Tarsal tunnel syndrome and corticosteroids

Tarsal tunnel syndrome, which involves compression of the posterior tibial nerve or one of its branches in the tarsal tunnel, is treated nonoperatively before opting for surgery. Corticosteroids are usually injected at the site of the tarsal tunnel to improve symptoms.

Corticosteroids, having been discovered in the 1940s, are now one of the most widely utilised medications worldwide. At any one time, 1% of the adult population in the UK use corticosteroids;¹ they are used for a variety of inflammatory and autoimmune disorders.² They are commonly prescribed in almost all areas of medicine: dermatology, ophthalmology, pulmonology, hematology, endocrinology, gastroenterology, and rheumatology, to name a few.^{2, 3} Despite the obvious benefits of corticosteroids, there are serious side effects related to their long-term use, including osteoporosis, metabolic disease, and increased risk of cardiovascular disease.^4-6

Inflammation and corticosteroids

The inflammatory response is an important natural response to injury and infection.³ The ultimate role of the inflammatory response is to remove the harmful agents and promote tissue repair.³ The innate and adaptive immune systems both play an overlapping role in inflammation; the innate immune system is primarily responsible for acute inflammation whilst the adaptive immune system is active in chronic inflammatory conditions.³

The production of natural steroid hormones

The adrenal gland, depicted in Figure 1, is made up of the cortex and medulla; the cortex produces steroid hormones including glucocorticoids, mineralocorticoids, and adrenal androgens, whilst the adrenal medulla produces the catecholamines (epinephrine and norepinephrine). The mineralocorticoids, the most important of all, which is aldosterone, act on the kidneys to increase sodium reabsorption and potassium excretion. The increased sodium reabsorption induces water reabsorption, which increases blood volume and, in turn, increases blood pressure.⁷

Figure 1: The structure of the adrenal gland and the hormones it produces. Adopted from https://www.biorender.com 

The main glucocorticoid produced by the adrenal glands is cortisol, the levels of which increase due to stress, which activates the hypothalamic-pituitary-adrenal (HPA) axis (discussed in further detail below). Cortisol stimulates the glucocorticoid receptors on target cells, which induces the expression of genes that regulate metabolism, the immune system, the cardiovascular system, growth, and reproduction.⁷ Cortisol has multiple roles, all of which are summarised in Figure 3.

The HPA axis is involved in producing glucocorticoids and adrenal androgens in the adrenal gland.⁷ Circadian rhythms and stressors activate the paraventricular neurons in the hypothalamus, which produce corticotropin-releasing hormone.⁷ The corticotropin-releasing hormone binds to receptors on the anterior pituitary gland, which produces corticotropin (ACTH).⁷ The corticotropin is released into the circulation, which then binds to receptors on the adrenal gland, which then produces at secretes glucocorticoids.⁷ There is a negative feedback loop of the HPA axis: circulating glucocorticoids negatively feed back to the hypothalamus and the anterior pituitary, thus inhibiting the release of CRH and ACTH, respectively. ⁷

Figure 2: The physiologic effects of cortisol.⁸

Corticosteroids are synthetic drugs that are similar to the natural steroid hormones produced by the adrenal glands in the body.² There are two forms of corticosteroids – mineralocorticoids and glucocorticoids. ⁹ The glucocorticoids are more relevant to this article as they are primarily involved in metabolism, and display anti-inflammatory, immunosuppressive, anti-proliferative, and vasoconstrictive properties.²

Mechanism of action of corticosteroids

Glucocorticoids produce their desired effects predominantly by interacting with the glucocorticoid receptor (GR) found in the cytoplasm of the target cells; this interaction results in the induction or repression of genes in leukocytes (white blood cells) and epithelial cells.^{3, 10, 11.} This means that anti-inflammatory genes are activated whilst pro-inflammatory genes are downregulated.^11-14 The downregulation of pro-inflammatory genes hinders the eventual production of inflammatory markers, including cytokines, chemokines, and cell adhesion molecules, which are all involved in the inflammatory response.^11-14

Types of systemic corticosteroids

There are many commercially available systemic corticosteroids, each with differences in potency, duration of action, and glucocorticoid to mineralocorticoid ratio; these properties all determine the indications of these compounds and how effective they are in treating specific conditions.² The common types of systemic corticosteroids are discussed in Table 2.

Table 2: The common systemic corticosteroids.

Side effects of long-term use of systemic corticosteroids

The most prominent side effects related to systemic corticosteroid use in adults are:

• Osteoporosis and fractures: A meta-analysis study of over 80 studies found that the use of at least 5 mg of prednisolone (or its equivalents) displayed a significant decrease in bone mineral density and was at an increased risk of fractures within 3 to 6 months of treatment¹⁷
• HPA axis effects: The insufficiency of cortisol by the adrenal glands, known as adrenal suppression, can occur due to systemic corticosteroids interfering with the HPA axis.¹⁸ It is important to note that adrenal sufficiency has been shown to occur even after 5 days of high-dose glucocorticoid treatment.¹⁹ Abruptly discontinuing treatment with systemic corticosteroids places patients at risk of developing adrenal suppression²⁰
• Hyperglycaemia and diabetes: Corticosteroid use puts patients at risk of developing hyperglycaemia – these effects can be observed within hours of treatment onset and appear to be dependent on dosage.²¹ Treatment with high doses puts pre-diabetic and diabetic patients at risk of insulin resistance²¹
• Cataracts and glaucoma: Patients using systemic corticosteroids are at risk of developing both cataracts and glaucoma, both of which appear to be dose-dependent²
• Cutaneous effects: The use of corticosteroids can induce cutaneous changes, including skin thinning, purpura, and red striae.² The former two are reversible; however, red striae are irreversible.^{2, 22} Importantly, corticosteroid use can impair the body’s natural ability to repair wounds²²
• Gastrointestinal events: Glucocorticoid treatment is associated with gastritis, peptic ulcers, dyspepsia, abdominal distension, and esophageal ulceration.² Contrary to popular belief, the risk of developing peptic ulcer disease is low for patients taking corticosteroids; however, such risk increases when patients consume nonsteroidal anti-inflammatory (NSAIDs) together with corticosteroids.² Patients are four times more likely to develop gastrointestinal events, including peptic ulcers, when using corticosteroids together with NSAIDs compared to those only consuming corticosteroids²³
• Cardiovascular disease and dyslipidemia: Patients using corticosteroids are at risk of developing side effects, placing them at risk of cardiovascular disease, including hypertension, hyperglycaemia, and obesity²
• Myopathy: A disorder affecting the muscles, known as myopathy, can occur in patients taking corticosteroids; myopathy is a catabolic event where muscle protein synthesis is reduced, and proteins are broken down, which results in muscle weakness²
• Psychiatric and cognitive disturbances: The onset of psychiatric disturbances, memory impairment, agitation, anxiety, fear, hypomania, insomnia, irritability, lethargy, mood lability, and psychosis, is dependent on the dose and duration of treatment²⁴
• Immunosuppression: Patients are at risk of developing infections due to the anti-inflammatory and immunosuppressive effects of corticosteroids²⁴

Children are also at risk of developing the abovementioned systemic side effects when undergoing treatment with corticosteroids; however, children are at risk of the delay of growth and puberty onset.²⁵

Special considerations

Drug-drug interactions

It is recommended that corticosteroids that are primarily metabolised by CYP3A4 – fluticasone and triamcinolone – should not be taken together with the protease inhibitor ritonavir (commonly used in HIV treatment) due to an increased risk of developing Cushing’s syndrome and adrenal suppression.^{26, 27} Other medications that corticosteroids could interact with, according to the NHS, include:²⁸

•  Anticoagulant medication (e.g., warfarin)
• Anticonvulsants (anti-seizure medication)
• Diabetes medication
• NSAIDs
•  Some vaccinations

It is recommended that you consult your doctor to make sure corticosteroids are safe to take with your current treatment regimen.²⁸

Summary

Tarsal tunnel syndrome, which involves compression of the posterior tibial nerve and/or its branches in the tarsal tunnel, is usually managed with corticosteroids along with other nonsurgical options before opting for surgery. Corticosteroids are one of the most widely used classes of drugs worldwide; although effective, they display a wide array of side effects that depend on the type of corticosteroid used, the length of use, as well as the dose. It is important to be aware of these side effects as well as the potential drugs corticosteroids are likely to interact with.