Although the clinical evidence to support these findings is limited, clinicians must carefully determine the type of steroid and dosage to be used for each individual patient. The risk of immunosuppression caused by a steroid-induced decrease in inflammatory response is not to be taken lightly.
Phys Sportsmed, 2015; Early Online:1–5
For that reason, multiple studies have reported the incidence of arthroplasty infection after the use of IA steroid injections. Only one study by the Mayo Clinic demonstrated a greater risk of infections on joints treated previously with this type of injection. There is no specific consensus on how long arthroplasty must be delayed to avoid this risk and therefore some clinicians use 2 months in order to avoid this unnecessary yet highly morbid risk [24]. A small amount of other side effects that have been reported include stoppage of lactation and transient menstrual disorder, thought to occur due to a decrease in estradiol. Other side effects may occur but are dependent on site of injection. For example, 12% of patients reported having ear, nose, and throat problems after a single epidural steroid injection – most were described as a transient change in voice [24]. Tachon’s Syndrome is a transient vagal response to IA or periarticular steroid injection that causes great anxiety to patients, but it is extremely rare – 1 event per 8000 injections. It consists of any of the following: diaphoresis, chest pain, hypotension, shortness of breath, and abdominal pain [24]. Ideal dosing schedule for IA corticosteroid shots The American College of Rheumatology advices physicians to only perform an IA steroid injection after 3 months from the previous injection. The safety of undergoing multiple corticosteroid injections in the knee joint over time has been well established in a clinical setting [25,26]. Most clinicians agree that for weight-bearing joints (such as the knee), a period of at least 8 to 12 weeks between corticosteroid injections is optimal [27]. Large doses which may occur with repeated dosing can cause more harm to the cartilage than benefit [3]. This corresponds with the empirical 3-month rule that is a common paradigm followed by many healthcare professionals. IA injection accuracy The clinician normally uses anatomic landmarks when performing an IA steroid injection. In the knee, this means palpating the patella and patellar tendon to determine the best access point to the joint. Depending on the condition of the skin and clinician preference, several options exist for the technical approach to knee IA corticosteroid injection [28]. Some of the more common injection sites include the superolateral portal, anteromedial portal, anterolateral portal, and mid-lateral portal. Importantly, injections placed via the superolateral or mid-lateral portal should be performed with the patient’s knee extended, while injections into the anteromedial and anterolateral portals should be performed with the knee flexed to ~ 60 to 90 [28]. The medial or lateral joint space can be used. The least commonly used and accurate is the infrapatellar bent knee approach [27]. The American College of Radiology advises that when performing musculoskeletal procedures, ultrasound should be used [29,30]. This, of course, is difficult in some settings as personnel may not be trained or an ultrasound device may not be available. While both methods are accepted, several authors have reported that a large number of anatomicalguided injections are inaccurately placed. One randomized
Current concepts of corticosteroid injections for knee osteoarthritis
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DOI: 10.1080/00913847.2015.1017440
controlled study demonstrated that one-third of all anatomically guided injections to 184 patients were inaccurate; these injections were done at the elbow, wrist, ankle, shoulder, and knee with the accuracy of a trainee using US guidance being greater than a seasoned rheumatologist using anatomical guidance [31]. Other studies and evidence-based summaries show that US-guided injections are more accurate, ranging from 69% to 100% compared to 39% to 100% anatomically guided injections. This same study reports the finding of increased clinical improvement with ultrasound-guided injection – 52% versus 23% in patients without US-guided injection. In a large randomized controlled trial, Sibbit et al. found that US-guided IA injections, decreased 8% of the cost per responder per year which amounted to US$7. The same authors also reported that US-guided IA injection, decreased outpatient treatment costs by 33%, US$64 per responder per year and also improved patient-recorded clinical outcomes and cost-effectiveness [30,32,33]. A study comparing these three injection sites in 126 knees suggests that injections using ultrasound were more accurate in the mid-lateral and superolateral portal (95% p < 0.05 and 100% p < 0.05, respectively) compared to medial portals which were only 75% accurate [14]. Many factors affect the accuracy of a single injection and therefore we advise clinicians to perform the method that they are most comfortable with and to use ultrasound when possible. Efficacy of different corticosteroid medications available A variety of corticosteroids are available such as betamethasone (Celestone), dexamethasone (Decadron) LA, triamcinolone acetonide (Kenalog), and methylprednisolone acetate (Depo-Medrol) [28]. The agent of choice depends on the condition being treated, the joint being injected, and overall the preference of the clinician. The more commonly used IA steroids used in the United States include triamcinolone acetonide (Kenalog) and methylprednisolone acetate (DepoMedrol) [34]. The typical dosage of both triamcinolone and methylprednisolone acetate is 40 mg in large joints such as the knee and hip, with lower doses used in the hands or feet [35]. The recommended interval between injections is at least 3 months [35]. Table 1 lists the commonly used IA corticosteroid injections. A critical literature review with up-to-date findings provides a summary of commonly used corticosteroids and their dosing [35]. The solubility and duration of action differs in each corticosteroid, and typically, the lower the solubility, the longer is the duration [3]. Therefore, careful Table 1. Commonly used corticosteroids. Steroid Common concentration (mg per ml)
Common equivalent dosea (mg)
Approximate duration of action (days)
Methylprednisolone acetate Triamcinolone acetonide Triamcinolone hexacetonide Dexamethasone acetate Dexamethasone sodium
40 40 40 8 8
8 14 21 8 6
40 or 80 10 or 40 20 8 4
Note: Steroid agents listed in order of prevalence of use. Dose equivalent to 40 mg of methylprednisolone acetate or triamcinolone acetonide (the most commonly used intraarticular steroid).
a
3
analysis of steroid pharmacokinetics should be considered in each treatment plan. What is the purpose in combining IA corticosteroids with local anesthetic agents? Local anesthetics such as lidocaine and bupivacaine are commonly used to provide rapid pain relief until the corticosteroid of choice begins to take effect [36]. Corticosteroids can often take 24 hours before the patient begins to experience relief while local anesthetics have a much shorter onset of action: lidocaine: ~ 1–2 minutes and bupivacaine: ~ 30 minutes. However, due to the limited duration of action of the local anesthetics, ranging from ~ 1 hour for lidocaine to ~ 8 hours for bupivacaine, the patient may experience a transient return of joint pain as the local anesthetic wears off, before the onset of the effects of the corticosteroid. If local anesthetic is used in combination with the corticosteroid, then the patient should be counseled as to the potential of a transient recurrence of pain in the first 1–2 days following injection. To further decrease the discomfort received by the patient, many clinicians also employ a topical vapocoolant on the skin prior to the injection [28]. Of note, there is some evidence for caution regarding chondrotoxicity when combining local anesthetic with corticosteroids. One in vitro study found that 88 mg of 1% lidocaine or 22 mg of 0.25% bupivacaine combined with betamethasone sodium phosphate, betamethasone acetate, methylprednisolone acetate, or triamcinolone acetate injected into a bioreactor simulating normal joint fluid with chondrocyte culture cell wells results in a pronounced chondrotoxic effect [37]. However, for single IA injections administered with at least 3-month intervals between injections, the chondrotoxicity is limited, and combination injections remain widely used by clinicians. What are the contraindications to IA corticosteroid use? Based upon a review of the best available evidence, the contraindications to IA injection are all relative. Certainly, allergies to the injection preparation products and/or injection agents are contraindications to injection. Other contraindications include active superficial skin/soft tissue infection (cellulitis), suspected IA infection, unstable coagulopathy, anticoagulant therapy, uncontrolled diabetes mellitus, and broken skin at the injection site [27,38,39]. Patients who are on anticoagulant therapy should be approached with caution, and certain precautions following injection such as placement of a pressure dressing, as well as pre-injection precautions, such as obtaining prothrombin time laboratory values, can be helpful. What are the alternatives to corticosteroids? IA injection of HA, also known as viscosupplementation, has been an extremely popular treatment option for knee OA. The efficacy of HA injections, especially when compared to corticosteroid injections, has become a topic of controversy within the orthopedic community. In 2006, a Cochrane review of 76 clinical trials determined that HA is effective for the
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treatment of knee OA and has a prolonged effect when compared with IA corticosteroids [40]. Further, a recent study comparing IA injection of HA efficacy to nonsteroidal antiinflammatory drugs (NSAIDs) concluded that IA injection of HA is equal to NSAIDs being continuously used for 5 weeks and has a better safety profile when considering side effects [41]. Recently, a systematic review and meta-analysis assessing the outcomes of IA corticosteroids versus HA injections was conducted, in which seven clinical trials analyzing 610 knees were described. The authors concluded that by week 4 following therapy, corticosteroids are relatively more effective for pain than HA, but that after 2 months, HA has greater efficacy [11]. This suggests that HA may be beneficial for longterm management of OA. In 2013, the American Academy of Orthopaedic Surgeons updated their clinical practice guidelines for the treatment of OA, and specifically noted that HA is no longer recommended as a modality for treating symptomatic OA. The authors noted that while several of the 14 studies included in their review demonstrated the effectiveness of HA, the overall combined results of all studies did not meet minimum clinically important improvement thresholds. This same workgroup did, however, recommend the use of IA corticosteroids for short-term pain relief of symptomatic OA. Certainly, further research into the efficacy of both treatment options is warranted. One of the biggest downsides to HA injections involves cost, and this should be taken into consideration if recommending HA therapy. In addition, several HA treatment regimens require serial injections over the series of 3–5 weeks, which may affect patient compliance and cooperation.
Conclusion IA corticosteroid injections have been shown to be safe and effective in treating the painful symptoms of OA of the knees. It may not be effective for all patients and the duration of effect can also be short although rapid in onset. This makes corticosteroid injections viable in the short term but may limit its ability to be used as a single long-term treatment option. Alternative options such as HA can be considered when IA corticosteroid injections fail to provide adequate pain relief. Recommendations Upon reviewing the literature it is clear that IA corticosteroids are effective but may not have an immediate onset of pain relief. Therefore, it may be beneficial to combine the corticosteroid of choice with a local anesthetic to offer the patient rapid pain relief. Although short-acting lidocaine is used for diagnostic purposes, a long-acting bupivacaine to prevent the flare and dilute the lidocaine (to prevent chondrotoxicity in large joints) is recommended. In addition, whenever possible the use of an ultrasound would enhance the accuracy of injections. Although the literature is not conclusive on treatment frequency, it is generally recommended to keep the injections limited to once every 3 months but can be earlier if symptoms warrant.
Phys Sportsmed, 2015; Early Online:1–5
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1] Blackwell DL, Lucas JW, Clarke TC. Summary health statistics for U.S. adults: National health interview survey, 2012. Vital Health Stat 10 2014;260:1–161. [2] Arroll B, Goodyear-Smith F. Corticosteroid injections for osteoarthritis of the knee: meta-analysis. BMJ 2004;328:869–70. [3] Pekarek B, Osher L, Buck S, Bowen M. Intra-articular corticosteroid injections: a critical literature review with up-to-date findings. Foot 2011;21:66–70. [4] Aspden RM. Osteoarthritis: a problem of growth not decay? Rheumatology 2008;47:1452–60. [5] Newton R. Anti-inflammatory glucocorticoids: changing concepts. Eur J Pharmacol 2014;724:231–6. [6] Bellamy N, Campbell J, Robinson V, et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2005:CD005328. [7] Creamer P. Intra-articular corticosteroid treatment in osteoarthritis. Curr Opin Rheumatol 1999;11:417–21. [8] Godwin M, Dawes M. Intra-articular steroid injections for painful knees. Systematic review with meta-analysis. Can Fam Physician 2004;50:241. [9] Farkas B, Kvell K, Czo€mpo€ly T, et al. Increased chondrocyte death after steroid and local anesthetic combination. Clin Orthop Relat Res 2010;468:3112–20. [10] Hepper CT, Halvorson JJ, Duncan ST, et al. The efficacy and duration of intra-articular corticosteroid injection for knee osteoarthritis: a systematic review of level I studies. J Am Acad Orthop Surg 2009;17:638–46. [11] Bannuru RR, Natov NS, Obadan IE, et al. Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Arthritis Rheum 2009;61:1704–11. [12] Cole BJ, Schumacher HR Jr. Injectable corticosteroids in modern practice. J Am Acad Orthop Surg 2005;13:37–46. [13] Orozco L, Munar A, Soler R, et al. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation 2013;95:1535–41. [14] Park Y, Lee SC, Nam HS, et al. Comparison of sonographically guided intra-articular injections at 3 different sites of the knee. J Ultrasound Med 2011;30:1669–76. [15] Kon E, Filardo G, Drobnic M, et al. Non-surgical management of early knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc 2012;20:436–49. [16] Habib G. Systemic effects of intra-articular corticosteroids. Clin Rheumatol 2009;28:749–56. [17] Hunter JA, Blyth TH. A risk-benefit assessment of intra-articular corticosteroids in rheumatic disorders. Drug Saf 1999;21:353–65. [18] Cardone DA, Tallia AF. Joint and soft tissue injection. Am Fam Physician 2002;66:283–8. [19] Kallock E, Neher J. Do intra-articular steroid injections affect glycemic control in patients with diabetes? J Fam Pract 2010;59:709–10. Available from Academic Search Premier, Ipswich, MA. [20] Douglas RJ. Corticosteroid injection into the osteoarthritic knee: drug selection, dose, and injection frequency. Int J Clin Pract 2012;66:699–704. [21] Jacobs TF, Vansintjan PS, Roels N, et al. The effect of Lidocaine on the viability of cultivated mature human cartilage cells: an in vitro study. Knee Surg Sports Traumatol Arthrosc 2011;19: 1206–13. [22] Behrens F, Shepard N, Mitchell N. Alterations of rabbit articular cartilage by intra-articular injections of glucocorticoids. J Bone Joint Surg Am 1975;57:70–6. [23] Blanco I, Krahenbuhl S, Schlienger RG. Corticosteroid-associated tendinopathies: an analysis of the published literature and spontaneous pharmacovigilance data. Drug Saf 2005;28:633–43. [24] Berthelot J-M, Le Goff B, Maugars Y. Side effects of corticosteroid injections: what’s new? Joint Bone Spine 2012;80:363–7.
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DOI: 10.1080/00913847.2015.1017440
Current concepts of corticosteroid injections for knee osteoarthritis
[25] Balch HW, Gibson JMC, El-ghobarey AF, et al. Repeated corticosteroid injections into knee joints. Rheumatology 1977;16:137–40. [26] Keagy RD, Keim HA. Intra-articular steroid therapy: repeated use in patients with chronic arthritis. Am J Med Sci 1967;253:45–51. [27] Neustadt DH. Intra-articular injections for osteoarthritis of the knee. Cleve Clin J Med 2006;73:897. [28] Schumacher HR, Chen LX. Injectable corticosteroids in treatment of arthritis of the knee. Am J Med 2005;118:1208–14. [29] AIUM practice guideline for the performance of a musculoskeletal ultrasound examination. J Ultrasound Med 2012;31:1473–88. [30] Lawson A, Kelsberg G, Safranek S. Clinical inquiry: does ultrasound guidance improve outcomes for steroid joint injections? J Fam Pract 2013;62:763a. [31] Cunnington J, Marshall N, Hide G, et al. A randomized, doubleblind, controlled study of ultrasound-guided corticosteroid injection into the joint of patients with inflammatory arthritis. Arthritis Rheum 2010;62:1862–9. [32] Berkoff DJ, Miller LE, Block JE. Clinical utility of ultrasound guidance for intra-articular knee injections: a review. Clin Interv Aging 2012;7:89. [33] Sibbitt WL, Band PA, Chavez-Chiang NR, et al. A randomized controlled trial of the cost-effectiveness of ultrasound-guided intraarticular injection of inflammatory arthritis. J Rheumatol 2011;38:252–63.
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[34] Centeno LM, Moore ME. Preferred intraarticular corticosteroids and associated practice: a survey of members of the American College of Rheumatology. Arthritis Care Res 1994;7:151–5. [35] Ringdahl E, Pandit S. Treatment of knee osteoarthritis. Am Fam Physician 2011;83:1287–92. [36] Saunders SF. Injection techniques in musculoskeletal medicine a practical manual for clinicians in primary and secondary care. 4th ed. Edinburgh: Churchill Livingstone/Elsevier; 2012. [37] Braun HJ, Wilcox-Fogel N, Kim HJ, et al. The effect of local anesthetic and corticosteroid combinations on chondrocyte viability. Knee Surg Sports Traumatol Arthrosc 2012;20:1689–95. [38] Stephens MB, Beutler AI, O’Connor FG. Musculoskeletal injections: a review of the evidence. Am Fam Physician 2008;78:971–6. [39] Courtney P, Doherty M. Joint aspiration and injection. Best Pract Res Clin Rheumatol 2005;19:345–69. [40] Bellamy N, Campbell J, Robinson V, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006:CD005321. [41] Ishijima M, Nakamura T, Shimizu K, et al. Intra-articular hyaluronic acid injection versus oral non-steroidal anti-inflammatory drug for the treatment of knee osteoarthritis: a multi-center, randomized, open-label, non-inferiority trial. Arthritis Res Ther 2014;16:R18–18.
REVIEW
Current concepts on the use of corticosteroid injections for knee osteoarthritis Tsun Yee Law 1, Chau Nguyen1, Rachel M. Frank2, Samuel Rosas1 and Frank McCormick3 The Physician and Sportsmedicine Downloaded from informahealthcare.com by Kainan University on 04/28/15 For personal use only.
1
Holy Cross Orthopedic Institute, Fort Lauderdale, FL, USA, 2Rush University Medical Center, Chicago, IL, USA, and 3LESS Institute, Miami, FL, USA
Abstract
Keywords
Intraarticular corticosteroid injections are commonly used by the primary care providers and orthopedic surgeons to treat knee pain associated with osteoarthritis (OA). There is a spectrum of options for treating knee OA, ranging from ice therapy to partial or total knee replacement surgery. In mid-range treatment spectrum are different kinds of injections, with the most widely used being corticosteroid and hyaluronic acid. In addition, there are different types of corticosteroids used and also commonly mixed with different local anesthetics. The purpose of this paper is address current concepts on the use of corticosteroid steroid therapy for the treatment of knee OA.
Corticosteroids, intraarticular, knee, osteoarthritis, injection
Introduction Currently, there are 51.8 million adults diagnosed with arthritis, amounting to 22% of the active adult population [1]. Knee osteoarthritis (OA) is one of the leading causes of disability in United States and worldwide [2]. There is a spectrum of options for treating knee OA, ranging from ice therapy to partial or total knee replacement surgery. In mid-range treatment spectrum are different kinds of injections, with the most widely used being corticosteroid and hyaluronic acid (HA). The purpose of this paper is address current concepts on the use of corticosteroid therapy for the treatment of knee OA. Mechanism of action of glucocorticoids in OA The complete mitigation of the inflammatory cascade in OA is not completely understood; however there is some literature to explain how cortisone reduces inflammation. Glucocorticoids reduce the proinflammatory effects of arachidonic acid by acting directly on nuclear steroid receptors which alter the synthesis of mRNA and proteins leading to changes in T-cell and B-cell functions, decreases in the levels of cytokines and enzymes, and inhibition of phospholipase A2 [3]. OA has a number of effects on the juxta-articular bone such as bone remodeling, subchondral bone sclerosis, subchondral cysts, and increased osteoblastic and osteoclastic activities [4]. Increased levels of cytokines, in general, have been found in subchondral OA bone, specifically IL-6 and TNF-a have been implicated in bone formation as well as inflammation of the synovium [4]. Further, it has been suggested that
History Received 23 October 2014 Accepted 6 February 2015 Published online 23 February 2015
the increased amounts of arachidonic acid found in bone marrow fat is the possible starting point of the bone growth by acting as a positive feedback mechanism [4]. The amount of TNF-a and IL-6 will diminish over a short period of time since the proinflammatory effects of arachidonic acid will no longer be expressed due to the repression process induced by steroids [4,5].
Effectiveness of intraarticular steroid injections Intraarticular (IA) corticosteroid therapy may provide shortterm pain relief in patients with knee OA, with low risk of adverse effects [6-8]. A systematic review of IA steroid injections for knee OA concluded that the beneficial effect of treatment commenced 1 week after injection and could last for 3–4 weeks [8,9]. A separate meta-analysis corroborated these results, noting short-term benefits of up to 2 weeks after injection and also reporting some longer-term benefit of up to 16 to 24 weeks [2]. A Cochrane systematic review conducted by Bellamy et al. further evaluated the efficacy of IA corticosteroids in the treatment of knee OA [6]. The review included results of 28 trials comparing IA corticosteroid to IA placebo. In brief, IA corticosteroids were shown to be more effective than placebo in pain reduction and patient global self-assessment at 1 and at 2–3 weeks post-injection [6]. Beyond 4–24 weeks post-injection, there were no significant changes in efficacy of IA corticosteroid [6]. The authors concluded that the beneficial effects of IA corticosteroid appear rapid but may be of short duration (1–3 weeks) [6]. An additional systematic review by
Correspondence: Tsun Yee Law, MD, Holy Cross Hospital, Orthopedic Research Institute, 5597 N. Dixie Highway, Fort Lauderdale, FL 33334, USA. E-mail: [email protected] 2015 Informa UK Ltd.
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Hepper et al. also determined that the duration of effect may be short and only consistently lasts for 1 week [10].
The Physician and Sportsmedicine Downloaded from informahealthcare.com by Kainan University on 04/28/15 For personal use only.
Potential side effects of cortisone injections A general concern expressed among the medical research community is whether long-term use of IA steroids would cause any deleterious effects on joints or tissues [11-15]. One study attempted to addressed these concerns by comparing clinical and radiographic outcomes in a group of 68 patients treated with repeated IA knee injections of triamcinolone acetonide 40 mg (Kenalog) with a control group of 34 patients receiving saline injection into the knee; both IA steroid and saline injections were given every 3 months over the course of 2 years [14]. The authors demonstrated no differences in joint space width between the two groups at both 1 and 2 years of treatment. There was a greater improvement in range of motion and pain control in the corticosteroid group compared to the saline group at the end of the first year. Further, there was a significant improvement in knee pain and stiffness in the corticosteroid group over the 2 years; these results were not demonstrated in the control group. This trial provides some evidence for the long-term effectiveness and safety of IA corticosteroid injections, with no acceleration of the progression of OA noted in the treatment group. While complications of IA corticosteroid treatment are infrequent, the most commonly reported unwanted side effects include atrophy of the skin at the injection site, facial flush, and post-injection flare (soreness and inflammation following the injection) [12]. The facial flush is more commonly seen ~ 16 hours after IA injection of triamcinolone and it lasts on average 36 hours [16]. The post-injection steroid flare is thought to be due to injecting the crystalline nature of deposteroids which causes a crystal-induced synovitis [17]. This typically will occur within the first 24–36 hours post-injection and is usually self-limited [18]. Systemic side effects such as infection, increased blood glucose, hypercortisolism, and others are rarely seen, although careful planning and precautions such as utilizing gloves should be taken to avoid them. However, there is some evidence in the literature that shows an acute 2- to 3-day rise in blood glucose in patients with diabetes after a single IA corticosteroid injection of methylprednisolone or betamethasone in the knee [19]. While there is only a limited amount of literature regarding dose and systemic effects, it has been suggested that a dose > 40 mg has no added benefit and therefore limiting the dose accordingly will lower the risk of systemic side effects [20]. Preclinical studies suggest certain corticosteroids and associated anesthetics can be harmful to the viability of cartilageproducing cells known as chondrocytes [9,21,22]. Tendon rupture, predominantly the Achilles tendon, is another serious possible adverse effect of IA corticosteroid use that the literature does not currently adequately address but is a possible concern [23]. Although the clinical evidence to support these findings is limited, clinicians must carefully determine the type of steroid and dosage to be used for each individual patient. The risk of immunosuppression caused by a steroid-induced decrease in inflammatory response is not to be taken lightly.
Phys Sportsmed, 2015; Early Online:1–5
For that reason, multiple studies have reported the incidence of arthroplasty infection after the use of IA steroid injections. Only one study by the Mayo Clinic demonstrated a greater risk of infections on joints treated previously with this type of injection. There is no specific consensus on how long arthroplasty must be delayed to avoid this risk and therefore some clinicians use 2 months in order to avoid this unnecessary yet highly morbid risk [24]. A small amount of other side effects that have been reported include stoppage of lactation and transient menstrual disorder, thought to occur due to a decrease in estradiol. Other side effects may occur but are dependent on site of injection. For example, 12% of patients reported having ear, nose, and throat problems after a single epidural steroid injection – most were described as a transient change in voice [24]. Tachon’s Syndrome is a transient vagal response to IA or periarticular steroid injection that causes great anxiety to patients, but it is extremely rare – 1 event per 8000 injections. It consists of any of the following: diaphoresis, chest pain, hypotension, shortness of breath, and abdominal pain [24]. Ideal dosing schedule for IA corticosteroid shots The American College of Rheumatology advices physicians to only perform an IA steroid injection after 3 months from the previous injection. The safety of undergoing multiple corticosteroid injections in the knee joint over time has been well established in a clinical setting [25,26]. Most clinicians agree that for weight-bearing joints (such as the knee), a period of at least 8 to 12 weeks between corticosteroid injections is optimal [27]. Large doses which may occur with repeated dosing can cause more harm to the cartilage than benefit [3]. This corresponds with the empirical 3-month rule that is a common paradigm followed by many healthcare professionals. IA injection accuracy The clinician normally uses anatomic landmarks when performing an IA steroid injection. In the knee, this means palpating the patella and patellar tendon to determine the best access point to the joint. Depending on the condition of the skin and clinician preference, several options exist for the technical approach to knee IA corticosteroid injection [28]. Some of the more common injection sites include the superolateral portal, anteromedial portal, anterolateral portal, and mid-lateral portal. Importantly, injections placed via the superolateral or mid-lateral portal should be performed with the patient’s knee extended, while injections into the anteromedial and anterolateral portals should be performed with the knee flexed to ~ 60 to 90 [28]. The medial or lateral joint space can be used. The least commonly used and accurate is the infrapatellar bent knee approach [27]. The American College of Radiology advises that when performing musculoskeletal procedures, ultrasound should be used [29,30]. This, of course, is difficult in some settings as personnel may not be trained or an ultrasound device may not be available. While both methods are accepted, several authors have reported that a large number of anatomicalguided injections are inaccurately placed. One randomized
Current concepts of corticosteroid injections for knee osteoarthritis
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controlled study demonstrated that one-third of all anatomically guided injections to 184 patients were inaccurate; these injections were done at the elbow, wrist, ankle, shoulder, and knee with the accuracy of a trainee using US guidance being greater than a seasoned rheumatologist using anatomical guidance [31]. Other studies and evidence-based summaries show that US-guided injections are more accurate, ranging from 69% to 100% compared to 39% to 100% anatomically guided injections. This same study reports the finding of increased clinical improvement with ultrasound-guided injection – 52% versus 23% in patients without US-guided injection. In a large randomized controlled trial, Sibbit et al. found that US-guided IA injections, decreased 8% of the cost per responder per year which amounted to US$7. The same authors also reported that US-guided IA injection, decreased outpatient treatment costs by 33%, US$64 per responder per year and also improved patient-recorded clinical outcomes and cost-effectiveness [30,32,33]. A study comparing these three injection sites in 126 knees suggests that injections using ultrasound were more accurate in the mid-lateral and superolateral portal (95% p < 0.05 and 100% p < 0.05, respectively) compared to medial portals which were only 75% accurate [14]. Many factors affect the accuracy of a single injection and therefore we advise clinicians to perform the method that they are most comfortable with and to use ultrasound when possible. Efficacy of different corticosteroid medications available A variety of corticosteroids are available such as betamethasone (Celestone), dexamethasone (Decadron) LA, triamcinolone acetonide (Kenalog), and methylprednisolone acetate (Depo-Medrol) [28]. The agent of choice depends on the condition being treated, the joint being injected, and overall the preference of the clinician. The more commonly used IA steroids used in the United States include triamcinolone acetonide (Kenalog) and methylprednisolone acetate (DepoMedrol) [34]. The typical dosage of both triamcinolone and methylprednisolone acetate is 40 mg in large joints such as the knee and hip, with lower doses used in the hands or feet [35]. The recommended interval between injections is at least 3 months [35]. Table 1 lists the commonly used IA corticosteroid injections. A critical literature review with up-to-date findings provides a summary of commonly used corticosteroids and their dosing [35]. The solubility and duration of action differs in each corticosteroid, and typically, the lower the solubility, the longer is the duration [3]. Therefore, careful Table 1. Commonly used corticosteroids. Steroid Common concentration (mg per ml)
Common equivalent dosea (mg)
Approximate duration of action (days)
Methylprednisolone acetate Triamcinolone acetonide Triamcinolone hexacetonide Dexamethasone acetate Dexamethasone sodium
40 40 40 8 8
8 14 21 8 6
40 or 80 10 or 40 20 8 4
Note: Steroid agents listed in order of prevalence of use. Dose equivalent to 40 mg of methylprednisolone acetate or triamcinolone acetonide (the most commonly used intraarticular steroid).
a
3
analysis of steroid pharmacokinetics should be considered in each treatment plan. What is the purpose in combining IA corticosteroids with local anesthetic agents? Local anesthetics such as lidocaine and bupivacaine are commonly used to provide rapid pain relief until the corticosteroid of choice begins to take effect [36]. Corticosteroids can often take 24 hours before the patient begins to experience relief while local anesthetics have a much shorter onset of action: lidocaine: ~ 1–2 minutes and bupivacaine: ~ 30 minutes. However, due to the limited duration of action of the local anesthetics, ranging from ~ 1 hour for lidocaine to ~ 8 hours for bupivacaine, the patient may experience a transient return of joint pain as the local anesthetic wears off, before the onset of the effects of the corticosteroid. If local anesthetic is used in combination with the corticosteroid, then the patient should be counseled as to the potential of a transient recurrence of pain in the first 1–2 days following injection. To further decrease the discomfort received by the patient, many clinicians also employ a topical vapocoolant on the skin prior to the injection [28]. Of note, there is some evidence for caution regarding chondrotoxicity when combining local anesthetic with corticosteroids. One in vitro study found that 88 mg of 1% lidocaine or 22 mg of 0.25% bupivacaine combined with betamethasone sodium phosphate, betamethasone acetate, methylprednisolone acetate, or triamcinolone acetate injected into a bioreactor simulating normal joint fluid with chondrocyte culture cell wells results in a pronounced chondrotoxic effect [37]. However, for single IA injections administered with at least 3-month intervals between injections, the chondrotoxicity is limited, and combination injections remain widely used by clinicians. What are the contraindications to IA corticosteroid use? Based upon a review of the best available evidence, the contraindications to IA injection are all relative. Certainly, allergies to the injection preparation products and/or injection agents are contraindications to injection. Other contraindications include active superficial skin/soft tissue infection (cellulitis), suspected IA infection, unstable coagulopathy, anticoagulant therapy, uncontrolled diabetes mellitus, and broken skin at the injection site [27,38,39]. Patients who are on anticoagulant therapy should be approached with caution, and certain precautions following injection such as placement of a pressure dressing, as well as pre-injection precautions, such as obtaining prothrombin time laboratory values, can be helpful. What are the alternatives to corticosteroids? IA injection of HA, also known as viscosupplementation, has been an extremely popular treatment option for knee OA. The efficacy of HA injections, especially when compared to corticosteroid injections, has become a topic of controversy within the orthopedic community. In 2006, a Cochrane review of 76 clinical trials determined that HA is effective for the
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T. Y. Law et al.
treatment of knee OA and has a prolonged effect when compared with IA corticosteroids [40]. Further, a recent study comparing IA injection of HA efficacy to nonsteroidal antiinflammatory drugs (NSAIDs) concluded that IA injection of HA is equal to NSAIDs being continuously used for 5 weeks and has a better safety profile when considering side effects [41]. Recently, a systematic review and meta-analysis assessing the outcomes of IA corticosteroids versus HA injections was conducted, in which seven clinical trials analyzing 610 knees were described. The authors concluded that by week 4 following therapy, corticosteroids are relatively more effective for pain than HA, but that after 2 months, HA has greater efficacy [11]. This suggests that HA may be beneficial for longterm management of OA. In 2013, the American Academy of Orthopaedic Surgeons updated their clinical practice guidelines for the treatment of OA, and specifically noted that HA is no longer recommended as a modality for treating symptomatic OA. The authors noted that while several of the 14 studies included in their review demonstrated the effectiveness of HA, the overall combined results of all studies did not meet minimum clinically important improvement thresholds. This same workgroup did, however, recommend the use of IA corticosteroids for short-term pain relief of symptomatic OA. Certainly, further research into the efficacy of both treatment options is warranted. One of the biggest downsides to HA injections involves cost, and this should be taken into consideration if recommending HA therapy. In addition, several HA treatment regimens require serial injections over the series of 3–5 weeks, which may affect patient compliance and cooperation.
Conclusion IA corticosteroid injections have been shown to be safe and effective in treating the painful symptoms of OA of the knees. It may not be effective for all patients and the duration of effect can also be short although rapid in onset. This makes corticosteroid injections viable in the short term but may limit its ability to be used as a single long-term treatment option. Alternative options such as HA can be considered when IA corticosteroid injections fail to provide adequate pain relief. Recommendations Upon reviewing the literature it is clear that IA corticosteroids are effective but may not have an immediate onset of pain relief. Therefore, it may be beneficial to combine the corticosteroid of choice with a local anesthetic to offer the patient rapid pain relief. Although short-acting lidocaine is used for diagnostic purposes, a long-acting bupivacaine to prevent the flare and dilute the lidocaine (to prevent chondrotoxicity in large joints) is recommended. In addition, whenever possible the use of an ultrasound would enhance the accuracy of injections. Although the literature is not conclusive on treatment frequency, it is generally recommended to keep the injections limited to once every 3 months but can be earlier if symptoms warrant.
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Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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