Knee Injection Medication

Platelet-rich plasma

It is unknown whether platelet-rich plasma (PRP) acts via local paracrine factors to alter pain, via production of new hyaline or fibrocartilage formation, a combination of the two, or another mechanism altogether. However, it is known that PRP contains higher-than-normal levels of cytokines and growth factors, including platelet-derived growth factor (PDGF), insulinlike growth factors (IGFs) 1 and 2, interleukin (IL)-8, keratinocyte growth factor (KGF), epidermal growth factor (EGF), connective tissue growth factor (CTGF), fibroblast growth factor (FGF), and transforming growth factor (TGF).

There are several methods of preparing the plasma rich in platelet-derived anti-inflammatory and growth factors. Whereas, by definition, the plasma to be used must be enriched to a platelet concentration higher than baseline, the optimal degree of enrichment is currently unknown. Anecdotal evidence has shown that the optimal dose may be at 2.5 times baseline and that high concentrations (5-9 times baseline) may actually have an inhibitory effect, though no clear studies have confirmed this point.

The benefits of white blood cells (WBCs) in the plasma are also unclear. Macrophages work to balance proinflammatory and anti-inflammatory aspects of healing, whereas neutrophils contain over 40 lysogenic enzymes and release free radicals and proteases, which can inhibit healing. However, types of leukocytes cannot be fractionated, so it may be more beneficial overall to include WBCs in the plasma despite any minor damage caused by the neutrophils.

Regardless of specific method used, there are four basic stages. First, the plasma is drawn using sterile technique, often from the antecubital fossa. The plasma is then centrifuged. Afterward, the PRP is separated. Finally, the PRP is injected into the knee joint. The amounts of blood drawn vary according to the procedure selected, but a commonly chosen amount of PRP to be injected is 3-5 mL per injection, with a series of three injections performed. ^{[19, 24, 25]}

The clinician should be aware of several details of PRP injection. The plasma is generally anticoagulated, most often with anticoagulant citrate dextrose (ACD), which has a lower pH than is physiologic. In that some growth factors are pH-sensitive, it is generally recommended to buffer the preparation to a physiologic level prior to injection. The number of times the plasma is centrifuged may also have an effect.

Plasma-rich growth factor (PRGF) obtained via a single-spin method and administered in a series of three injections is the most common method used. However, a series of three injections of PRP obtained following two spin cycles has also shown significant benefit, despite greater short-term side effects (eg, pain and swelling). ^[24]

Given the complexity of the procedure and equipment used to prepare the PRP, it is highly recommended that the practitioner attend a workshop or course on the preparation and use of PRP before performing the procedure in an office setting.

Numerous manufacturers produce equipment for preparation of PRP, and each manufacturer has its own recommendations for the preparation method and quantities of plasma used. Two such devices are the Arthrex ACP and the Biomet GPS III.

The Arthrex ACP Double Syringe Method reduces 10 mL of blood into 3 mL of PRP via a single centrifuge cycle at 1500 rpm for 5 minutes, allowing the top portion of plasma to be drawn up for use. The GPS III Platelet Concentration System reduces 27 mL of blood to 3 mL of PRP via a single centrifuge cycle at 3200 rpm for 15 minutes. The practitioner may also choose to use a double-spin technique—for example, spinning a quantity of blood at 1500 rpm for 5 minutes, separating off the top layer of plasma for a second cycle at 6300 rpm for 20 minutes, and removing half the remaining plasma volume.

Of these three methods, the single cycle of 27 mL at 3200 rpm for 15 minutes produces the highest concentration of platelets and growth factors overall. ^[25]

Corticosteroids

Corticosteroids used in this setting are listed in Table 1 below.

Table 1. Corticosteroid Agents Used in Knee Injection ^{[26, 27]} (Open Table in a new window)

Class Summary

These agents have anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids have profound and varied metabolic effects. In addition, these drugs modify the body's immune response to diverse stimuli. (See Table 1 in Medication Summary.)

No large trials have evaluated the various preparations of steroids. The most useful study on this subject is from the 1993 survey from the American College of Rheumatology, in which the most notable finding was the geographic variation of steroid preparations used by physicians.

Subsequent small trials/surveys reveal that (1) methylprednisolone (Depo-Medrol) and triamcinolone acetonide (Kenalog) cause less local postinjection flares than longer-acting agents do; (2) triamcinolone acetonide (Kenalog) and triamcinolone hexacetonide (Aristospan) are less soluble and therefore longer-acting; (3) less soft-tissue atrophy and risk of tendon rupture is seen with dilution of the steroid by lidocaine; and (4) precipitation of steroid crystals out of solution occurs with the addition of methylparabens in local anesthetics.

Dexamethasone acetate (Baycadron)

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This agent decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability. Dosage varies with the degree of inflammation and the size of the affected area.

Methylprednisolone acetate (Depo-Medrol, Medrol, Solu-Medrol, A-Methapred)

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Methylprednisolone acetate decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Dosage varies with the degree of inflammation and the size of the affected area.

Hydrocortisone acetate (Solu-Cortef, Cortef, A-Hydrocort)

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Hydrocortisone acetate decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Dosage varies with the degree of inflammation and the size of the affected area.

Prednisolone (Millipred, Orapred, Orapred ODT, Prelone)

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Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body. Alternative corticosteroids may be used in equivalent dosage.

Betamethasone (Celestone, Celestone Soluspan)

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Betamethasone is the drug of choice for intraarticular injections. It does not crystallize if used with paraben-free anesthetic preparations.

Class Summary

Hyaluronic acid helps form the structural integrity of the synovium and cartilage and to lubricate the synovial joint. Hyaluronic acid can interact with proinflammatory mediators and bind to CD44 receptors on the chondrocytes to modulate cell proliferation, migration, and gene expression.

Several hyaluronic acid preparations are available for clinical use. Brand names of various hyaluronic acid derivatives include the following:

-Euflexxa: 2-mL solution of 1% sodium hyaluronate 10 mg/mL into each knee

-Hyalgan: 2-mL solution of sodium hyaluronate 10 mg/mL

-Orthovisc: 2-mL solution of 15 mg/mL

-Supartz: Supplied as a sterile nonpyrogenic solution in 2.5-mL prefilled syringe containing sodium hyaluronate 10 mg/mL

-Synvisc: 2-mL solution of hylan polymers (hylan G-F 20) 8 mg/mL

-Synvisc One: Supplied as a sterile nonpyrogenic solution in a 10-mL glass syringe containing three doses (48 mg) of hylan G-F 20

Hyalgan, Supartz, and Osteoartz contain sodium hyaluronate compounds, with the molecular weight range of 0.5-1.2 × 10⁶ Da, and require three or five injections about 1 week apart. Orthovisc and Euflexxa contain ibid compounds, with a molecular weight range of 1.0-3.6 × 10⁶ Da, and require three or four weekly injections. Synvisc and Synvisc One contain hylan G-F 20, with the molecular weight of 6 × 10⁶ Da, and require three and one injection(s), respectively.

Euflexxa is prepared from bacterial fermentation, whereas all the others are prepared from cockscomb. ^[28]

Hyaluronate derivatives (Euflexxa, Hyalgan, Orthovisc, Supartz, Synvisc, Synvisc One)

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Hyaluronate derivatives function as tissue or joint lubricant, which act to modulate the interactions between adjacent tissues.

Class Summary

An intraarticular botulinum A neurotoxin knee joint injection may provide therapeutic pain relief for patients with advanced knee osteoarthritis. The mechanism of pain reduction by botulinum neurotoxin A may be due to neurotransmitter-mediated inhibition of sensory neurons, rather than via neuromuscular junction blockade.

Preparations of botulinum toxin type A include Botox, Dysport, and Xeomin. ^{[9, 8]}

IncobotulinumtoxinA (Xeomin)

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IncobotulinumtoxinA is botulinum toxin type A that is free of complexing proteins found in the natural toxin from Clostridium botulinum. This drug is an acetylcholine release inhibitor and neuromuscular blocking agent.

AbobotulinumtoxinA (Dysport)

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AbobotulinumtoxinA binds to receptor sites on the motor nerve terminals and, after uptake, inhibits release of acetylcholine, blocking transmission of impulses in neuromuscular tissue.