Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?

INTRODUCTION — This topic will review specific aspects of intraarticular and soft tissue glucocorticoid injections, including the dose and selection of the glucocorticoid preparation as well as some general clinical considerations. We will also discuss the role of other injectable agents. The technique, indications, and complications that can occur with intraarticular and periarticular injections of glucocorticoids are discussed separately. (See "Joint aspiration or injection in adults: Technique and indications" and "Joint aspiration or injection in adults: Complications".)

Intraarticular injections of chemicals or short-lived radionuclides, which are sometimes used as an alternative to surgical synovectomy, are discussed elsewhere (see "Synovectomy for inflammatory arthritis of the knee"). Injections for subacute and chronic low back pain are also discussed separately. (See "Subacute and chronic low back pain: Nonsurgical interventional treatment", section on 'Glucocorticoid and other injections'.)

USE OF GLUCOCORTICOID INJECTIONS — Glucocorticoid injections are commonly used to treat painful musculoskeletal conditions, but there is a lack of consensus regarding their efficacy for various conditions [1]. Some of the more common uses for depot glucocorticoid injections include inflammatory arthritides, tendinopathies, and nerve compression syndromes, which are discussed in detail within the specific topic reviews.

Pharmacology — Some of the major differences among the depot glucocorticoid preparations pertain to differences in solubility, crystal structure, and duration of action, as well as other aspects of the chemical structure [2]. Solubility is an important characteristic because compounds with lower solubility are thought to remain at the injected site for longer periods of time and result in lower systemic levels when compared with a compound of higher solubility. However, there are some data to suggest that decreased solubility does not always correlate with a more sustained clinical effect. As an example, in a randomized trial comparing the effectiveness of triamcinolone hexacetonide and methylprednisolone acetate in patients with a symptomatic knee osteoarthritis (OA), methylprednisolone acetate appeared to have longer-lasting effects even though it is a comparatively more soluble compound [3].

The crystal structures of the different glucocorticoid preparations also vary and can sometimes be difficult to distinguish from other intraarticular crystals related to an inflammatory arthritis such as monosodium urate (MSU), calcium pyrophosphate dihydrate, and hydroxyapatite [4]. In addition to the actual glucocorticoid, there are other chemical ingredients and changes in the preparation such as the preservatives as well as the addition of a fluorine group. In particular, flocculation of the glucocorticoid (precipitation of glucocorticoid crystals out of solution into a less bioavailable paste) can occur with mixing of agents with different pH ranges.

Choice of glucocorticoid preparation — Depot formulations are designed to stay at the injection site and display mostly local effects, although systemic effects can occur. There is limited evidence to guide the selection of a specific glucocorticoid depot formulation for injection [2].

The choice of different depot glucocorticoid formulations in a given practice is largely based on considerations that include availability, cost, and versatility of the agent (eg, ability to use for both joint and soft tissue injections). The author uses triamcinolone acetonide in standard doses proportional to the size of the structure injected. Typical doses of commonly used long-acting (depot) intraarticular glucocorticoids for adults are presented in a table (table 1).

There are no large, randomized trials of various preparations with both toxicity and efficacy as endpoints [5,6]. In a survey designed to gather information about practice patterns among members of the American College of Rheumatology (ACR), the most commonly used depot glucocorticoids were methylprednisolone acetate (35 percent), triamcinolone hexacetonide (31 percent), and triamcinolone acetonide (22 percent) [7]. Among the more commonly used glucocorticoids, there were regional differences, with triamcinolone acetonide preferred in the West, methylprednisolone acetate in the East, and triamcinolone hexacetonide in the Midwest. Triamcinolone hexacetonide is no longer marketed in the United States but is available in some other countries.

Variation of dose by anatomic location — Glucocorticoid doses should vary with the structure injected. Dose should decrease along with the size of the targeted structure to avoid atrophy as well as to allow space to administer the volume without having to inject against pressure. Comparative doses for injecting different-sized joints are presented in a table (table 1).

The author uses triamcinolone acetonide at standard doses of 40 mg (1 mL) for a large joint (knee, shoulder), 30 mg for medium-sized joints (wrist, ankle, elbow), and 10 mg for small spaces (metacarpophalangeal and proximal interphalangeal joints, tendon sheaths). We mix the glucocorticoid with an equal volume of lidocaine or preservative free normal saline; the rationale for this is discussed in detail below. (See 'Should the glucocorticoid be mixed with a local anesthetic?' below.)

Should the glucocorticoid be mixed with a local anesthetic? — In the absence of definitive data, we typically dilute the glucocorticoid preparation with an equal volume of lidocaine for a specific indication [2]. Lidocaine mixed with epinephrine should be avoided because if injected into a hand, epinephrine can cause prolonged vasospasm of digital arteries.

The major rationales for dilution with local anesthetic are:

●Use of the immediate relief from the anesthetic as evidence of good placement of the injection [8].

●Decrease the propensity of the glucocorticoid to cause atrophy.

●Decrease the tendency of the glucocorticoid crystals to serve as an irritant or proinflammatory factor (so-called postinjection flare) before the biochemical effect of the glucocorticoid takes over. (See "Joint aspiration or injection in adults: Complications".)

However, these observations in support of mixing the glucocorticoid preparation with local anesthetic must be balanced against at least three concerns: contamination of multidose vials; potential flocculation when the glucocorticoid is mixed with lidocaine; and potential chondrotoxicity of the anesthetics, buffers, and bacteriostatic preservatives [9,10]. Multidose vials are a known, small infection risk compared with single-dose vials. Also, the pH change that occurs when suspensions and solutions of differing pH ranges are combined can lead to flocculation of the resulting glucocorticoid suspensions. Theoretically, this reaction should decrease the bioavailability of the glucocorticoid, but it seems to make little practical difference in duration of efficacy. A pH below 4.5 is harmful to chondrocyte cultures in vitro, as are higher concentrations of the local anesthetics themselves [11]. Dilution of the injected solution by threefold or more due to the normal volume of synovial fluid present in a large joint, as well as shorter elimination half-life of the anesthetics and buffers within the injected joint versus the longer half-life of the glucocorticoid preparations, are factors. Both of these factors obscure the clinical implications of the in vitro observations on chondrocyte viability.

Clinical considerations

Frequency of injection — We limit the use of intraarticular and soft tissue glucocorticoid injections for any given indication. Safe frequency of injection is not an absolute number but varies according to the risk to chondrocyte viability and cartilage depth inherent to each disease: low for OA, high for rheumatoid arthritis (RA), and irrelevant for knees affected by juvenile idiopathic arthritis (JIA), where leg length discrepancy risk dominates over cartilage concerns. The appropriateness of repeated glucocorticoid injections is discussed within the relevant topic reviews. (See "Management of moderate to severe knee osteoarthritis", section on 'Limited role of intraarticular glucocorticoid injections' and "Initial treatment of rheumatoid arthritis in adults", section on 'Intraarticular glucocorticoids' and "Polyarticular juvenile idiopathic arthritis: Treatment", section on 'Intraarticular glucocorticoids'.)

In general, however, there are no clear evidence-based recommendations as to the appropriate number of injections from a risk-benefit perspective for most indications. As an example, the use of repeated intraarticular glucocorticoid injections for OA continues to fall out of favor as there is increasing evidence that serial injections have negative effects on the progression of cartilage damage in knee OA [12,13] (see "Management of moderate to severe knee osteoarthritis", section on 'Limited role of intraarticular glucocorticoid injections'). In addition, intraarticular glucocorticoid injections for patients with hip OA may be associated with an increased risk of rapidly destructive hip disease (see "Management of hip osteoarthritis", section on 'Limited role of intraarticular glucocorticoids'). However, these adverse outcomes described for OA may not apply to patients with active RA (see "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on 'Intraarticular therapy'). Repeated injections for chronic tendinopathies or bursitis are typically discouraged given that glucocorticoids could potentially be harmful and increase the risk of tendon rupture. As an example, several studies suggest that glucocorticoid injections for lateral epicondylitis result in more recurrences and possible worse long-term outcomes. (See "Elbow tendinopathy (tennis and golf elbow)", section on 'Glucocorticoid injections'.)

Contraindications — Contraindications to intraarticular or soft tissue glucocorticoid injections, along with the corresponding rationales, are listed below [14]:

●Periarticular infection – Intraarticular injection could introduce local infection into the joint

●Septic arthritis – Intraarticular glucocorticoids could exacerbate existing infection, and known septic joint constitutes an absolute contraindication to glucocorticoid injection

●Periarticular fracture – Glucocorticoids may theoretically inhibit bone healing [15,16]

●Joint instability – Worsening of joint instability is thought to result from weakening of the capsule and ligaments as well as the development of subchondral osteonecrosis [17]

●Juxtaarticular osteoporosis – Glucocorticoids could theoretically worsen bone density

Joint injection in patients receiving anticoagulation is generally not a contraindication for aspiration or injection with smaller-gauge needles and is discussed separately. (See "Joint aspiration or injection in adults: Technique and indications", section on 'Approach to the patient on anticoagulants'.)

There are also limited data suggesting that patients awaiting total joint replacement surgery should not have a glucocorticoid injection as this may increase the risk of intraoperative or postoperative infection of that joint. A systematic review found insufficient evidence to confirm whether there was an increased risk of infection associated with receiving an intraarticular glucocorticoid injection in the hip prior to total hip arthroplasty [18]. However, a subsequent retrospective study with 173,958 patients undergoing primary total hip arthroplasty (THA) found an increased risk of periprosthetic joint infection after THA among patients who received an intraarticular glucocorticoid injection within the three months prior to surgery [19]. Thus, based on limited data, we typically leave a window of at least three months after intraarticular joint injection prior to arthroplasty.

Complications — Serious complications associated with intraarticular or soft tissue glucocorticoid injections are uncommon, but can occur. The major complications are discussed in detail separately. (See "Joint aspiration or injection in adults: Complications".)

USE OF OTHER INJECTABLE AGENTS

Hyaluronic acid derivatives — Derivatives of hyaluronic acid have been used for the treatment of patients with knee osteoarthritis (OA), but there is limited evidence demonstrating benefit. The evidence describing the use of intraarticular hyaluronic acid derivatives and addressing their efficacy in knee OA is discussed separately. (See "Management of knee osteoarthritis", section on 'Hyaluronans'.)

As with any intraarticular injection, there is a small risk of infection (see "Joint aspiration or injection in adults: Complications", section on 'Infectious complications'). Another rare complication is an acute postinjection flare, termed pseudoseptic reaction, which may occur in 11 percent of injections [20,21]. These reactions generally occur within one week of injection and after a follow-up injection rather than after the first injection, involve an effusion from 10 to 70 mL in volume, have nucleated cell counts of 3500 to over 100,000, and show a differential of approximately 50 to 90 percent of polymorphonuclear leukocytes. In addition, the fluids are culture negative and, with a few exceptions, show no crystals. Nonbirefringent intracellular material in Wright-stained leukocytes in synovial fluid was seen in six of eight patients in one observational study [21].

With the hylan G-F 20 preparation (Synvisc), some cases of acute calcium pyrophosphate crystal arthritis (pseudogout) have occurred two or three days after hyaluronate injection [22].

Platelet-rich plasma injections — Platelet-rich plasma (PRP) injections have been used in an attempt to treat various musculoskeletal conditions such as tendinopathies, plantar fasciitis, and OA. The mechanism of action is not well understood, but PRP is thought to provide growth and repair mediators to the tissues. Overall, routine use of PRP injections is not recommended for most musculoskeletal conditions. The use of PRP injections is discussed in detail in separate topic reviews. (See "Overview of the management of overuse (persistent) tendinopathy", section on 'Autologous blood and platelet-rich plasma injection' and "Plantar fasciitis", section on 'Ineffective and experimental treatments' and "Hamstring muscle and tendon injuries", section on 'PRP and other biologic injections' and "Elbow tendinopathy (tennis and golf elbow)", section on 'Platelet-rich plasma and other biologic injections' and "Management of knee osteoarthritis", section on 'Platelet-rich plasma' and "Investigational approaches to the management of osteoarthritis", section on 'Platelet-rich plasma'.)

Investigational agents — A number of experimental injectable agents or methods that are not routinely used are discussed below.

●Several disease-modifying antirheumatic drugs (DMARDs), including methotrexate and tumor necrosis factor (TNF) inhibitors, have been investigated as intraarticular agents for use in various forms of inflammatory arthritis, but they have mixed results [23-29]. This approach is not in general use. (See appropriate topic reviews.)

●Microspheres of gelatin and chondroitin, as well as liposomes, have been tested in experimental animals to control the release of protein drugs within the injected joint [30]. As an example, complement receptor-1 linked to a membrane addressin successfully downregulated inflammation in the adjuvant arthritis rat model [31].

●In 24-month follow-up of a proof-of-concept trial, intraarticular injection of sprifermin (rhFG-18), a recombinant human fibroblast growth factor, increased femorotibial cartilage depth measured by magnetic resonance imaging (MRI) [32]. However, the effect size is small and the clinical relevance remains uncertain. Long-term durability of this effect and the clinical relevance of these findings remains unknown. The therapy is not yet approved by regulatory agencies.

SUMMARY AND RECOMMENDATIONS

●Choice of glucocorticoid preparation – The choice of different depot glucocorticoid formulations in a given practice is largely based on considerations that include availability, cost, and versatility of the agent (eg, ability to use for both joint and soft tissue injections). The author uses triamcinolone acetonide in standard doses proportional to the size of the structure injected. Alternative glucocorticoids for intraarticular injection include depot methylprednisolone and triamcinolone hexacetonide. (See 'Choice of glucocorticoid preparation' above.)

●Variation of glucocorticoid dose by anatomic location – Glucocorticoid doses should vary with the structure injected. We use triamcinolone acetonide for intraarticular and soft tissue injections at standard doses starting with 40 mg (1 mL) for a large joint, 30 mg for medium-sized joints, and 10 mg for small spaces, including interphalangeal joints and tendon sheaths. (See 'Variation of dose by anatomic location' above.)

●Mixing the glucocorticoid with a local anesthetic – In the absence of definitive data, we typically dilute the glucocorticoid preparation with an equal volume of lidocaine for a specific indication. (See 'Should the glucocorticoid be mixed with a local anesthetic?' above.)

●Frequency of injection – We limit the use of intraarticular and soft tissue glucocorticoid injections for any given indication. Safe frequency of injection is not an absolute number but varies according to disease. (See 'Frequency of injection' above.)

●Contraindications – Contraindications to intraarticular or soft tissue glucocorticoid injections include periarticular infection, septic arthritis, periarticular fracture, joint instability, and juxtaarticular osteoporosis. Joint injection in patients receiving anticoagulation is generally not a contraindication for aspiration or injection with smaller-gauge needles and is discussed separately. (See 'Contraindications' above and "Joint aspiration or injection in adults: Technique and indications", section on 'Approach to the patient on anticoagulants'.)

●Complications – Serious complications associated with intraarticular or soft tissue glucocorticoid injections are uncommon. (See 'Complications' above.)

●Limited role of other injectable agents – Routine use of other injectable agents such as hyaluronic acid and platelet-rich plasma (PRP) injections are generally not recommended for most musculoskeletal conditions. (See 'Use of other injectable agents' above and "Management of knee osteoarthritis", section on 'Hyaluronans'.)