Overview and Description
Steroid injections play a prominent role in musculoskeletal care and pain management in PM&R; this article will review steroid pharmacology, various types of steroids, indications, basic techniques, adverse effects and complications.
Naturally occurring corticosteroids can be classified as mineralocorticoids, glucocorticoids, and adrenal androgens. The primary glucocorticoid found in humans is cortisol and is produced by the adrenal cortex under the regulation of the hypothalamic-pituitary-adrenal axis1. Normal production is approximately 5-10 mg/m2 per day, which is roughly equivalent to 20-30 mg/day of hydrocortisone or 5-7 mg/day of oral prednisone2,3. Synthetically produced cortisol analogues are commonly used for injections.
Glucocorticoids are lipophilic and diffuse through the cell membrane to bind glucocorticoid receptors in the cytoplasm. High dose glucocorticoids alter sodium and calcium cycling at the membrane of the cell to cause rapid decrease in inflammation. They target a wide variety of cells, including T-lymphocytes, macrophages, fibroblasts, neutrophils, eosinophils, and basophils 4.
Steroids act as powerful anti-inflammatories primarily through reducing the transcription of genes involved in inflammation but also through the increased synthesis of phospholipase A2 inhibitors, decreasing bradykinin, histamine, prostaglandins and leukotrienes and directly stabilizing neural membranes and inhibiting C-fiber transmission 5,6,7.
The most commonly used synthetic corticosteroids are derivatives of prednisolone; methylation of prednisolone produces methylprednisolone, while fluorination of prednisolone produces triamcinolone, betamethasone and dexamethasone. Fluorination may also lead to increased absorption and potency7,8.
Relevance to Clinical Practice
Potency, Solubility, Size, and Duration
There are numerous corticosteroids available, both particulate and non-particulate, all with varying potency, solubility, and duration. Particulate steroids like methylprednisolone and triamcinolone must undergo hydrolysis, lowering their solubility and theoretically lasting longer at the injection site when compared to non-particulate steroids like dexamethasone.
Particulate preparations, while commonly used for peripheral injections, may have serious adverse events when used for axial spine injections, including blood vessel injury or spasm, or even embolization through vessels causing spinal cord infarction. Methylprednisolone has significantly higher percentage of large particles and may occlude vessels. Light microscopy studies have demonstrated that the particles in these steroid preparations are either larger than red blood cells or form aggregates larger than red blood cells9. Triamcinolone preparations have an intermediate particle size and betamethasone has the smallest particle size of the particulate steroids9,10.
Chart 1: Potency, Solubility and Preparations*
Steroids are frequently used both for diagnostic and therapeutic purposes and to control inflammation when more conservative measures (i.e. NSAIDs, rest, ice, compression, elevation, physical therapy) have been exhausted6. Typically, steroids can provide short-term pain relief (from weeks to months); few injections are associated with long-term relief of symptoms.
Studies support the use of corticosteroid injections for carpal tunnel syndrome, trigger finger, de Quervain’s tenosynovitis, and bursitis and tenosynovitis associated with rheumatic diseases. The role of corticosteroid injectables for rotator cuff disease is unclear12. The use of injectable corticosteroids has shown to provide short term pain relief for subacromial impingement syndrome, adhesive capsulitis, medial and lateral epicondylitis, and hip or knee osteoarthritis13.
Although spinal steroid injections are commonly used for treatment of axial pain due to traumatic or degenerative conditions, the US Food and Drug Administration (FDA) has not approved any drug for spinal injection to treat neck and back pain. FDA requires the addition of a Warning to the drug labels of injectable corticosteroids to describe the risks of rare but serious adverse events, including loss of vision, stroke, paralysis, and death14.
A steroid injection is contraindicated in the setting of overlying soft tissue infections, sepsis, bacteremia, anatomic inaccessibility, an uncooperative patient, articular instability, septic arthritis, avascular necrosis, osteonecrosis, periarticular fracture and Charcot joints. A joint with a surgical implant would be a relative contraindication6.
Precautions should be taken with patients with diabetes mellitus, as part of their picture of overall comorbidities. The American Academy of Orthopedic Surgeons15, American College of Sports Medicine16, American Diabetes Association17, and American Medical Society for Sports Medicine18 do not have established recommendations with regards to steroid injections in patients with diabetes mellitus. However, precautions should be taken after an injection is performed. Transient increases in post-injection blood glucose levels (BGL) were noted in ten studies. Mean blood sugar elevations have ranged from 125 to 320 mg/dL with peak post-injection BGL occurring within 1 to 5 days. BGL returned to baseline within 10 days and usually in less than 24 hours. Patients with Type1 DM or insulin-dependent diabetes mellitus (IDDM) had higher post-injection BGL than those with Type 2 DM not requiring insulin in two studies. Patients with HgA1C >7.0% had BGLs that were higher and lasted longer than those with lower HgA1C levels. Although none of the studies specifically evaluated complications from elevated BGL, no adverse events were reported in any of the studies19.
Precautions should be taken with patients on anticoagulation. There have been studies which have established the safety of continuing anticoagulation with warfarin before joint aspirations/injections with only a small increased risk of bleeding20. However, practitioners should ensure the patient’s INR is in the therapeutic range and that the patient is not experiencing any episodes of unexplained bruising or bleeding21. Studies also confirm that there is no need to hold and it is safe to continue anti-platelet drugs and direct oral anticoagulants, such as Xarelto and Eliquis before steroid injections 21,22. The possibility of bleeding, bruising, or hemarthrosis should always be discussed with the patient and documented.
Precautions should be taken with patients being treated for a psychotic illness. Systemic steroids can trigger or aggravate a psychotic episode. Consider discussing with a patient’s psychiatrist before providing an injection21.
Before injection, the steroid is frequently diluted with an equal volume of anesthetic. The immediate analgesic response may help confirm placement and also may facilitate the spread of the steroid to a larger surface area, potentially increasing its efficacy. In addition, it may decrease the risk of atrophy when placed in smaller or superficial structures such as the hand. Dilution does increase the risk of infection, especially when using multidose vials. In addition, the parabens in local anesthetics such as lidocaine may lead to flocculation, or precipitation of the steroid mixture in the syringe23.
The most commonly used diluents are lidocaine hydrochloride and bupivacaine hydrochloride (MarcaineTM). Lidocaine typically comes in three concentrations: 0.5% – 5mg/ml, 1.0% – 10mg/ml, and 2.0% – 20mg/ml. Lidocaine acts rapidly within seconds and with an estimated duration of 30 minutes. Bupivacaine typically comes in two concentrations 0.25% – 2.5mg/ml and 0.5% – 5mg/ml. Bupivacaine has more of a slower onset, taking 30 minutes to achieve its full effect, with an estimated duration of 8 hours or more21.
Preservatives can be added to anesthetics to prevent the growth of microorganisms introduced during the manufacturing process24. Such preservatives are commonly added to anesthetics dispensed in multi-dose containers and less commonly added to drugs intended for single use25. Anesthetic solutions containing anti-microbial preservatives (e.g. benzyl alcohol or parabens-containing compounds) should not be used for epidural or spinal anesthesia because the safety of these agents has not been established with regard to these injections, either intentional or accidental26. Preservative free anesthetic solutions should be used for these injections.
Common Injection Procedures
- Thoroughly cleanse skin with alcohol, betadine or chlorhexidine.
- Use a 21-30 gauge needle (larger diameter and 2 length for larger joints, smaller diameter and shorter length for superficial injections).
- Aspirate prior to injection.
- Negative aspiration cannot rule out intravascular injection.
- Synovial fluid aspiration is ideal as it confirms needle placement, fluid should be yellow and clear and any changes from the norm should prompt further investigation including fluid analysis, culture and sensitivities. Steroid should not be injected if there is a suspicion or risk of infection.
- The injectate should flow relatively easily into the intraarticular or bursal space; if resistance is encountered, repositioning should be attempted6.
Chart 2: Suggested guidelines for intraarticular injections6,23,21: There is lack of consensus on optimal dosing, therefore dosage adjustment of medication/diluent can be done.
Steroids have been increasingly utilized in spinal interventions and steroid selection (particulate versus non-particulate) can help reduce risk of injury to the patient.
Central nervous system injuries have been attributed to blood vessel injury, spasm or embolization of particulate steroid through vessels. Blood vessel injury can be attributed to direct needle trauma or effects of dye. Embolization, however, can cause segmental infarct directly related to effects of particulate size in various steroid formulations. Methylprednisolone has a higher percentage of large particles, followed by Triamcinolone, and Betamethasone has the smallest particle size10. Particulate steroids are typically utilized for lumbosacral, sacroiliac, and facet injections. For cervical procedures, dexamethasone, a non-particulate steroid, is preferred as an inadvertent intravascular injection with a particulate steroid could have life threatening consequences. The safety of preservative agents, such as benzyl alcohol or methylparaben, found in diluents has not been established with regard to intrathecal injection26. But there have been case studies documenting adverse events associated with preservatives that include – lower extremity weakness with sensory deficits27, epidural tissue damage28, and chronic adhesive arachnoiditis29. For safety purposes, these preservative free anesthetic solutions should be used as diluents for all steroid injections to the spine.
Chart 3: Typical steroid selection and dosing for interventional spine procedures*
Side effects can be broken down into local effects and systemic effects:
- Local side effects
- infection (rare as evidenced by one study that found an infection incidence of 0.005% in more than 400,000 consecutive injections32)
- post-injection flare (2-6% of patients, crystal induced synovitis causing inflammation, typically lasts up to 12-48 hours and is treated with NSAIDs and ice6)
- skin changes/hypopigmentation
- tissue/fat atrophy
- tendon rupture
- avascular necrosis
- Systemic Side Effects
- steroid presence in bloodstream (intraarticular methylprednisolone acetate of either 40 or 80 mg led to detectable levels in the serum with peak levels at 2 and 12 hours post-injection)
- suppressed endogenous serum cortisol level for 1 week post-injection33
- acute hyperglycemia, persisting for up to 3 days with a peak glucose level of 300 mg/dL34
- facial flushing (up to 15% of patients, most frequently associated with triamcinolone10,34)
Insoluble steroids have been linked to worsened local and systemic side effects because of their longer duration in tissue. Triamcinolone aggregation within serum suggested that the embolization of particulate corticosteroids in transforaminal injections could be the cause of rare complications that include spinal cord and brain infarction35.
The safe maximum number and frequency of steroid injections is uncertain. Most studies have evaluated safety in the context of rheumatoid arthritis and osteoarthritis.
In rheumatoid arthritis, studies have shown no change in joint arthroplasty rates between patients who received four or more injections annually versus those receiving less frequent injections10,23.
In osteoarthritis, intraarticular steroid knee injections versus saline injections every 3 months for 2 years produced no significant difference with regards to cartilage thickness, suggesting that steroids in osteoarthritis patients were neither chondrodestructive nor chondroprotective36. Osteoarthritis patients tend to have a shorter duration of action with most of the benefit lasting a maximum of 6 weeks.
For intra-articular injections, corticosteroid use has shown to be beneficial at lower doses and shorter duration of exposure. Higher doses and longer duration were shown to cause gross cartilage damage and chondrotoxicity37.
More recent studies suggest that chronic joint injections may accelerate cartilage degeneration and osteoarthritis progression, and should be avoided in patients with subchondral insufficiency fractures and osteonecrosis 38, 39.
Due to the potential of corticosteroid side effects, general recommendations are that steroid injections be performed no more than 3-4 times annually9, although rheumatoid patients may be able to tolerate more frequent injections23.
It is important to be aware of where the medications that are being utilized come from. In 2012 there was an outbreak of fungal meningitis associated with methylprednisolone from a specific compounding pharmacy. As compounding pharmacies are not registered with the FDA, consider using a pharmacy that participates in voluntary accreditation with the Pharmacy Compounding Accreditation Board7.
Intramuscular glucocorticoids are generally avoided due to risk of muscle atrophy4.
Non-systemic administration is preferred to systemic if at all possible due to the many adverse effects that come with glucocorticoids4.
Gaps in Knowledge/ Evidence Base
Past studies have demonstrated non-statistically significant superiority of particulate over non-particulate steroids in the short-term treatment of lumbar radicular pain but newer studies have failed to demonstrate any difference over longer follow up periods40. Based on the paucity of literature, the Spine Intervention Society currently recommends that physicians continue to make risk-benefit calculations with regards to particulate versus non-particulate steroids.
Controversy exists regarding whether injections with steroids produce superior clinical effects compared with local anesthetics or saline. Although in some studies steroids were found to be superior than control agents at 1 month, 3 months, and 6 months post injection, with diminishing pain control from 3 months to 1 year41, epidural corticosteroid injections for radiculopathy or spinal stenosis with sodium chloride solution or bupivacaine were shown to be ineffective by others, or suggesting that lidocaine alone or lidocaine in conjunction with steroids were significantly effective42.
Overall, further studies are needed to help clarify optimal steroid selection, dosing and frequency and the efficacy of landmark guided versus ultrasound guided peripheral joint injections40,43.
Cutting Edge/ Unique Concepts/ Emerging Issues
Ultrasound guidance is becoming increasingly popular in both peripheral and axial injections as a means of improving accuracy without the radiation exposure of fluoroscopy.
Some physicians have started using intrathecal betamethasone in cancer patients, especially those with vertebral bone metastases, when conservative options have been exhausted. Intrathecal steroid injection was found to provide long lasting analgesia without any apparent complications in pelvic and perineal cancer patients44.
It has also been speculated that complications from intrathecal steroid injection stem from chemical additives such as antioxidants and preservatives31.
Low dose of a single intra-articular dexamethasone injection has shown promise in prevention of post traumatic osteoarthritis45.
Extended-release triamcinolone acetonide (TA-ER) injected intra-articular is one of the newer steroid formulations that in some studies provided significant knee pain reduction compared with saline-placebo at week 1246, and consistently exceeded the pain relief of saline-placebo at 5-6 months, suggesting that TA-ER may be an effective non-opioid treatment option47.
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Original Version of the Topic
David Haustein, MD, Daren Subnaik, DO. Steroids and Corticosteroids. Published 4/13/2016
Laurentiu Dinescu, MD
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Maksim Shmargun, MD
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Abhishek Reddy, MD
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Vivek Mukherjee, MD
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