Injectable Corticosteroids in Modern Practice

Home , Cortivazol, Joint injection, Prednisolone tebutate

Brian J. Cole, MD, MBA, and H. Ralph Schumacher, Jr, MD

Abstract

Long-lasting, crystalline suspensions of injectable corticosteroids have been used to may be preceded by a mild initial in- treat joint and soft-tissue disorders for many years; they decrease inflammation by flammatory response immediately reducing local infiltration of inflammatory cells and mediators. Depot formulations following the injection.3 differ in their characteristics. Compounds with low solubility are thought to have In addition to local effects, intra- the longest duration of action but may cause tissue atrophy when used in soft tis- articular corticosteroids may elicit sues. Intra-articular corticosteroids are commonly used to treat osteoarthritis and dose-related systemic effects. Marked inflammatory arthritis: meta-analyses confirm their benefit in reducing pain and improvements in inflammatory mark- symptoms. Intra-articular corticosteroid injections have been shown to be safe ers, such as erythrocyte sedimentation and effective for repeated use (every 3 months) for up to 2 years, with no joint space rate (ESR) and C-reactive protein narrowing detected. Fewer clinical trials are available for extra-articular uses for level, can occur in patients with rheu- injectable corticosteroids, although there is evidence of efficacy in a variety of soft- matoid arthritis (RA) who receive tissue conditions. The accuracy of injections affects outcomes. Postinjection flare, intra-articular treatment with cortico- facial flushing, and skin and fat atrophy are the most common side effects. Systemic steroids. Effects of intra-articular cor- complications of injectable corticosteroids are rare. ticosteroids are frequently observed J Am Acad Orthop Surg 2005;13:37-46 on noninjected involved joints, further suggesting the importance of systemic effects. However, the effect on noninjected joints is variable, ranging from First used for arthritic joints more than and retention of crystals at the site of no response to complete response. 50 years ago, injectable corticosteroids injection. Understanding the different remain a mainstay of treatment of formulations, the factors that affect out- many causes of acute joint or soft-tissue come, and the common complications Commonly Used Depot pain. In a survey, 51% of rheumatolo- is necessary to use injectable cortico- Corticosteroids gists stated that they used injectable steroids appropriately for both intra- corticosteroids frequently; an additional articular and soft-tissue conditions. Corticosteroids are available in sev- 42% used them at least some of the eral different formulations, includ- time.1 The results of using injectable corticosteroids, however, have not been Mechanism of Action rigorously evaluated. Controlled tri- Dr. Cole is Director, Rush Cartilage Restoration als with these agents have been few, The pathways by which injectable de- Center, Rush University Medical Center, Chica- and much of the evidence concern- pot corticosteroids mediate symptom go, IL. Dr. Schumacher is Chief of Rheumatology, ing both efficacy and safety remains relief are not completely understood, VA Medical Center, Philadelphia, PA. anecdotal. This may be because these and they may differ from the mech- drugs are indeed assumed to be ef- anisms associated with systemic cor- Dr. Cole or the department with which he is affiliated has received research or institutional fective as well as because of the dif- ticosteroids. Local action of decreas- support from Pfizer. Dr. Schumacher or the ficulty in measuring subjective out- ing inflammation in synovial tissues department with which he is affiliated serves as a comes, such as pain or swelling. is believed to be the primary effect of consultant to or is an employee of Pfizer. Despite the scarcity of high-quality depot corticosteroids. The effect is clinical trial data, a large body of lit- particularly profound on edema as Reprint requests: Dr. Cole, Rush University Medical Center, Suite 1063, 1725 W Harrison erature is available related to inject- well as the number of lymphocytes, Avenue, Chicago, IL 60612. able corticosteroids. Depot formula- macrophages, and mast cells.2 Other tions vary in their physical and studies have found reductions in in- Copyright 2005 by the American Academy of pharmacologic characteristics, partic- flammatory cells in joints after corti- Orthopaedic Surgeons. ularly with regard to their solubility costeroid injections, although this

Vol 13, No 1, January/February 2005 37 Injectable Corticosteroids in Modern Practice ing pills, ointments, and soluble and pal tunnel syndrome and trigger drocortisone acetate, betamethasone depot parenteral formulations. Of ﬁnger. sodium phosphate, betamethasone these, only depot formulations are The choice of depot corticosteroid acetate, and prednisolone tebutate. suitable for injecting joints. Depot is based on a variety of consider- Because many facilities keep only one formulations tend to remain at the ations, including the availability, cost, or two depot corticosteroids on hand, injected site for a long period of time versatility, and pharmacokinetics of the versatility of an agent can play a and display mainly local effects. the agent. In a survey of members of key role in its use. The ability of meth- Water-soluble formulations, such the American College of Rheumatol- ylprednisolone acetate to be used for as dexamethasone, diffuse rapidly ogy (ACR), the most commonly used both joint and soft-tissue injections from the injected regions and exert depot corticosteroids were methyl- likely contributes to its widespread mostly systemic effects. Neverthe- prednisoloneacetate(35%),triamcin- use5-10 (Table 1). less, soluble formulations are useful olone hexacetonide (31%), and triam- for certain extra-articular conditions cinolone acetonide (22%).4 Other Pharmacokinetics of the upper extremities, such as car- available preparations include hy- In general, the pharmacokinetics

Table 1 Characteristics of Depot Corticosteroids* Average Solubility Serum Peak Plasma Duration (% Half-Life Concentration of Action Generic Name wt/vol)5 Crystal Structure6 (days) (ng/mL) (days)† Fluorinated Betamethasone NA Betamethasone acetate: 6.37 10.8 Approximately Yes sodium 10 to 20 µm, (after 7-mg 98,9 phosphate and rod-shaped with injection in betamethasone blunted ends, negative one knee7) acetate birefringence; difficult to distinguish from sodium urate crystals Hydrocortisone 0.002 NA NA NA 6-409 No acetate Methylprednisolone 0.001 Small, pleomorphic, 5.8 11.8 7-8410 No acetate tendency to (dose not agglutinate, strong speciﬁed) birefringence Prednisolone 0.001 Small, pleomorphic with NA NA 10-158,9 No tebutate a branched and irregular conﬁguration, positive birefringence Triamcinolone 0.004 Very similar to 3.2-6.47 Approximately 11 148,9 Yes acetonide methylprednisolone (after 40-mg acetate, but with a injection into one slightly increased knee)7 tendency to agglutinate and slightly stronger birefringence Triamcinolone 0.0002 15 to 60 µm, rod-shaped, 4.67 Approximately 3 8-90+10 Yes hexacetonide negative birefringence; (after 40-mg difficult to distinguish injection into one from sodium urate knee)7 crystals

NA = not available. * Unless otherwise noted, information is derived from the manufacturer’s prescribing information. † Most studies were short-term. Estimates of duration of pain relief were, in many cases, based on clinical impression.

38 Journal of the American Academy of Orthopaedic Surgeons Brian J. Cole, MD, MBA, and H. Ralph Schumacher, Jr, MD of depot corticosteroids are not as injected with normal saline, beta- a meta-analysis13 and suggests that un- well studied as those of intravenous methasone acetate crystals disap- derstanding of the mechanism of ac- formulations,andconventionalphar- peared from the fluid within 24 hours, tion of these agents is incomplete. macokinetic parameters, such as whereas triamcinolone hexacetonide peak plasma concentrations and se- crystals were still present at 48 hours, Chemical Structure and rum half-life, may not be relevant to and prednisolone tebutate crystals Considerations the local actions of depot formula- lasted throughout the 7-day study.11 The addition of a fluorine group tions. The serum half-life influences In rat air pouches injected with MSU to the base corticosteroid molecule the systemic effects associated with crystals, betamethasone resulted in a can increase absorption and activity, injected corticosteroids, but its im- rapid but mild decrease in inflamma- but it may also result in increased side pact on local activity with intra- tion. Triamcinolone hexacetonide and effects.14 However, patients who ex- articular use is less clear and proba- prednisolone tebutate dramatically perience adverse reactions to a fluo- bly is negligible. suppressed inflammation at 7 days, rinated compound may be able to tol- but their use also resulted in atrophy erate a nonfluorinated compound. Solubility and necrosis of the membranes. All Chemical incompatibility between Solubility is a key issue because three corticosteroid preparations re- injectable corticosteroids and other compounds with lower solubility sulted in an increase in MSU crystals agents can result in flocculation. In- may maintain effective synovial lev- on the synovial surface and in the jectable corticosteroids are often com- els for a longer time and produce low- number of tissue deposits of MSU bined with local anesthetics because er systemic levels than would com- (tophi-like formations).11 This study injecting both agents not only provides pounds with greater solubility. In a thus highlights the different proper- immediate pain relief but also can ver- comparison of triamcinolone ace- ties of various injectable corticoster- ify that the site injected was the source tonide and triamcinolone hexace- oid formulations and the potential of pain.15 In some cases, combinations tonide, Derendorf et al7 found that to- impact of these characteristics on both of corticosteroids and anesthetics are tal absorption amount was similar efficacy and side effects. available from the manufacturer. If not, between the two compounds. How- In humans, depot corticosteroid the mixture should be carefully in- ever, the absorption rates were mark- crystals have been detected in sy- spected for the formation of precip- edly different, with triamcinolone novial fluid for up to 1 month after itates before injection. hexacetonide released more slowly joint injection.3,6 The crystal struc- than triamcinolone acetonide, result- tures of different preparations vary ing in lower peak plasma levels. A (Table 1), and light microscopy may Intra-articular Injections lower systemic level of corticosteroids not always be able to differentiate is generally viewed as a favorable fea- between corticosteroid crystals and Uses ture because of potential reductions other crystals involved in inflamma- The most common and best- in systemic toxicity. However, lower tory arthritis, such as MSU, calcium studied use of injectable corticoster- plasma levels also may result in re- pyrophosphate dihydrate, and hy- oids is for joint disorders. ACR guide- duced effects on inflammation at non- droxyapatite.3 lines support the value of these injected sites. Although compounds treatments of acute knee pain in os- with low solubility are well suited for Duration of Action teoarthritis16 and for joints affected by intra-articular injections, they may The reported ranges for duration RA.17 Other joint conditions that may not be appropriate for soft-tissue in- of action vary widely between differ- respond to corticosteroid injections jections because of associated side ef- ent corticosteroids and sometimes include juvenile RA, crystal deposi- fects, particularly atrophy of sur- even for the same corticosteroid. Al- tion diseases (ie, gout and pseudo- rounding tissues.5 though some data suggest that de- gout), systemic lupus erythematosus creased solubility correlates with a and mixed connective tissue disease, Crystal Structure sustained clinical effect, this is not nec- acute traumatic arthritis, psoriatic ar- Direct examinations of corticoster- essarily always the case. In one clin- thritis, ankylosing spondylitis, and ar- oid crystals have been performed. In ical trial, triamcinolone hexacetonide, thritis associated with inflammatory one study,corticosteroid formulations a compound with lower solubility, gastrointestinal disorders. The main were injected into rat subcutaneous showed a less durable clinical effect goal of treatment is to relieve pain and air pouches 24 hours after injection when injected into osteoarthritic knees control synovitis in affected joints. An with either normal saline or mono- than did a more soluble compound, associated benefit of reducing syno- sodium urate (MSU) crystals to stim- methylprednisolone acetate.12 This vitis may be increased ability to ex- ulate inflammation. In air pouches finding also is supported by data from ercise and improve muscle strength.

Vol 13, No 1, January/February 2005 39 Injectable Corticosteroids in Modern Practice

Intra-articular injections also have nificant benefits associated with intra- ability. Neither corticosteroid medi- been useful in controlling pain and articular corticosteroids (P = 0.009), ated significant reductions in stair decreasing rehabilitation time after but long-term improvements may re- climbing time.12 arthroscopic knee surgery.18,19 Follow- quire higher doses (50 mg equivalent Raynauld et al23 reported that re- ing diagnostic knee arthroscopy, the of prednisone). Five studies reported peated intra-articular corticosteroid in- addition of methylprednisolone to changes in pain on a visual analog jections into the knee were safe and intra-articular injections of bupiv- scale (VAS) 2 weeks after treatment, effective for up to 2 years. In this acaine plus morphine, compared with and the pooled data from these stud- double-blind trial, 66 patients were a saline injection and bupivacaine/ ies found a statistically significant randomized to receive triamcinolone morphine injection, resulted in signif- effect in favor of treatment (P = acetonide or saline into the study knee icant benefits in pain reduction dur- 0.00001).21 every 3 months for up to 2 years. As- ing leg lift (P = 0.0001 and P = 0.006, The meta-analysis by Godwin and sessments of the primary outcome— respectively), flexion to 90° (P = 0.001 Dawes13 examined five randomized progression of joint space narrowing— and P = 0.002), and walking up and placebo-controlled trials published be- revealed no significant differences down stairs (P = 0.0001 and P = tween 1980 and 1999 that reported between treatment groups in mean 0.008).18 Injection of intra-articular tri- pain outcomes on a VAS.All five stud- joint space width at 1 and 2 years. Pa- amcinolone acetonide after arthro- ies also were included in the meta- tients who received intra-articular cor- scopic knee surgery also resulted in analysis of Arroll and Goodyear- ticosteroids showed a significant (P significantly lower pain scores (P < Smith.21 Pooled data indicated that = 0.05) improvement in range of mo- 0.05 to P < 0.01) and significantly few- treated patients were more likely than tion compared with placebo at 1 year. er requests for rescue analgesia (0% placebo patients to achieve clinically Other parameters, including pain, stiff- versus 53%; P < 0.001) compared with significant pain reduction at 1 week ness, and physician’s and patient’s glo- saline.19 and at 3 to 4 weeks. By 6 to 8 weeks, bal assessments, were not statistical- no significant reductions in pain were ly different between treatment groups Clinical Trial Data observed. The pain relief appeared to at 1 and 2 years. However, area-under- Few controlled long-term studies vary depending on the compound the-curve analyses for knee pain at are available assessing the duration used. None of the three studies night and knee stiffness found a sig- of pain relief after intra-articular cor- using triamcinolone hexacetonide nificant difference (P = 0.05 for both) ticosteroid injection. Variations in find- showed an effect on pain beyond 1 over 2 years in favor of patients re- ings range from 1 week with only mar- week. In contrast, methylprednisolone ceiving intra-articular corticosteroids. ginal benefit relative to placebo20 to showed a significant effect on pain at This study thus supports the safety dramatic pain relief lasting up to 13 3 weeks, and cortivazol (a cortico- of long-term corticosteroid injections weeks.10 Two recent meta-analyses steroid not approved for use in the and their ability to improve clinical have tried to reconcile these data for United States) continued to reduce symptoms over the course of 2 years.23 osteoarthritis of the knee.13,21 The meta- pain at 4 weeks.13 Fewer data are available on the use analysis by Arroll and Goodyear- A recent trial that compared meth- of intra-articular corticosteroids in the Smith21 included 10 placebo-controlled ylprednisolone acetate and triamcino- treatment of joints affected by RA. randomized trials, published between lone hexacetonide supported the sus- However, some studies suggest that 1958 and 2003, in which improvement tained effect of methylprednisolone the duration of pain relief may be of symptoms was included as an out- acetate in patients with knee osteoar- longer than for osteoarthritis. In a ret- come. Jadad quality scores, which pro- thritis.12 In 57 randomly assigned pa- rospective study, a sustained clinical vide an estimate of the overall qual- tients, both methylprednisolone ace- remission occurred in 75% of inject- ity of each study on a scale of 0 (lowest tate and triamcinolone hexacetonide ed joints during the 7-year follow-up. quality) to 5 (highest quality), ranged resulted in significant (P < 0.01) dif- However, these patients also were re- from2to5.22 All six studies that ex- ferences in VAS-measured pain reduc- ceiving systemic therapy with disease- amined symptom improvement at 2 tion at 3 weeks (change from baseline modifying antirheumatic drugs.24 weeks reported greater improvement of 13.7 and 32.9 mm, respectively). Although the literature indicates in patients who received intra-articular However, at 8 weeks, only methyl- that many patients respond to intra- corticosteroids compared with place- prednisolone showed a significant (P articular corticosteroid therapy, there bo, and the pooled data were highly < 0.05) effect on pain scores (change are no consistent data on the duration significant for the overall effect (P < from baseline of 18.3 and 7.6 mm, re- of pain relief after injection. Individ- 0.00001). The two methodologically spectively). Similar results were ob- ual patients respond differently, and sound studies that examined improve- tained with Lequesne index scores, a specific agents also may vary in their ment at 16 to 24 weeks also found sig- measure of symptom severity and dis- effects. Study design, injection tech-

40 Journal of the American Academy of Orthopaedic Surgeons Brian J. Cole, MD, MBA, and H. Ralph Schumacher, Jr, MD nique, the condition being treated, cessful aspiration also confirms that the benefits of resting joints may not and type and frequency of outcome the injection was intra-articular. be immediately apparent but can be assessments also may contribute to The combination of intra-articular notable during the recovery period. the wide disparities observed. A trial corticosteroids plus joint lavage may Clinical experience provides further of this therapy is needed to determine provide modest short-term benefits. support for the benefits of resting effectiveness in any given patient. Compared with patients who received joints after injection of intra-articular lavage alone, significantly (P = 0.004) corticosteroids.24 Practical Considerations more patients treated with intra- One of the factors that may affect articular methylprednisolone ace- the variability in response to intra- tate and lavage met Osteoarthritis Extra-articular Injections articular injections is placement of the Research Society International re- needle. A radiographic study of injec- sponse criteria at 4 weeks (33% ver- Uses tions into various joints found that 56 sus 58%, respectively).29 However, no Corticosteroid injections are also (52%) of 108 injections were definite- significant differences were observed useful in treating a variety of nonar- ly intra-articular; the others either at other time points (2, 8, 12, or 24 ticular disorders, particularly overuse were extra-articular or the location weeks) or with other outcomes, includ- syndromes (eg, tendinitis, bursitis, could not be clearly determined from ing pain and stiffness.29 The short-term ligament sprain, tenosynovitis), acute the radiograph.25 More accurate nature of this benefit may explain why athletic injuries, and nerve compres- placement resulted in better clinical other studies have not detected ad- sion syndrome. Rather than entering outcome. Improvements in joint in- ditional improvements when these the joint, extra-articular injections are flammation were observed in 59% of techniques are combined. targeted to the area surrounding the patients whose injections were intra- Although one controlled study joint (periarticular), into tendons (eg, articular compared with 37% of pa- found that resting the joint after in- lateral epicondylitis), or above ten- tients whose injections were extra- jection is helpful,30 another study did dons (eg, subacromial space above articular.25 A more recent study that not find such a benefit.31 These dif- the rotator cuff). Table 2 shows the focused exclusively on intra-articular fering conclusions probably can be most common uses of corticosteroid injections into the knee found a high- explained by the different time course injections among orthopaedic sur- er accuracy rate of 75%, with entry of assessments. The authors of the geons.32 through the lateral midpatellar por- study that did not find a benefit con- The effects of injectable corticoster- tal resulting in the highest rate of cor- ducted assessments at baseline, 48 oids in nonarticular locations are not rect placement (93%).26 hours, and 10 months. They did not completely understood. In some cas- The generally accepted recommen- detect any changes in pain or tender- es, intramuscular injections of rela- dation for frequency of intra-articular ness, swelling, or range of motion in tively soluble corticosteroids may re- injections is no more than once every rheumatoid joints rested for 48 hours lieve polyarticular inflammation 3 months into the same joint.17 How- after injection compared with non- through systemic absorption and pro- ever, this is more an empiric recom- rested joints.31 In contrast, the authors vide benefits for weeks.5 However, in- mendation than an evidence-based of the study that found a benefit to flammation is not always associated one and likely was originally found- resting joints examined patients for with tendinopathies; when present, ed on concerns of possible arthrop- up to 24 weeks after injection. Patients inflammation may be necessary for athy. who did not rest joints and those who the healing process. Corticosteroids Some studies suggest that synovial rested joints for a minimum of 24 may act through different mecha- fluid aspiration should accompany hours after injection showed similar nisms to mediate symptom relief of intra-articular injections. Successful improvements at 3 weeks. Improve- noninflammatory conditions. aspiration of synovial fluid at the time ments in pain and stiffness were gen- of corticosteroid injection is signifi- erally maintained over 24 weeks in Clinical Trial Data cantly (P < 0.01) associated with treat- patients in the rested group but not There are few controlled clinical ment response27 and with significant in those in the nonrested group. At trial data of nonarticular uses of cor- (P = 0.001) reductions in relapses in 24 weeks, the rested group showed ticosteroids on which to base treat- the 6 months after the injection.28 The notable improvements in median ar- ment decisions.33,34 In a systematic re- explanation for this phenomenon eas under the curve in pain score, view by Smidt et al,33 13 randomized may have to do with a decrease in stiffness score, knee circumference, controlled trials were identified in symptoms (ie, pain, stiffness) because walking time, and C-reactive protein which corticosteroid injections were of reductions in the effusion or to re- measures compared with the nonrest- used in patients with lateral epi- duced dilution of the injection. Suc- ed group.30 This study suggests that condylitis. All but one of the studies

Vol 13, No 1, January/February 2005 41 Injectable Corticosteroids in Modern Practice

costeroid injections. The authors sug- In another randomized trial of pa- Table 2 Most Common Extra-articular Uses gest that high-quality studies with tients with carpal tunnel syndrome, for Corticosteroid Injections by longer follow-up periods are needed methylprednisolone acetate plus li- Orthopaedic Surgeons to resolve the role of injectable cor- docaine was compared with lidocaine ticosteroids in lateral epicondylitis.33 alone.42 At 1 month, 77% of patients Orthopaedic The use of corticosteroids in the in the corticosteroid group (23/30) Condition Surgeons* (%) treatment of trigger finger is support- did not require further treatment, Elbow epicondylitis 93 ed by two randomized controlled compared with 20% of the patients in Shoulder bursitis 91 studies.35,36 In both, a single injection the lidocaine-only group (6/30). Al- Greater trochanteric 91 of a local anesthetic in combination though some of the responders began bursitis with either methylprednisolone ace- to experience symptoms over time, at de Quervain’s 87 tate35 or betamethasone36 successful- 12 months, 50% of the corticosteroid tenosynovitis ly treated trigger finger in about 60% group (15/30) still did not require fur- Shoulder bicipital 81 of patients, whereas local anesthetic ther treatment compared with 7% of tendinitis alone improved the condition in the lidocaine-only group (2/30). A Pes anserine 78 about 20% of patients. A retrospective lower rate of long-term responses was bursitis study of 235 patients with 338 prima- reported in a recent prospective study Plantar fasciitis 73 ry trigger fingers provided further ev- of 73 patients.43 In this study, 10% of Myofascial trigger 70 idence for the use of injectable cor- patients remained asymptomatic 1 points ticosteroids for this condition.37 In this year after receiving three betametha- Carpal tunnel 56 study, 49% of fingers showed resolu- sone injections into the carpal tunnel syndrome tion or improvement after a single in- and wearing a wrist splint for 9 Finger 52 jection; an additional 23% improved weeks. Patients with recent mild to tenosynovitis after two injections. Corticosteroid in- moderate symptoms seemed to have Tarsal tunnel 37 jections also may be effective in the better responses to corticosteroid in- syndrome treatment of de Quervain’s tenosyn- jections than did those with long- Achilles tendinitis 33 ovitis.38,39 In a prospective study, ap- lasting or more severe symptoms. Back pain (epidural 24 proximately 90% of patients respond- Buchbinder et al34 performed a space injection) ed to treatment.38 Cochrane review of corticosteroid in- * Percent of 233 surveyed orthopaedic Carpal tunnel syndrome also may jections for shoulder pain. Pooled surgeons who use corticosteroid respond to corticosteroid injections. data indicated that subacromial cor- injections for a given condition. In a Cochrane review of five random- ticosteroid injection was superior to Adapted with permission from Hill JJ 40 Jr, Trapp RG, Colliver JA: Survey on ized trials, Marshall et al conclud- placebo in treating rotator cuff disease the use of corticosteroid injections by ed that corticosteroid injections were but was comparable to nonsteroidal orthopaedists. Contemp Orthop more effective than placebo in reliev- anti-inflammatory drugs. For adhe- 1989;18:39-45. ing symptoms for up to 1 month. Cor- sive capsulitis, a possible short-term ticosteroid injections also provided benefit of corticosteroid injections greater clinical improvement than did was suggested, but there were insuf- had poor internal validity scores, thus oral corticosteroids for up to 3 months ficient data for pooling, and more limiting the conclusions that could be after treatment. In one randomized high-quality studies are required.34 drawn from pooled data. Neverthe- trial, 30 patients received oral place- A review of the treatment of less, the data indicate that cortico- bo for 10 days along with a single anserine bursitis identified two stud- steroid injections resulted in superi- methylprednisolone acetate injection ies involving corticosteroid injections or short-term (<6 weeks) outcomes in into the carpal tunnel; another 30 and concluded that this is the only pain and global improvement com- patients received oral prednisolone treatment modality with proven suc- pared with injections with local an- daily for 10 days along with a single cess in treating this condition.44 In one esthetics or with conservative treat- saline injection.41 Compared with the trial, corticosteroid injections result- ment. Comparisons with placebo oral prednisolone group, the group ed in notable reductions in pain com- were made in only two studies, and receiving methylprednisolone injec- pared with naproxen (corticosteroid, the data were inconsistent. Of the six tions experienced significant im- 70% significantly improved and 30% studies that examined intermediate (6 provements in symptoms at 8 and 12 resolved; naproxen, 58% and 5%, re- weeks to 6 months) or long-term (>6 weeks (P = 0.002 and P = 0.004, respectively). months) outcomes, none found sig- spectively). Further time points were The use of injectable corticoste- nificant differences in favor of corti- not assessed. roids to treat trochanteric bursitis has

42 Journal of the American Academy of Orthopaedic Surgeons Brian J. Cole, MD, MBA, and H. Ralph Schumacher, Jr, MD not been assessed in a randomized tri- edged in the 2002 ACR update of the Side Effects al. However, an open observational Guidelines for the Management of Rheu- The most common side effects of study of a single injection of be- matoid Arthritis: “Glucocorticoid injec- corticosteroid injections are postinjec- tamethasone mixed with lidocaine tion of joints and periarticular struc- tion flare, facial flushing, and skin or has been conducted.45 More than tures is safe and effective when fat atrophy.49 The frequency of these three fourths (77%) of patients report- administered by an experienced phy- events depends on the compound ed pain relief at 1 week after injection, sician.”17 This statement reflects a and dose administered, the route of and 61% continued to report im- large body of clinical data. A recent administration, and how closely pa- provement in pain at week 26. These prospective evaluation of 1,147 intra- tients are followed after the proce- data suggest that corticosteroid injec- articular and periarticular corticoster- dure. Postinjection flare, typically tions can provide long-lasting bene- oid injections with methylpredniso- marked by pain in the injected joint fit for trochanteric bursitis. lone acetate found a very low rate of or at the site of injection, affects 1% complications, with transient injec- to 10% of patients. In most cases, ad- Practical Considerations tion pain the most common (6.7% of verse reactions occur later the same As with intra-articular injections, patients).48 The only long-term effects day; a lag time of 24 to 48 hours was the accuracy of needle placement can persisting beyond 6 months involved reported by about 10% of affected pa- be a key factor in the outcome of soft- two cases of subcutaneous lipodys- tients in one study.48 Postinjection tissue disorders. In one study that trophy, which were attributed to in- pain and flares may be caused by the used radiographic contrast material sufficient depth of injection. needle puncture but more common- to track injection accuracy during lo- As with all procedures, however, ly are thought to result from chem- cal corticosteroid injections to the in certain instances, corticosteroid in- ical synovitis in response to the inject- shoulder, only 14 (37%) of 38 proce- jections should not be used. Absolute ed crystals.6 In most cases, analgesic dures were found to be accurately contraindications to corticosteroid in- therapy or ice packs adequately con- placed. Subacromial injections (29% jections include a suspected or known trol discomfort, and symptoms sub- accurate placement) were more dif- joint infection, the presence of a pros- side within 48 hours.48 ficult than glenohumeral injections thetic joint, or a fracture in the joint Facial flushing occurs in up to 15% (42%).46 Outcomes in patients who re- being injected. Caution should be of patients and is particularly com- ceived accurately placed injections used in patients with joint instability, mon in women. The onset is usually were superior to outcomes in those coagulopathy, or overlying cellulitis within a few hours of injection, and whose injections were inaccurately or infection.5 symptoms may linger for 3 to 4 placed (Fig. 1). Significant (P < 0.05) differences in changes from baseline between the two groups were found Accurate Inaccurate in stiffness, loss of function, flexion, and abduction. 20* Use of sonography could increase 20 the accuracy of injection location and 17* thereby improve outcomes. In a study in which blinded subacromial corti- 15 costeroid injections were compared with ultrasonography-guided injec- 10 tions in patients with painful shoul- 8 ders, the group receiving guided injections had significantly greater improvements in pain scores (P < 5 3.3 2.9* 2.8* 0.001) and in shoulder function (P = 1.7 2 0.012) at 6 weeks compared with the 0.9 0.4 Mean Improvement from Baseline group receiving blinded injections.47 0 Power Stiffness Loss of Flexion Abduction Function Safety Figure 1 Mean improvement from baseline in clinical outcomes of patients with shoulder The excellent overall safety record of symptoms who received either accurately or inaccurately placed corticosteroid injections. There were significant differences in four of five outcome parameters (* = P < 0.05).46 injectable corticosteroids is acknowl-

Vol 13, No 1, January/February 2005 43 Injectable Corticosteroids in Modern Practice days.49 Skin or fat atrophy after injection (Fig. 2) may be more common with less soluble agents, such as the triamcinolone compounds.49 In the prospective study of methylprednisolone acetate complications by Kumar and Newman,48 4 (0.6%) of 672 patients reported subcutaneous lipo- dystrophy. Effects lasted beyond 6 months in two patients. Of the less common side effects, joint sepsis is of the greatest concern, with reported incidences ranging from 1 in 3,000 to 1 in 50,000.50 Cur- rent rates may be even lower because of improved sterile technique and the availability of corticosteroid preparations in prefilled syringes, which reduces handling. In a survey of 191 orthopaedic surgeons, rheumatologists, and general practitioners, only 12.6% had ever encountered septic arthritis Figure 2 A, Right shoulder of an 18-year-old woman after a corticosteroid injection into the subcutaneous fat resulted in localized fat atrophy. B, Coronal T1-weighted MRI scan with after corticosteroid injection of the gelatin capsule against region of fatty atrophy demonstrating marked volume loss in sub- knee, and only 3% had encountered cutaneous fat. it more than once.50 Case reports have documented the occurrence of tendon ruptures in pa- Systemic Effects The ability of intra-articular injec- tients after corticosteroid injections.51 Systemic effects of injectable cor- tions to suppress the hypothalamic- These appear to be associated with in- ticosteroids are influenced by the pituitary-adrenal (HPA) axis is well jections placed directly within tendons, agent used, dose, frequency, and documented.55-57 Suppression is usu- which may accelerate degeneration of number of joints injected.49 Systemic ally mild and transient. In one study the already damaged tissue. effects from corticosteroid injections in which 11 patients received intra- Although animal studies have sug- are generally milder than with oral articular injections of methylpred- gested that corticosteroid injections or intravenous formulations. Al- nisolone acetate, 9 showed an aver- may have deleterious effects on artic- though osteoporosis is a known side age 21.5% reduction in serum cortisol ular cartilage, studies in humans have effect of systemic glucocorticoids, a levels 24 hours after injection. By 72 not shown similar results. In a trial study of the effect of intra-articular hours after injection, eight had re- in which patients with osteoarthritis triamcinolone acetonide on markers turned to normal physiologic cortisol of the knee received triamcinolone ac- of bone metabolism found no net ef- levels.56 However, prolonged HPA etonide 40 mg or placebo injections fects on bone resorption and only a axis suppression (5 to 7 weeks57 and every 3 months for up to 2 years, no transient effect on bone formation.54 11 weeks55 after the last injection) has difference in loss of joint space was Furthermore, improvements in mo- been reported, in one case accom- observed at the 1- or 2-year follow- bility may help counteract osteo- panied by Cushing’s syndrome.55 up evaluations.23 In another study of porotic effects. Corticosteroid-associated HPA axis patients with RA, joint arthroplasty Corticosteroid-induced myopathy suppression could pose a particular surgery was no more common dur- is a possible consequence of therapy, problem during situations involving ing a 7-year follow-up in a joint that but it has not been reported after intra- physical stress, such as surgery. received four or more intra-articular articular injections. Corticosteroid- Corticosteroids can increase hepatic injections per year than in those that induced myopathy is more common glucose synthesis and antagonize in- received less frequent injections.52 In with fluorinated corticosteroids (tri- sulin effects, resulting in worsening children with chronic arthritis, treat- amcinolone and dexamethasone) than of preexisting glucose intolerance.14 ment of joints with intra-articular tri- with nonfluorinated compounds (hy- Transient increases in blood glucose amcinolone hexacetonide did not ap- drocortisone and methylpredniso- levels may be seen in patients receiv- pear to affect cartilage integrity.53 lone)14 (Table 1). ing corticosteroid injections. Howev-

44 Journal of the American Academy of Orthopaedic Surgeons Brian J. Cole, MD, MBA, and H. Ralph Schumacher, Jr, MD er, in a study in which patients with mon, and local adverse effects usu- other soft-tissue complaints, as well. diabetes received soft-tissue injections ally are mild and transient. Despite their long history of use, of methylprednisolone acetate for A large body of clinical trial data questions remain concerning inject- rheumatic complaints, no significant supports the efficacy of intra-articular able corticosteroids. Reports on the changes were detected in fasting or corticosteroid injections, particularly comparative effectiveness and safety predinner blood glucose readings dur- for patients with knee osteoarthritis. of different preparations in various ing the 14 days after injection.58 Intra-articular corticosteroids also ap- conditions are largely anecdotal, and pear to effectively control pain in controlled high-quality studies of rheumatoid joints and after arthro- these agents in comparison with oth- Summary scopic knee surgery. Evidence sup- er therapies for soft-tissue disorders porting the use of injectable cortico- are needed. Factors affecting the du- Injectable corticosteroids can provide steroids for soft-tissue disorders is less rability of treatment effect are incom- dramatic relief of pain and symp- well established, although the efficacy pletely understood. An improved un- toms, although often this effect lasts of these compounds in the treatment derstanding of the mechanisms by for no more than a few weeks. Other of trigger finger, carpal tunnel syn- which injectable corticosteroids re- benefits of injectable corticosteroid drome, and anserine bursitis seems lieve symptoms, particularly in non- therapy include allowing the patient clear. Nevertheless, the experience of inflammatory conditions, could be to regain mobility and to participate many clinicians suggests that inject- useful in designing more effective more fully in rehabilitation pro- able corticosteroids can play an im- therapeutic agents and in providing grams.17 Systemic effects are uncom- portant role in the management of optimal patient care.

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46 Journal of the American Academy of Orthopaedic Surgeons