This chapter reviews the clinical pharmacology, pharmacokinetics, therapeutic mechanisms, and side effects of corticosteroids and botulinum toxins. Radiocontrast agents are reviewed in greater detail elsewhere in this text. All of these drugs have the potential to produce physiologic toxicity and therefore should be administered appropriately and in the smallest dose that will reliably produce the desired effect; an increase in total dose or volume should not be used to compensate for inadequate injection technique. In addition, this chapter reviews the main characteristics of the available injectable bone cements, their use, and their handling as an effective treatment in vertebral compression fractures. Novel techniques involving gene therapy in the treatment of chronic, unrelenting pain syndromes are also explored.
Corticosteroids
Corticosteroids (CSs) are key mediators in the maintenance of normal physiology and in the complex adaptive mechanisms that protect an organism in the setting of internal or external stressors. CSs maintain the function and integrity of many important physiologic and biochemical processes, including the regulation of protein, carbohydrate, and lipid metabolism. Naturally occurring corticosteroids are classified into three functional groups: mineralocorticoids, glucocorticoids, and adrenal androgens.
Mineralocorticoids maintain normal fluid and electrolyte balance. Glucocorticoids (GCs) act primarily to enhance the production of high-energy fuel, glucose, and reduce other metabolic activity. Injections of glucocorticoids for the relief of vertebrogenic, arthritic, and radiculopathic pain are widely accepted.
General Effects of the Endogenous Corticosteroids
Physiologic Effects of Corticosteroids
GCs stimulate hepatic gluconeogenesis, increase hepatic glycogen content, and inhibit insulin-mediated peripheral blood glucose uptake. They modulate protein metabolism by decreasing peripheral protein synthesis (by inhibiting amino acid incorporation) and stimulating protein catabolism while stimulating protein and enzyme synthesis in the liver. CSs regulate lipid metabolism largely by potentiating catecholamine-enhanced activation of cellular lipase, resulting in lipolysis.
GC actions on protein and lipid tissues vary in different parts of the body. Whereas cortisol can deplete the protein matrix of the vertebral column (trabecular bone), there may be minimal effect on long bones (compact bone). For adipose tissue, the subcutaneous lipid cell mass of the arms and legs decreases while that of the abdomen and interscapular area increases.
Cortisol maintains vascular responsiveness to circulating vasoconstrictors and, in high doses, may restore circulatory function in shock (hemorrhage, endotoxin, anaphylaxis, and trauma). Hemodynamically, GCs modulate α-adrenergic receptor synthesis and cell density, prevent α-adrenergic receptor desensitization and uncoupling, and inhibit nitric oxide synthase.
Cortisol maintains the microcirculation in the setting of acute inflammation by reducing capillary endothelial permeability and preventing edema formation. GCs modulate the immune response at many levels. They cause leukocytosis by enhancing the release of mature leukocytes from the bone marrow as well as inhibiting their egress from the circulation.
Steroid Synthesis
All CSs are produced in the cortex of the adrenal gland, which is composed of three distinct zones. The outer zone, the zona glomerulosa, produces mineralocorticoids, specifically aldosterone, which is synthesized in response to stimulation by the renin-angiotensin-aldosterone system or hyperkalemia. The middle zone, the zona fasciculata, comprising more than 70% of the cortex, is the site of glucocorticoid production. Cortisol is the primary glucocorticoid and represents about 80% of GC production. The inner zone, the zona reticularis, produces GCs and in some species small amounts of androgens.
Adrenocortical cells contain large stores of lipid used for steroidogenesis. Adrenocorticotropic hormone (ACTH) induces physiologic, molecular, and morphologic changes in the adrenal cortex. In addition to releasing GCs, the adrenal gland undergoes upregulation of steroidogenic cytochrome P-450 mRNAs, as well as hypervascularization and cellular hypertrophy and hyperplasia.
Circulating plasma lipoproteins provide most of the cholesterol for steroid synthesis. Cholesterol uptake by the adrenal cortex is mediated by the low-density-lipoprotein (LDL) receptor, whose quantities increase with ACTH stimulation. The first and rate-limiting step in steroid biosynthesis is the conversion of cholesterol to pregnenolone under the control of ACTH and by the cytochrome P-450 enzymes in the mitochondria and smooth endoplasmic reticulum. Corticosterone is the immediate precursor to cortisol, and it is the principal glucocorticoid in certain animal species.
Adrenal steroids share a common carbon skeleton, the cyclopentanoperhydrophenanthrene ring, composed of three cyclohexane rings and one cyclopentane ring ( Fig. 44.1 ). Variation among naturally occurring steroid compounds is related to the manner in which hydrogen, hydroxyl, and oxygen radicals and carbon atoms are attached to the basic steroid nucleus. Cortisol and other anti-inflammatory steroids contain a two-carbon chain attached to position 17, and are termed C21 steroids. Even the commonly administered steroid cortisone must be converted in vivo to hydrocortisone (cortisol) by the liver before it is biologically active.
Steroid Secretion
Cortisol secretion is under the control of the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol synthesis depends on three factors: negative feedback by serum cortisol levels, normal circadian cycle, and responses to central nervous system (CNS) activation by physical and emotional stress. During nonstress periods, cortisol production is under the influence of CNS activation by baroreceptor, chemoreceptor, nociceptor, and emotional afferent signals.
Negative Feedback
Cortisol exerts a negative feedback inhibition of corticotropin-releasing hormone (CRH) secretion by binding to specific steroid receptors in the CNS. It also inhibits both ACTH secretion and proopiomelanocortin (POMC) gene transcription. Systemic hypoperfusion, with decreased adrenal blood flow and certain drugs, may also inhibit cortisol synthesis.
Circadian Pattern of Secretion
It is estimated that human cortisol production is approximately 5 to 10 mg/m per day. This amount is the equivalent of about 20 to 30 mg/day of hydrocortisone or 5 to 7 mg/day of oral prednisone. The range of the circadian pattern of cortisol production varies more than threefold. Peak levels of ACTH and cortisol secretion occur between 4 and 8 a.m. There is minimal production of cortisol during the evening, and the lowest levels are observed between 8 p.m. and 12 a.m. In abnormal sleep-wake cycles, this diurnal pattern will adjust, so that peak cortisol levels occur just prior to awakening.
CNS Control of Secretion
Baroreceptor and chemoreceptor afferent inputs to the medulla are transmitted via the pons to the hypothalamus. Nociceptive afferent signals activate both the medulla and thalamus, which independently activate the hypothalamus via the paleocortex limbic system. Emotional triggers also activate the hypothalamus through the paleocortex limbic system. The arrival of afferent input into the hypothalamic paraventricular nucleus stimulates the synthesis of CRH, which is secreted into the hypophyseal portal system to the anterior pituitary, causing ACTH release. In addition to afferent signals, other substances can stimulate the hypothalamus to secrete CRH and cause ACTH release. These include the proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor α (TNF-α). Other substances that influence CRH and ACTH secretion include vasopressin, angiotensin II, norepinephrine (NE), prostaglandin F 2α (PGF 2α ), and thromboxane A 2 (TXA 2 ). Cortisol synthesis can increase 5- to 10-fold during severe stress, to a maximal level of approximately 100 mg/m per day.
Pharmacokinetics and Pharmacodynamics of the Steroids
Cortisol circulates in the blood in three forms: free cortisol (5%), protein-bound cortisol, and cortisol metabolites. It is this unbound (free) portion that is the physiologically active hormone. Approximately 90% of cortisol is bound to cortisol-binding globulin (CBG), also known as transcortin, and albumin. CBG has a high affinity for cortisol but is present in small amounts. The second serum-binding protein, albumin, binds cortisol with less affinity but is abundantly present. During stress, there is a characteristic increase in total cortisol blood levels, including an increase in the unbound percentage. The level of CBG is increased in high-estrogen states, in pregnancy, and during administration of contraceptives. Most synthetic glucocorticoids have less affinity for CBG (approximately 70% binding), and this may account for their propensity to produce cushingoid symptoms at low doses. Cortisol primarily is metabolized in the liver, with subsequent renal excretion of the metabolites.
Corticosteroid Levels in Stress Response and in Various Clinical Situations
Endogenous Corticosteroids
Cortisol levels increase within minutes of stress, whether physical (trauma, surgery, exercise), psychological (anxiety, depression), or physiologic (hypoglycemia, infection). Pain, fever, and hypovolemia all cause a sustained increase in ACTH and cortisol secretion. Surgery is associated with elevations in ACTH and cortisol levels, which usually persist for 24 to 48 hours. The magnitude of the stress response is directly proportional to the extent of surgical trauma. Less extensive procedures such as surgery on the joints, breasts, or neck produce a 36% increase in cortisol levels, whereas laparotomy is associated with an 84% increase in the serum cortisol level for 2 days postoperatively. Adult adrenal glands produce about 50 mg of cortisol/24 hours during minor surgery and 75 to 150 mg/24 hours during major surgery.
Elevated levels of circulating cytokines, which appear within minutes of trauma, stimulate the HPA axis to increase production of cortisol. Increased tissue corticosteroid levels are an important protective and life-sustaining response in these settings. Corticosteroids improve survival in stress by reducing the duration of shock, decreasing the severity of inflammation, improving vessel contractility and hemodynamics, and preventing inflammatory cell recruitment, proliferation, and release of proinflammatory mediators. Corticosteroids also improve outcome by modulating α-receptor responsiveness to catecholamines. GCs both increase the number of α receptors and prevent uncoupling of the α receptor from adenylate cyclase.
Exogenous Corticosteroids
The introduction of cortisone, a purified glucocorticoid preparation, revolutionized the treatment of a number of medical diseases and provided physiologic replacement in patients with adrenal insufficiency. Shortly thereafter, a number of case reports and studies appeared describing the catastrophic effects of inadequate corticosteroid supplementation in glucocorticoid-treated patients with medical or surgical stresses. Glucocorticoid therapy is the most common cause of secondary adrenal insufficiency. Initially, glucocorticoid administration suppresses CRH and ACTH stimulation. Over time, tertiary iatrogenic adrenal insufficiency develops as the adrenal gland atrophies. Adrenal atrophy may persist for months, following even short courses of corticosteroid therapy.
The dose and duration of corticosteroid administration are only fair predictors of the extent of adrenal suppression, because ACTH and cortisol production vary greatly among individuals. The time to recovery from HPA suppression is highly variable, ranging from 2 to 5 days to 9 to 12 months. The hypothalamus is the first to be suppressed by steroid dosing but the first to recover (normalizing ACTH in several months), whereas the adrenal glands are the last to be suppressed and the slowest to recover, a process that may take 6 to 12 months. Data regarding corticosteroid-induced adrenal suppression are varied. Suppression of the HPA axis should be anticipated in any patient who has been receiving more than 30 mg/day of hydrocortisone (or 7.5 mg of prednisolone or 0.75 mg of dexamethasone) for more than 3 weeks.
Given the large variation in cortisol production in healthy patients, it is difficult to predict the need for GC supplementation during stress. Also, the adrenal response to acute medical illness is variable. An intact HPA axis is paramount to survival during periods of major stress and critical illness. Adrenal insufficiency with decreased GC levels is associated with a significantly increased mortality in these settings. Adrenal suppression should be suspected in patients receiving corticosteroids, and these patients should receive replacement GCs when facing major surgery or critical illness.
Expert recommendations have suggested lower doses and shorter duration of glucocorticoid administration ( Table 44.1 ). Patients undergoing minor procedures such as routine dental work, skin biopsy, inguinal repair, or minor orthopaedic surgery only require their normal daily dose of replacement, and not a supplemental dose. Some clinicians have advocated using hydrocortisone continuous infusions to limit the rapid clearance and peaks and nadirs of bolus therapy. Others have suggested using longer-acting glucocorticoid agents, such as methylprednisolone or dexamethasone.
| Surgical Stress | Glucocorticoid Dosage | Medical Stress | Glucocorticoid Dosage |
|---|---|---|---|
| Minimal | |||
| <1 hr under local anesthesia (e.g., dental work, skin biopsy) | Usual replacement dose, 15-30 mg hydrocortisone/day | Nonfebrile cough or upper respiratory tract infection | Usual replacement dose, 15-30 mg hydrocortisone/day |
| Minor | |||
| Inguinal hernia repair Colonoscopy | Intravenous hydrocortisone 25 mg equivalent at start of the procedure 5 mg of methylprednisolone IV on day of procedure only; usual replacement dose after procedure | Viral illness Bronchitis Uncomplicated urinary tract infection Uncomplicated cellulitis | Double or triple the usual dose of glucocorticoid until recovery (e.g., 40-60 mg oral hydrocortisone daily in divided doses) |
| Dental procedure requiring > 1 hr under local anesthesia (multiple extractions) | Double the daily dose of glucocorticoid on day of procedure; usual replacement dose next day | ||
| Moderate | |||
| Open cholecystectomy Segmental colon resection Lower limb revascularization Total joint replacement Abdominal hysterectomy | Intravenous hydrocortisone 75 mg/day (25 mg every 8 hr) or 10-15 mg of methylprednisolone on day of procedure; taper over the next 1-2 days to usual replacement doses in uncomplicated cases | Gastroenteritis Pneumonia Pyelonephritis | Intravenous hydrocortisone 25 mg every 8 hr until recovery |
| Severe | |||
| Cardiothoracic surgery Whipple procedure Esophagogastrectomy Total proctocolectomy Liver resection Pituitary adenomectomy Dental procedures under general anesthesia | Intravenous hydrocortisone 150 mg/day (50 mg every 8 hr) or 20-30 mg of methylprednisolone; taper over the next 2-3 days to usual replacement dose in uncomplicated cases | Pancreatitis Myocardial infarction Labor | Intravenous hydrocortisone 150 mg/day; taper once clinical condition is stable |
| Critical Illness/Intensive Care | |||
| Major trauma Life-threatening complications | Maximum 200 mg/day intravenous hydrocortisone (50 mg every 6 hr or by continuous infusion) | Septic shock | Maximum 200 mg /day intravenous hydrocortisone (50 mg every 6 hr or by continuous infusion 0.18 mg/kg/hr + 50 mcg/day of fludrocortisone until shock is resolved); may take several days to a week or more; gradually taper, following vital signs and serum sodium level determination |
Corticosteroids Used in Clinical Practice
Cortisol has a half-life of 70 to 90 minutes, whereas all synthetic analogues of cortisol have longer half-lives, based on slower rates of metabolism. The half-life does not reflect duration of action, which is best represented by the duration of ACTH suppression. Short-acting synthetic GCs have durations of action of 8 to 12 hours; these include the active agent hydrocortisone and the inactive cortisone (converted by the liver to the biologically active cortisol). The intermediate-acting GCs prednisone, prednisolone, methylprednisolone, and triamcinolone have durations of action of 24 to 36 hours. Prednisone is an inactive agent, which is metabolized to the active agent prednisolone by the liver. The longest acting GCs, dexamethasone and betamethasone, have durations of action longer than 48 hours ( Table 44.2 ).
| Steroid | Half-Life (hours) | Relative Glucocorticoid Activity | Relative Mineralocorticoid Activity | Glucocorticoid Dose Equivalency (mg) | Relative Anti-inflammatory Activity |
|---|---|---|---|---|---|
| Short Term | |||||
| Cortisone | 8-12 | 1 | 1 | 25 | NAE |
| Hydrocortisone | 8-12 | 0.8 | 0.6 | 20 | 1 |
| Intermediate Acting | |||||
| Prednisone | 8-36 | 4 | 0.8 | 5 | NAE |
| Prednisolone | 8-36 | 4 | 0.8 | 5 | 3 |
| Methylprednisolone | 18-36 | 5 | 0.5 | 4 | 6.2 |
| Triamcinolone | 18-36 | 5 | 0 | 4 | 5 |
| Long Acting | |||||
| Dexamethasone | 36-54 | 20-30 | 0 | 0.75 | 26 |
| Betamethasone | 36-54 | 20-30 | 0 | 0.6 | NAE |
Short-acting GCs are advantageous when a rapid clinical effect is desired such as in allergic reactions. Long-acting agents are of interest for their prolonged anti-inflammatory effects and are well suited for disorders requiring inhibition of ACTH secretion. Because all GCs have some mineralocorticoid effect, their administration can have profound consequences for patients with impaired cardiovascular function. The shorter-acting GCs have the highest mineralocorticoid potency, and the long-acting agents have the weakest.
Therapeutic Effects of Corticosteroids
Corticosteroids are predominantly used in interventional pain management because of their proven anti-inflammatory effects with subsequent temporary relief of symptoms. They are the most potent and effective agents in controlling inflammation through numerous mechanisms, including effects on cytokines, inflammatory mediators, inflammatory cells, nitric oxide synthase, and adhesion molecules.
Effects on Cytokines
Cytokines are important mediators of inflammation, and the pattern of their expression largely determines the magnitude and persistence of the inflammatory response. Steroids have potent inhibitory effects on cytokine transcription and synthesis, especially the ones relevant in chronic inflammation (IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-α, and granulocyte-macrophage colony-stimulating factor). Steroids interfere with cytokine synthesis by blocking their synthesis. They inhibit the synthesis of the IL-2 receptor and oppose the induction of IL-2 and T-lymphocyte activation and proliferation.
Effects on Inflammatory Mediators
The activation of phospholipase A 2 leads to the hydrolysis of arachidonic acid from membrane phospholipids and the production of arachidonic acid metabolites. Arachidonic acid metabolism via the cyclooxygenase pathway produces prostaglandins and thromboxanes, and through the lipoxygenase pathway it produces leukotrienes. Steroids increase the synthesis of lipocortin (annexin) 1, a phospholipase A 2 inhibitor, and thus decrease the production of inflammatory mediators such as leukotrienes, prostaglandins, and platelet-activating factor. GCs also upregulate the transcription of other anti-inflammatory genes such as neutral endopeptidase and inhibitors of plasminogen activator.
The primary anti-inflammatory effect of steroids appears to be the suppression of transcription of genes involved in inflammation such as collagenase, elastase, plasminogen activator, cyclooxygenase (COX)-2, and most chemokines. Steroids directly inhibit the transcription of a cytosolic form of phospholipase A 2 induced by cytokines, and they inhibit the gene expression of cytokine-induced COX-2 in monocytes. Cortisol, 6-methylprednisolone, and dexamethasone suppress lipopolysaccharide-induced synthesis of PGE 2 and cyclooxygenase-2 expression and activity in human monocytes. In addition, steroids inhibit the synthesis of early genes c-fos and c-jun triggered by increased levels of mediators of inflammation such as leukotriene B 4 and platelet-activating factor.
Effects on Inflammatory Cells
GCs interfere with macrophage activity by impairing phagocytosis, intracellular digestion of antigens, and macrophage release of IL-1 and TNF-α. By inhibiting the expression of chemokines, GCs prevent the activation and recruitment of inflammatory cells, including eosinophils, basophils, and lymphocytes. Steroids also markedly decrease the survival of certain inflammatory cells, such as eosinophils. Eosinophil activity is dependent on the presence of cytokines IL-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-γ. The presence of these cytokines promotes prolonged eosinophil survival, increased adhesion molecule expression, potentiated eosinophil degranulation, and movement of eosinophils across an endothelial barrier. Steroid administration blocks these cytokine effects, leading to programmed cell death, or apoptosis. GCs cause an expansion in the number of circulating neutrophils secondary to decreased adherence to vascular endothelium (demargination) and stimulation of bone marrow production. GCs interfere with T-cell mediated immunity. They inhibit the production of T lymphocytes by downregulating T-cell growth factors IL-1β and IL-2, and they inhibit the release of various T-lymphocyte cytokines.
Effects on Nitric Oxide Synthase
Various cytokines induce nitric oxide synthase (NOS), resulting in increased nitric oxide production. Nitric oxide increases plasma exudation in inflammatory sites. Steroids potently inhibit the inducible form of NOS in macrophages, and steroid pretreatment prevents the induction of NOS expression by endotoxin.
Effects on Adhesion Molecules
Adhesion molecules facilitate the trafficking of inflammatory cells to sites of inflammation. The expression of the adhesion molecules E-selectin, P-selectin, and intracellular adhesion molecule-1 on the surface of endothelial cells is induced by the cytokines IL-1β and TNF-α. These adhesion molecules enable the endothelium to recruit leukocytes actively and nonselectively, including neutrophils, eosinophils, mononuclear cells, and basophils from the circulation. GCs are effective and potent inhibitors of TNF-α and IL-1 release from macrophages, monocytes, and other infiltrating cells. There is a second class of cytokines that selectively activate the endothelium—IL-4 and IL-13, two cytokines associated with allergic diseases. Their release causes the endothelial expression of vascular cell adhesion molecule-1 only. Consequently, only circulating basophils, eosinophils, monocytes, and lymphocytes, but not neutrophils, can bind to the endothelial surface.
Other Anti-inflammatory Effects
Steroids inhibit plasma exudation from postcapillary venules at inflammatory sites. This effect is delayed, suggesting that gene transcription and protein synthesis are involved. It appears that the antipermeability effect is linked to the synthesis of vasocortin. In addition to nuclear anti-inflammatory effects, GCs also have direct effects on cells and cell membranes. Cortisol stabilizes lysosomal membranes, thus inhibiting lysosomal enzyme release. GCs prevent the sequestration of water intracellularly and the swelling and destruction of cells. GCs inhibit leukocyte accumulation and complement-induced polymorphonuclear neutrophil (PMN) aggregation and decrease PMN chemotaxis, T-cell and B-cell proliferation, and the differentiation and function of macrophages.
Other Mechanisms of Pain Relief
Following peripheral nerve injury, a number of morphologic and biochemical changes occur at the injury site including the formation of neuromas, which leads to increased electrical excitability. Ectopic discharge from the injury site leads to a persistent afferent barrage, which maintains neuralgic pain and paresthesias. GCs have been demonstrated to suppress spontaneous ectopic neural discharge originating in experimental neuromas and prevent the later development of ectopic impulse discharge in freshly cut nerves. The topical application of methylprednisolone was noted to block transmission of C-fibers but not the A-β fibers.
Side Effects of Corticosteroids
Short courses of GC therapy (less than 2 to 3 weeks) are usually safe. Side effects from short-term therapy are rare but may include fluid retention, hyperglycemia, elevated blood pressure, mood changes, menstrual irregularities, gastritis, Cushing’s syndrome, increased appetite, weight gain, increased infections, delayed wound healing, and acneiform eruptions. Long-term GC therapy with near-physiologic GC doses is relatively safe. With long-term supraphysiologic doses of steroids, more serious side effects may occur.
Cushing’s Syndrome
Cushing’s syndrome is characterized by sudden weight gain, hypertension, glucose intolerance, oligomenorrhea, decreased libido, and spontaneous ecchymoses. There is centripetal weight gain, involving thickening of the facial fat that rounds the facial contour (moon facies), enlargement of the dorsocervical fat pad (buffalo hump), and truncal obesity. The development of multiple striae wider than 1 cm on the abdomen or proximal extremities is almost unique to Cushing’s syndrome. Mild hirsutism, acne, personality changes, depression, insomnia, and edema also occur. Despite the external signs of excess GC production, patients receiving GCs develop adrenal atrophy and are at risk for adrenal crisis in the setting of stress. Laboratory tests reveal low blood ACTH and cortisol and low urinary cortisol levels.
Skeletal Effects
Osteoporosis, aseptic necrosis, and growth retardation are all potential complications of long-term GC therapy. Osteoporosis occurs in as many as 50% of patients treated with long-term supraphysiologic doses of prednisone. Trabecular bone, found in the axial skeleton (vertebrae and ribs), is more susceptible to demineralization due to high metabolic turnover rate (eight times more) when compared with that of cortical bone. Corticosteroid-induced osteoporosis (CIOP) has a multifactorial cause–impaired intestinal absorption of calcium coupled with its increased renal excretion, increased osteoclast activity with resultant bone resorption, inhibition of osteoblast activity with decreased bone synthesis, and secondary hyperparathyroidism. The incidence of fractures in patients receiving GCs has been reported to be between 10% and 20%. Patients at greatest risk for corticosteroid-induced osteoporosis are postmenopausal women, children, immobilized patients, and patients with rheumatoid arthritis. Agents such as activated vitamin D products, hormone replacement therapy, fluoride, calcitonin, and bisphosphonates have been shown to maintain or improve bone mineral density in corticosteroid-induced osteoporosis.
Aseptic necrosis is a severe musculoskeletal complication of GC therapy. It occurs with greater incidence in alcoholics, patients with systemic lupus erythematosus, patients with fatty degeneration of the liver, patients with altered lipid metabolism, and renal transplantation patients. The mechanism is related to deposits of fat in terminal arterioles of certain sites of bone. The femoral head is the site most commonly affected, although the humeral head or knee may also be involved. Bone pain is almost always the first symptom and precedes radiologic signs of osteonecrosis by up to 6 months.
Muscle Effects
The incidence of myopathy secondary to high-dose GC therapy has been reported to vary from 7% to 60%. There is no consistent relationship between the dose and duration of steroid administration and the occurrence of myopathy, but the condition develops more often with the use of potent fluorinated steroids such as triamcinolone, dexamethasone, and betamethasone. Symptoms include skeletal muscle weakness, tenderness, and pain with proximal or pelvic muscles typically affected. Recovery may take months to 1 year; treatment includes a reduction in the GC dose and physical therapy with a rehabilitation exercise program.
Ophthalmologic Effects
Cataracts and glaucoma may occur with chronic GC therapy. Steroid-induced cataracts occur in the posterior subcapsular region of the lens and may be asymptomatic until well formed. Children are at greatest risk for this complication. Glaucoma is caused by swelling of collagen strands at the angle of the anterior chamber of the eye, with resistance to the outflow of aqueous humor. The process is usually reversible after GC therapy is discontinued.
Gastrointestinal Effects
Nausea and vomiting are not uncommon with oral steroid therapy. Peptic ulcer disease is slightly increased with GC therapy and is more likely to be gastric than duodenal. GCs cause a decrease in mucus production and mucosal cell renewal. Concomitant use of aspirin and nonsteroidal anti-inflammatory drugs increase this risk and should be avoided, along with tobacco and alcohol, which also are ulcerogenic.
Metabolic Effects
Hyperglycemia results from GC effects of increased hepatic glucose synthesis and increased gluconeogenesis. GCs also antagonize peripheral insulin effects and can occasionally produce insulin resistance. Exacerbation of glucose intolerance is common, but the development of new cases of diabetes mellitus is not, and ketoacidosis is rare. Weight gain is a common side effect of GC therapy and may be the result of increased appetite or fluid retention. Facial edema and fat are estimated to occur in 10% to 25% of patients on steroid therapy for 2 months.
Hyperlipidemia is another metabolic consequence of GC therapy and is likely secondary to relative insulin resistance. Increased plasma triglyceride levels are more common than increased cholesterol levels. Patients with previous lipid level elevations are at higher risk for this side effect. Electrolyte abnormalities such as hypokalemic alkalosis may also occur, usually with GCs possessing strong mineralocorticoid properties.
Cardiovascular Effects
Hypertension, edema, and atherosclerosis may occur with GC therapy. Elevations in blood pressure occur because of increased sodium retention and vasoconstriction. GCs cause vasoconstriction by potentiating the effect of norepinephrine and opposing the effect of endogenous vasodilators such as histamine. This side effect occurs more frequently in patients with preexisting hypertension, older adults, GCs with high mineralocorticoid potency, and high-dose or prolonged (longer than 2 weeks) glucocorticoid treatment courses. Edema occurs from fluid retention secondary to sodium retention. With initial GC dosing, there is a paradoxical diuresis caused by an early blockade of antidiuretic hormone release.
Hematologic Effects
Blood cell effects, immunosuppression, and impaired fibroplasia occur with steroid therapy. Immunosuppression is produced by GCs at many levels. GCs increase the release of granulocytes from bone marrow, thus increasing the number of circulating leukocytes. Lymphopenia occurs, with predominant depression of T-cell production and decreased eosinophil counts with enhanced eosinophil destruction. Tissue inflammation is reduced by inhibition of cytokine production and by impaired chemotaxis of macrophages, neutrophils, basophils, and eosinophils. There is inhibition of the metabolism of arachidonic acid into prostaglandin and leukotriene mediators, as well as a direct inhibition of COX-2. Steroid therapy increases susceptibility to many bacterial, fungal, viral, and parasitic infections. Wound healing is delayed by GC inhibition of fibroblasts, collagen production, and suppression of wound reepithelialization.
Nervous System Effects
Mood changes, nervousness, euphoria, insomnia, and headache are common side effects of GC therapy and are dose related. Psychosis is an uncommon side effect and is seen more commonly in patients with previous psychiatric disorders.
Cutaneous Effects
Skin changes typical of the hyperadrenal state may occur; these include purpura, telangiectasia, atrophy, striae, pseudo-scars, and facial plethora. The skin becomes thin and fragile. Hair growth changes include transient scalp hair loss and hirsutism on other parts of the body. Hyperpigmentation or hypopigmentation may occur, as well as acneiform eruptions. Steroid acne commonly presents on the back and chest as fine, uniform papulopustules.
Pregnancy and Lactation
There appears to be no teratogenic contraindication to corticosteroid therapy in pregnancy. However, intrauterine growth retardation has been reported, and steroid use late in pregnancy may cause adrenal suppression in the fetus. Corticosteroids are secreted in small amounts into breast milk, thus exposing the infant to the risk of adrenal suppression.
Injectable Steroids in Interventional Pain Management
The most commonly used synthetic CSs for interventional pain procedures are derivatives of prednisolone (analog of cortisol) either by methylation (methylprednisolone) or fluorination (triamcinolone, betamethasone, and dexamethasone). As most corticosteroid solutions contain water-insoluble CS esters, they appear as microcrystalline suspensions in commercial preparations. Dexamethasone preparations are free of ester CSs and appear clear and nonparticulate. In the commonly used particulate CS preparations, the biologically active moiety is released by the action of cellular local esterases (hydrolysis) and therefore has the potential of lasting longer at the level of placement (joint, nerve root, intra-articular facets, etc.). On the other hand, the water-soluble CS solutions are taken up quickly by the cells and have a quicker onset of effect, but with a possible reduced duration of action. Many in vitro studies have demonstrated that for the ester CSs, in addition to variations in particle size, there are also differences in propensity of different CS crystals to aggregate into larger particles. Concentration of crystals also varies to compensate for different potencies and to allow equivalent doses between different CSs ( Table 44.3 ).
