The main caveat of this chapter is that all steroids are systemic. Steroids, that is, corticosteroids, may be the first or second most commonly used class of medication in pain clinics, as well as orthopedic and other musculoskeletal clinics. The primary aim of this chapter is to detail the potential adverse events associated with corticosteroids themselves and to briefly review corticosteroid pharmacology and technical aspects. Clinical efficacy evidence is not reviewed here because it has been done extensively elsewhere; instead, a review of steroid-specific risks is presented to aid decision making on whether a steroid should even be used in the first place. If all steroids are systemic, then any adverse event related to steroids could potentially result from steroids administered in the pain clinic, whether or not such has been reported in the literature. Let not steroids be understood the least by those who use them the most.

Spinal injections containing steroids are generally safe. Recent events have focused attention on these procedures, such as the fungal meningitis outbreak caused by contaminated steroids and the recent Food and Drug Administration (FDA) Safety Alert, both of which are explained in detail in this chapter. However, a 7-year retrospective of 4265 epidural steroid injections (ESIs) in 1857 patients found no major complications and a minor complication rate of 2.4%, consisting mostly of increased pain or pain at the injection site or persistent numbness.¹ The ASA Closed Claims study reports 114 major complications, including nerve injury, infection, headache, worse pain, brain damage, and death.² However, in truth, we do not know the complication rate because there is no mandated reporting.³

Cortisone was first isolated from the adrenal gland in 1935.⁴ As initiates, we may cringe at the word “cortisone” when that is the limit of one’s self-report of medical history. “Steroid” for purposes here refers to corticosteroid medications, which are now usually synthetic derivatives of the endogenous corticosteroids produced by the adrenal cortex in response to stimulation by adrenocorticotropic hormone (ACTH). All corticosteroids have mineralocorticoid and glucocorticoid potency in varying proportions and may have metabolic effects on every organ system. As part of the glucocorticoid effect, corticosteroids have powerful anti-inflammatory action.

ACTH is a 39–amino acid peptide cleaved from a larger precursor protein, pro-opiomelanocortin (POMC), and it exerts actions via the melanocortin receptor subtypes (MC2R in the adrenal cortex). ACTH from the pituitary stimulates adrenal cortex production and release of glucocorticoids, mineralocorticoids, and dehydroepiandrosterone. In clinical practice, a synthetic ACTH analog, cosyntropin, is given in a high dose to test the ability of the hypothalamic–pituitary–adrenal (HPA) axis response of increased cortisol production.

The HPA is a cooperation of these three organs in maintaining glucocorticoid levels. Three HPA mechanisms are: (1) diurnal rhythm or fluctuation in steroidogenesis, (2) negative feedback loop wherein excess glucocorticoid decreases ACTH, and (3) positive stress response wherein steroidogenesis is increased. Corticotropin-releasing hormone (CRH) from the hypothalamus is transported to the anterior pituitary, where it binds receptors on corticotrope cells, resulting in ACTH production. Arginine vasopressin (AVP), also from the hypothalamus, stimulates release of ACTH. In negative feedback, glucocorticoid binds glucocorticoid receptors on pituitary corticotropes and inhibits release of ACTH and production of its precursor, POMC. The stress response can trump negative feedback, and although the mechanisms are less known, the immune system is involved. Administered corticosteroids suppress ACTH release from the pituitary; as a result, the adrenal gland is less stimulated to produce cortisol.

Pharmacologic effects of corticosteroids include anti-inflammatory and neural blockade, and ultimately, pain relief. Corticosteroids decrease the inflammatory cascade by inhibiting phospholipase A2, resulting in decreased release of arachidonic acid. With less arachidonic acid to act as substrate for cyclooxygenase, production of leukotrienes and prostaglandins is reduced. Pharmaceutical corticosteroids are metabolized by the hepatic P450 cytochrome; topical, injected, and inhaled steroids bypass the liver initially.⁵ Such corticosteroids include ESIs. Steroids may also prolong the effects of local anesthetics.^6,7

Commonly cited steroid dose equivalencies are estimates based on systemic glucocorticoid effects (e.g., hydrocortisone 20 mg prednisone or prednisolone 5 mg ≈ dexamethasone 0.75 mg). The physiologic level of corticosteroid production is often cited as equivalent to 20 to 30 mg/day of hydrocortisone (Tables 80-1 and 80-2).

Adverse effects are common in patients treated chronically with corticosteroids even at low doses. Adverse events are seen after any route, including oral, intraarticular, epidural, inhaled, nasal, ocular, and topical.⁵ More than 90% of such patients treated for 60 or more days reported adverse effects, and 55% reported serious events, including weight gain, cataracts, and fractures.⁸ Certain populations well known to be at risk from chronic steroid treatment have been studied more, and there are even guidelines to suggest prevention and management of corticosteroid-induced side effects. For the spine and pain clinic population, it is possible that some guidelines are needed as well. For example, guidelines are available on the prevention and management of steroid-induced osteoporosis and diabetes.^9,10 Timing of steroid doses in the morning is suggested as a way to mimic the natural pattern and reduce adverse effects. For patients with diabetes, recommendations include more frequent monitoring and medication adjustment. For those with osteoporosis, guidelines include bone density assessment and treatment.

ADVERSE EFFECTS AND OSTEOPOROSIS

Glucocorticoids inhibit calcium absorption in the gastrointestinal tract, decrease renal tubule calcium reabsorption, and stimulate bone resorption. They decrease cellular activity and the viability of osteoblasts, including induction of apoptosis.⁹ These actions contribute to steroid-induced osteoporosis. In a retrospective study of postmenopausal women treated with spinal injections for pain, exposure to less than 200 mg total dose of triamcinolone in 1 year may not increase the risk of osteoporosis.¹¹ Another retrospective study showed an increased risk of osteoporosis in postmenopausal women receiving more than 400 mg of triamcinolone, or about 14 injections, over a 3-year period.¹² A prospective observational study showed that a single ESI in postmenopausal women is followed by decreased bone mineral density of the hip.¹³ Mitra advocates a 3-month interval between steroid injections because the relative risk of fracture decreases after cessation of steroid treatment, back toward the baseline risk, mostly within 3 months.¹⁴

Steroid-induced myopathy, characterized by proximal muscle weakness, has been reported after ESIs.¹⁵

ADVERSE EFFECTS

Corticosteroids’ mineralocorticoid activity causes sodium (and water) retention and potassium excretion.⁵ These may lead to fluid retention, weight gain, hypertension, and congestive heart failure, which have been reported after ESIs.^15–18

BLOOD SUGAR ELEVATION

Glucocorticoids cause insulin resistance, thereby causing blood glucose elevation.¹⁰ Specifically, the liver secretes more glucose, and muscle and fat decrease glucose uptake because these tissues respond less to insulin. Steroid-induced diabetes is diagnosed and treated with the same American Diabetes Association guidelines. Spinal and other injections with steroids are likely to cause a temporary elevation in blood glucose, and patients should be cautioned. A prospective cohort of 12 patients with diabetes demonstrated blood glucose increase of about 106 mg/dL after ESI, but the elevation only lasted 3 days.¹⁹ Another prospective cohort of 30 patients with diabetes demonstrated blood glucose increase from 160 to 286 mg/dL after ESI, but the elevation only lasted 2 days, and there was no rise in Hgb A1C.²⁰ A single observational study with only five subjects showed no change in glucose tolerance in patients with diabetes receiving an ESI.²¹ These studies are limited because they have few subjects, and they screened for well-controlled diabetes. In the authors’ experience, blood glucose elevation can persist for the duration of action of the steroid, perhaps a few weeks, and sometimes is significant enough to require medical attention.

Exogenous glucocorticoids in excess may result in Cushing’s syndrome (Table 80-3). Recall that exogenous steroids suppress pituitary ACTH expression. In contrast, Cushing’s disease is a primary pituitary cause of increased ACTH and then increased cortisol production. Secondary adrenal suppression and adrenal insufficiency may result from excess exogenous steroid. These have been reported after ESIs.^15–18

Steroid used for acute flareups of pain is often supplied orally as a “taper” of several days’ duration; there are many forms of a short course of oral glucocorticoids. If given for less than 1 week, no long-term tapering is typically required. Exogenous steroids administered longer than 1 week begin to inhibit hypothalamic CRH and pituitary ACTH release. The resulting atrophy of the adrenal glands can take weeks to months to recover. During the time while the adrenal glands are weakened, there is a risk of adrenal insufficiency. For this reason, long tapers of low-dose steroids are used while the adrenal glands recover, and higher “stress doses” may be used in times of need during recovery (Table 80-4).