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13 Articles in Volume 11, Issue #4
Diagnosing and Managing Hand Osteoarthritis
Difficult Migraine Patient
Electromagnetic Applications In Biology and Medicine
Excerpt from the Book Avoiding Opioid Abuse While Managing Pain
Hormone Therapies: Newest Advance in Pain Care
Make the Family Your Best Friend
Medications for Chronic Pain—Opioid Analgesics
Nonpharmacologic Remedies for Back Pain During Pregnancy
Reconsidering and Revising Evidence-Based Practice in Pain Medicine: Steps Toward Sustaining the Profession?
The Value of Blood Analysis for Compliance Monitoring
Treatment of Neuropathic Pain: The Role of Unique Opioid Agents
Understanding Potential Complications Of Epidural Steroid Injections
Unmasking Post-traumatic Headache

Understanding Potential Complications Of Epidural Steroid Injections

Practitioners need to understand and educate their patients regarding the full scope of potential side effects that can occur when receiving epidural steroids.

Corticosteroids are a common component of nearly all therapeutic injections for pain management that physicians perform. Whether they are used in a trigger-point injection performed by a primary care physician in an office or in a precision cervical epidural injection performed under fluoroscopic guidance, steroids have become one of the most commonly used injectable pain medications in the United States.

Despite the indisputable rise in the number of pain interventions, little has been written about the potential side effects of administering steroids into the epidural space. In fact, many premier textbooks allocate only a couple of pages to exploring glucocorticoid mechanism of action and then only briefly mention potential side effects.1 This lack of understanding has led many practitioners to naïvely view steroids as benign drugs without fully comprehending the broad scope of potential side effects that can occur when steroids are injected into the epidural space.

Undoubtedly, adverse effects from epidural steroid injections are not usually lethal, but they can carry significant morbidity and may be very disconcerting to patients. To understand the full scope of complications that can arise from epidural administration of glucocorticoids, it is necessary not only to understand the technical/mechanical complications that occur with needle placement, but also to grasp the role of pharmacokinetics, steroid particulate size, and, most importantly, how glucocorticoids affect nearly every organ system.

History

Glucocorticoids have slowly and steadily become more common in the pharmacologic toolbox of the modern physician. In the early 1900s, as medicine grew in its understanding of the inflammatory cascade, so, too, grew the role for steroids as a treatment modality to modulate and downregulate excess inflammation. In 1950, the Nobel Prize in Physiology or Medicine was awarded jointly to three researchers, Edward Calvin Kendall, Tadeus Reichstein, and Philip Showalter Hench, “for their discoveries relating to the hormones of the adrenal cortex, their structure, and biological effects.”2

Corticosteroids were first administered into the epidural space in the 1950s to treat sciatica, with the thought that direct deposition of medications at the site of inflammation would have a more pronounced and longer duration of action.3 Since that time, we have developed a greater understanding of how corticosteroids administered in the epidural space can modulate epidural radiculitis. There are numerous histologic and biochemical studies that have shown that there is an upregulation of substance P, calcitonin gene-related peptide (CGRP), N-methyl-d-aspartate (NMDA), and glucocorticoid receptors in lamina 1 and 2 of the dorsal horn, a key location where first-order sensory neurons synapse onto second-order sensory neurons.4 The presence of glucocorticoid receptors at that key synapse suggests that glucocorticoids modulate sensory/pain transmission either through their anti-inflammatory properties or by serving as reversible local anesthetics. Despite these basic science studies elucidating potential mechanisms of action when corticosteroids are administered into the epidural space, the complete mechanisms are still not clearly known.

Endogenous cortisol is a lipophilic, 6-ring carbon structure produced by the adrenal glands. In a nonstressed person, normal production of cortisol is 10 to 20 mg per day. Glucocorticoids are derivatives of cortisol and have numerous physiologic effects, primarily immunologic and metabolic. In the 60 years since steroid pathways were elucidated, various synthetic glucocorticoid preparations have been created, usually by substituting the outer carbon moieties on the primary 6-ring steroid structure. These synthetic glucocorticoids are more potent than cortisol, dramatically potentiating the immunologic and metabolic effects while minimizing but not fully eliminating mineral corticoid activity.

Synthetic glucocorticoids have higher receptor binding affinities for the glucocorticoid receptor and alter endogenous cortisol function by taking over the hypothalamic–pituitary–adrenal (HPA) axis. Once attached to the receptor, glucocorticoids function to induce numerous cellular changes by altering nuclear transcription (see Figure 1).

Figure 1. Chemical structure of endogenous cortisol (left), dexamethasone (right)

After glucocorticoids are injected into the epidural potential space, they can function as a medication depot, exerting prolonged anti-inflammatory action and pain/sensory signal modulation. Inevitably, the glucocorticoids are absorbed though the epidural venous plexus into systemic circulation, where they can cause numerous side effects. Finally, the agents are metabolized and eliminated from circulation by the liver. Seemingly every tissue including skin, neuronal tissue, muscle, and bone alter their function in some way when exposed to the glucocorticoid signal (see Figure 2).

Figure 2. Diagram of hypothalamic–pituitary–adrenal axis.

Cutaneous Changes

In addition to local depigmentation, skin fragility, easy bruising, and development of telangiectasia, facial flushing can be a very common side effect after an epidural steroid injection. Although not a lethal reaction, the appearance and feeling can be uncomfortable for many patients. The mechanism of steroid-induced flushing is thought to be from both immunoglobulin E (IgE) and histamine release; it is independent of route of administration and has been seen with a variety of steroid preparations.5

Commonly cited incidence numbers in many textbooks have ranged from 0.1% to 11%.6,7 Yet a recent prospective study by Kim et al aimed to further elucidate this issue.8 Kim and his team enrolled 150 patients who underwent interlaminar epidural corticosteroid injections with 16 mg of dexamethasone. They reported that 42 of the 150 patients (28%) experienced self-reported flushing, most of which occurred after discharge (30 of 42). Interestingly, 67% of those who reported flushing were female; all events resolved within 48 hours of onset.

Osteoporosis and Bone Changes

Glucocorticoids are known to change calcium homeostasis, causing a rapid assault on bone through a synergetic reduction in bone formation and an increasing bone breakdown. Patients on chronic steroid therapy are known to have a higher rate of vertebral and rib fractures stemming from the presence of micro-fractures left over from glucocorticoid-induced osteoblast apoptosis.9 Fortunately, glucocorticoid injections, when administered via the epidural space, have not been shown to change bone mineral density (BMD) or increase fracture risk. Manchikanti et al prospectively evaluated 100 patients undergoing epidural steroids injections versus epidural injections without glucocorticoid.10 The patients in the steroid-treatment arm each received an average cumulative dose of 146 mg of methylprednisolone acetate. At baseline, the steroid-treated patients had a BMD score of 0.4967; after 1 year of intermittent epidural corticosteroid exposure, the BMD did not change (0.5000). The investigators concluded that changes in BMD as a result of epidurally administered steroids are very rare. Acute vascular necrosis (AVN), affecting the femoral head or other large joints, is also a rare complication seen in patients on chronic steroid therapy.11 We could not find any published reports of AVN secondary to an epidural steroid injection.

Hyperglycemia

One of the many metabolic actions of glucocorticoids is to increase circulating levels of glucose. This hyperglycemia stems from both increased gluconeogenesis in the liver and peripheral tissue insulin resistance. In patients who are on long-term steroid therapy, this can lead to the clinical phenomenon of “steroid diabetes.” Studies have shown that insulin resistance can develop for 2 to 5 days after intra-articular corticosteroid injections and can be problematic in patients with poorly controlled preexisting diabetes.12 Additional studies looking at hyperglycemia specifically after an epidural corticosteroid injection confirmed that although insulin resistance may develop, clinical elevations in blood sugar are less likely. Younes et al studied 29 patients who received 3 sequential weekly epidural corticosteroid injections or intra-articular injections.13 They subsequently noted that patients did show mild elevations in postprandial glucose levels but no change in fasting blood sugars. Maillefert et al studied 9 patients after they received 15 mg of epidural dexamethasone injection and did not see any changes in fasting blood sugars on days 0, 2, and 7 after the injection.14

Cardiovascular Effects

As many clinicians are aware, the primary cardiovascular effect of oral corticosteroid therapy is hypertension, an all-too-common event. Both a multinational cohort study and a prospective study showed a 2- to 3-times-greater relative risk for the development of angina, myocardial infarction, or transient ischemic attack (TIA) in patients taking chronic oral corticosteroids.15 The pathophysiology of hypertension in the presence of glucocorticoids is believed to be due to changes in circulating volume and vascular resistance. Younes et al noticed a transient increase in mean systolic blood pressure of 5 mm Hg, which returned to baseline 3 weeks after injection.13 Maillefert, using dexamethasone, did not show any difference in blood pressure measurement a week after the epidural corticosteroid injection.14

HPA Axis Suppression

The HPA axis controls many autonomic and homeostatic functions. Large doses of iatrogenic glucocorticoids provide negative feedback to the HPA axis, leading to adrenal insufficiency and symptoms that may include malaise, anorexia, nausea and vomiting, and hypotension. The most important risk factors leading to the development of adrenal insufficiency from steroid therapy include maximum dose, duration, and total cumulative dose. Physiologic reductions in serum adrenocorticotropic hormone (ACTH) can be seen for 1 to 2 weeks after a single epidural steroid injection.

Maillefert’s review of epidural injections with dexamethasone, a nonparticulate steroid with theoretically shorter duration of action, still demonstrated profound decreases in serum ACTH and free cortisol levels on postinjection days 1 and 7, with normal ACTH levels returning on day 21.

When injections are done serially, the suppression is longer and more intense. One study found suppression of ACTH after serial steroid injections, and it took a full 3 months for normal HPA function to return.16 Hsu demonstrated that doubling the dose of triamcinolone more than doubled HPA depression—that is, 40 mg of triamcinolone caused HPA suppression for 1 day, but when 80 mg of triamcinolone was given, the HPA suppression lasted for nearly 2 weeks.17 Epidural injections that are performed simultaneously with other injections (eg, facet, piriformis, etc.) also have the potential to increase the length of serum ACTH suppression.18

The HPA axis is critically involved in fertility and the menstrual cycle. Chronic steroid administration has been shown to lower fertility in both men and women because of inhibition of endogenous sex hormones. There have been case reports of heavy and painful menstrual bleeding after epidural steroid injections, which were thought to be due to inhibition of the hypothalamic–pituitary–ovarian axis.19

Neurologic/Psychiatric Effects

Glucocorticoid administration, either acutely or chronically, can have an effect on cognition, mood, and sleep and can alter the behavioral response to stress. In times of acute stress, endogenous glucocorticoids work through glucocorticoid receptors in the central nervous system to induce alterations in neurotransmitter milieu that can lead to apoptosis in the amygdala and the frontal lobes. When these pathways are chronically exposed to steroids, the resultant apoptosis can be so impressive that differences in brain mass and ventricular volume can be seen on magnetic resonance imaging. In addition, these patients may clinically demonstrate low manic levels or increased irritability and lability. Although no reports of mood changes have been reported in the pain literature after one epidural corticosteroid injection, there have been case reports of headache, insomnia, depression, and frank psychosis in patients who have had multiple steroid-based pain procedures in a short period of time.20

Infection

Although inflammation is generally thought to be a negative process, it plays a critical defensive role in the ability of the body to isolate and attack sources of infection. Infectious complications from injectable corticosteroids are most commonly due to skin flora that are tracked into deeper tissues at the time of needle placement. G1616lucocorticoids have a profound inhibitory effect on T- and B-cell humeral response and also direct inhibition of cellular phagocytosis, thereby potentially providing a safe harbor for the bacteria that have penetrated the skin and reached the epidural space.

In the immune-compromised individual, the concern is even greater because of the possibility of spread of opportunistic bacteria. There have been many reports of epidural abscesses as well as vertebral osteomyelitis, commonly from skin flora.21

Spinal Cord Infarction

In addition to the potential for direct needle trauma to neural tissues, much has been written about the potential for emboli-induced spinal cord damage after an epidural steroid injection. Although the true incidence is difficult to obtain because of underreporting, 8 cases of lumbar spinal cord infarction have been published to date.22 The near-instantaneous onset of paralysis has led to reflection and several studies trying to elucidate the pathologic mechanism for such disastrous results.23 Different hypotheses have been proposed, with the first implicating direct needle trauma leading to dissection or vasospasm of the radicular artery or the artery of Adamkiewicz.24

Although needle trauma and dissection remain very real possibilities, more recent studies point to arterial embolization from corticosteroid particulates as the etiologic event. Many of the commonly used injectable corticosteroids have particulate compositions with molecular structures that are larger than the size of a red blood cell.25 The increased particulate size creates the potential for distal capillary occlusion and resultant neurologic/spinal cord ischemia. Subsequent edema can trigger further ischemia. Particulate-containing steroids have been implicated because there has not been a reported case of spinal cord infarction in which nonparticulate corticosteroids were used. In addition, animal studies demonstrate that direct intra-arterial deposition of particulate corticosteroids in a swine model leads to very high mortality versus the deposition of nonparticulate corticosteroids, which does not lead to increased mortality (see Table).26

Table. Particulate and Nonparticulate Steroids

Conclusion

The potential for side effects from glucocorticoids administered into the epidural space are numerous. Side effects are dose-, location-, and duration-dependent, but there is no thres-

hold dose below which the side-effect profile is significantly diminished. Practitioners need to understand and educate their patients regarding the full scope of potential side effects that can occur when receiving epidural steroids. Practitioners should also consider limiting the dose and frequency of epidural corticosteroid injections and using nonparticulate corticosteroids for transforaminal epidural injections. Finally, because the efficacy of adding corticosteroids to epidural injections is not clear, practitioners should consider the option of epidural injections with only local anesthetics—leaving out the corticosteroids altogether.27

Spine graphic

 

Last updated on: September 13, 2011
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