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What steroids can we inject?

Quick history of injectable steroids

Hench in 1950 was awarded the Nobel Prize in Physiology for discovering that corticosteroids have important anti-inflammatory effects. 

Corticosteroids can be classified as mineralocorticoids (eg, aldosterone), which control water and electrolyte physiology, and glucocorticoids (egcortisol), which control metabolism and inflammation.

Initially Hydrocortisone was injected in joints by Hollander in 1951 who established the practice

A number of corticosteroid-like molecules have been synthesized to be used in drug therapy

Steroids used in musculoskeletal conditions:

Corticosteroids used in MSK injection therapy are synthetic derivatives of prednisolone​. Methylprednisolone is the methyl derivative of prednisolone.

Commonly injected steroids such as: Betamethasone, Dexamethasone, and Triamcinolone Acetonide are all fluorinated derivatives of prednisolone.

This modification decreases solubility and therefore increases duration of action​. They have been shown to be more highly associated with tendon rupture and subcutaneous atrophy compared with non-fluorinated compounds. Most clinicians recommend only using fluorinated corticosteroids for intra-articular injections, where there is minimal risk to soft tissues.

Water soluble steroids 

Betamethasone sodium phosphate and betamethasone acetate. Dexamethasone sodium phosphate SPC (Summary of Product Characteristics) for Betamethasone and Dexamethasone indicates for systemic usage only.​

The above freely water soluble preparations are taken up rapidly by cells and have a quicker onset of effect​. The disadvantage is that they also have a reduced duration of action.​

Depot Steroids

Most corticosteroid preparations contain corticosteroid esters, which are highly insoluble in water and form microcrystalline suspensions. The potential advantage of corticosteroid ester preparations is that they require hydrolysis by cellular ester-ases to release the active component and consequently should last longer in the joint than do non-ester preparations.

Steroid Particulates and injection therapy

Compounds with low solubility are well suited for intra-articular injections, they may not be appropriate for soft-tissue injections because of associated side effects, particularly atrophy of surrounding tissues.​

Particulate preparations are thought to act as a depot, which increases the duration of action through a continuous and slow release of the drug. It has been shown that particulate formulations offer a small but statistically significant clinical benefit (Brennan, 2019)

 

Common (long acting) particulate steroids on the market:

Common particulate preparations on the market:

Betamethasone sodium phosphate/ betamethasone acetate (Celestone Soluspan), Methylprednisolone acetate (DEPO-Medrol), Triamcinolone acetonide (Kenalog).

Common side effects of particulate steroids

Hypopigmentation:

Hypopigmentation is characterised by a lightening in skin colour, mostly affecting the peripheral cutaneous regions possibly due to thinner dermal layers.
It appears to affect people with darker skin (Ghunawat, 2018) and affects
Incidence: 1 to 4% of adults following local corticosteroid injection (Papadopoulos, 2009; Park, 2013)
The hypothesized etiology of hypopigmentation with corticosteroids relates to decreased melanocyte function. and the linear or streaky pattern often characteristic of hypopigmentation is due to lymphatic spread (Schwartz, 2012)
Re-pigmentation has been reported to occur as early as 1 month but may take up to 1 year for significant improvement (Kaur 2002, Saour, 2009)

Lymphatic spread

In the presence of low concentration of steroids it is bound to plasma proteins. When steroid concentration suddenly increases a small fraction of steroid is in a free state and allowed to enter cells.

It is thought that steroid molecules (Triamcinolone Acetonide) can then enter the lymphatic system causing a linear ray distribution of depigmentation (Schwartz, 2012)

Subcutaneous fat atrophy

Subcutaneous fat atrophy (lipoatrophy) is a serious adverse event that may occur following corticosteroid injection into soft tissue. It may be more common in women (Kim, Lee, & Lee, 2015).
Lymphatic spread into the dermal and subdermal tissues has been hypothesized as the mechanism the but cause still remains unknown.
High doses of corticosteroids have been implicated with Triamcinolone acetonide due to its larger molecular size and longer half-life (Kim et al., 2015). Although there are also reports of this occurring with Depomedrone.

Example of fat atrophy:

Summary:

  • Particulate steroids due to depots are thought to be more effective due to steroid releasing slowly over time.
  • Depomedrone is most suitable for superficial soft tissues.
  • Depomedrone is generally considered to cause fewer side effects in superficial soft tissue structures. Triamcinolone Acetonide has larger particulates and shows more aggregation than Depomedrone it is associated with more frequent side effects in soft tissue such as depigmentation and lipodystrophy (Kaur, 2002; Kikuchi, 1975).
  • Triamcinolone is generally recommended for larger joints and deeper located soft tissue structures
  • Triamcinolone Acetonide was shown in 2 out of 4 level 1 studies to be more effective than other steroids (Hepper: 2009).
  • Triamcinolone Hexacetonide is recommended in inflammatory joint conditions where it is more potent than other steroids (Blyth, 1994, Zulian, 2003) but the evidence does not show it to be superior for osteoarthritic knee conditions. (Dieppe, 1980, Friedman; 1980 and Gaffney; 1995)