Spinal injections have been performed for many years, most often for the management of axial, paraspinal, and radicular pain. They have evolved over the years with increasing popularity, with the number of epidural steroid injection procedures doubling from 2000 to 2008,¹ and have become essential therapies for the pain management clinician. Spinal injections can be used therapeutically, for treatment, or diagnostically, for the localization and identification of potential painful targets. As a result of their increasing use in pain management and their economic impact, they have been studied extensively, and their efficacies have been challenged. Despite controversy and contradicting results of numerous outcome studies, spinal interventional therapies will likely continue to play a significant role in interdisciplinary pain care.

The purpose of this chapter is to discuss commonly performed spinal interventions, especially epidural steroid injections and facet injections, with an emphasis on information that is clinically relevant to pain management specialists.

HISTORY OF SPINAL INJECTIONS

Spinal injections of substances for the treatment of low back and lower extremity pain^2,3 and for inoperable cancer of the rectum⁴ were described in 1901,⁵ with the use of medications, including cocaine and procaine, via multiple routes of administration, including epidurally, intrathecally, and via the sacral hiatus. In 1909, reports were published on the use of epidural anesthesia for the treatment of sciatica⁶ followed in the 1920s and 1930s by emerging treatments for sciatica with varying degrees of benefit and duration.^7,8

With the discovery of Compound E (cortisone) in 1936^9–11 and by 1950 its improvement of conditions, including rheumatoid arthritis,¹² and with the beneficial intraarticular effects of a longer acting steroid, Compound F (hydrocortisone),¹³ including the histologically confirmed reduction of synovial membrane inflammation, the stage was set for numerous anti-inflammatory pain management procedures along with continuing investigations of its efficacy and mechanisms of actions.^14–20 By the 1950s, many pain management clinics were in operation,^21,22 and today, many interdisciplinary pain treatment facilities are in existence.

CLASSIFICATION OF SPINAL INJECTIONS

Spinal injections for pain management have been performed for many years, both for diagnostic and therapeutic purposes. They can be functionally categorized both by location (i.e., cervical, thoracic, lumbar, or sacral) and by purpose: (i.e., diagnostic or therapeutic). A significant proportion of procedures performed at modern pain clinics include epidural steroid injections and facet joint injections. Other common interventions include sympathetic blocks, provocative discography, and medial branch radiofrequency neurotomy. Epidural steroid injections can be subcategorized by the route of administration of medication, usually via transforaminal, interlaminar, or caudal approaches, with or without the use of a catheter.

Zygapophyseal or facet injections that are therapeutic in nature tend to be intraarticular, and although they can be therapeutic and diagnostic, medial branch blocks are usually performed to provide diagnostic information and to predict the potential benefit of facet denervation via radiofrequency neuroablation.

EPIDURAL STEROID INJECTIONS

Epidural injections of glucocorticoids may be helpful in some patients for the treatment of axial lumbar, thoracic, and cervical pain, and radicular lower and upper extremity and thoracic radicular pain. Historically, injection of steroids into the epidural space followed the observation of the beneficial effects of intraarticular injection of steroids into osteoarthritic joints,²³ with the first use of hydrocortisone in 1952 periradicularly²⁴ and in 1953 caudally.²⁵

The emergence of interventional pain management as a specialty has led to a significant increase in the use of interventional techniques, prompting continuous review and the establishment of evidence-based practice guidelines for the management of spinal pain.²⁶ With hospital-based and dedicated pain treatment facilities performing these and other types of injections²⁷ and with a 100% increase in the frequency of epidural injections between 1998 and 2003²⁸ and between 2000 and 2008, epidural steroid injections are the most commonly performed intervention used in the United States to manage chronic and subacute low back pain (LBP).²⁹

Various causes of sciatic pain have been proposed, including pressure on the spinal nerve by disc fragment or bone spur;³⁰ however, nerve root compression does not always produce pain, and patients without a history of sciatic pain have had disc protrusion or herniation found on postmortem examination.³¹ Additionally, myelographic and magnetic resonance imaging (MRI) abnormalities have been found in asymptomatic individuals,^32,33 and surgical decompression does not relieve symptoms in every case. Confusing the picture even more, many patients with sciatic pain have no imaging-based evidence of nerve root compression. This may suggest that radicular pain is multifactorial.

Although mechanical nerve root compression can cause sensory and motor dysfunction, inflammation may also be a source of neural pain.³⁴ Structures in the vicinity of the nerve root, including injured disc tissue,³⁵ injured vertebral endplates leading to disc degeneration,³⁶ degenerated lumbar intervertebral discs per se,³⁷ facet joints, and epidural tissues, may each modulate neural activity, leading to increased sensitivity and pain-generating discharges and heightened sensitivity to pressure.³⁸ Current imaging modalities may be unable to demonstrate anatomic abnormalities responsible for spinal or radicular pain, especially if the abnormalities are not macroscopic.

In 1950, inflammation and edema was noted in nerve root biopsy samples from patients undergoing laminectomy,³⁹ and it was observed that swollen nerve roots shrank as sciatic symptoms improved.⁴⁰ Similar observations were found in patients treated with intramuscular dexamethasone.⁴¹ Increased concentrations of inflammatory and neurochemical mediators found in intervertebral discs, including phospholipase A₂,⁴² and pain-related neuropeptides in nerve endings in the discs and epidural structures^43,44 may contribute to axial or radicular symptoms. Cells from degenerated disc fragments produce numerous inflammatory mediators, including tumor necrosis factor (TNF) and inflammatory cytokines,⁴⁵ and the released inflammatory mediators and TNF may penetrate within intraneural capillaries, causing axonal ischemia, which is responsible for nerve root pain.⁴⁶

Glucocorticoids inhibit the synthesis or release of many inflammatory substances⁴⁷ and may prevent cell-mediated inflammation that can stimulate nociceptive nerve endings.⁴⁸ In radicular pain, glucocorticoids may mitigate early effects of inflammation, including edema, fibrin deposition, capillary dilation, leukocyte aggregation, and phagocytosis, and late effects such as capillary and fibroblast proliferation, collagen deposition, and scar formation.²⁷ LBP per se may respond to the effects of glucocorticoid through its reduction of inflammation specifically in the posterior longitudinal ligament and the outer annulus of the intervertebral disc.²⁷ Injecting glucocorticoid near the sites of inflammation achieves a higher concentration than that obtained by systematic administration.

Many studies have investigated the efficacy of epidural steroid injections in the cervical, thoracic, and lumbar regions, reporting conflicting results, likely because of the difficulty in studying pain treatment modalities. Significant variations exist with regard to the numerous mechanisms of pain generation and the natural course of acute and chronic back and upper and lower extremity pain. Factors that must be considered in these investigations include injection variability, the route of administration (transforaminal vs. interlaminar), the use of fluoroscopic guidance and contrast, operator experience, spinal anatomy, degenerative change, surgical hardware or granulation tissue affecting the spread of medication, timing and frequency of administration, and prior surgical procedures.

Results from one systematic review of lumbar interlaminar epidural steroid injections show a significant reduction of pain scores in patients with lumbar radiculitis compared with no therapy and compared with conservative management without injection therapy.⁴⁹ In the cervical region, a study regarding immediate pain score after a single image-guided cervical transforaminal epidural steroid injection does not predict the long-term effectiveness of the procedure.⁵⁰ The literature supporting or refuting the use of epidural steroid injections for the treatment of chronic mid and upper back pain caused by disc herniation, radiculitis, and other causes is scant.⁵¹

There will likely continue to be emerging and sometimes conflicting evidence on the cost effectiveness⁵² and efficacy^53–58 of epidural steroid injections or the choice of medications, routes of administration, and the timing of injections.

Sources of axial spinal pain (cervical, thoracic, and lumbar) are numerous. These include intervertebral discs, nerve root dura, facet joints, ligaments, muscles, and fascia; in the lumbar region, the sacroiliac joints; and in the cervical region, the atlanto-axial and atlanto-occipital joints. The lumbar facet joint was suspected as a source of LBP, spinal instability, and leg pain in 1911,⁵⁹ and by 1933, the lumbar facet joint was recognized by Ghormley as part of a distinct LBP syndrome “facet syndrome.”⁶⁰ Provocative intraarticular facet joint injections of hypertonic saline were used and described in 1976⁶¹ to investigate lumbar facet–mediated pain patterns. Medical literature has identified the lumbar, thoracic, and cervical facet joints as independent pain generators.

Inflammation within the joint capsule can decrease thresholds of nerve endings in the facet capsules with resulting elevated baseline discharge rates, and stretch or excessive stretch may damage axons or the joint capsule, with activation of nociceptors leading to prolonged neural discharges.⁶² In the lumbar region, facet-mediated pain may present with axial spinal, paraspinal, buttock, or leg distribution patterns;⁶³ similarly, cervical facet–mediated pain may present as axial and paraspinal pain with radiation to the upper extremities or as headache.⁶⁴ In the thoracic region, based on experience with cervical and lumbar facet joints, thoracic facet–mediated pain can be axial or paraspinal, with radiation to the upper back and chest wall.⁶⁵ Because facet-mediated pain may coexist with other sources of axial pain or radicular pain, in clinical practice, it may be helpful to consider each component individually.

The diagnostic and therapeutic utility of cervical, thoracic, and lumbar facet injections has been investigated in numerous studies. Medial branch blocks, named for targeting the sensory innervations of facet joints, are frequently performed for diagnostic purposes to determine the role of the facet joint as a mediator of pain in lumbar, thoracic, and cervical regions. Localizing the facet joints to target may be difficult with two facet joints at each vertebral level (left and right), and the potential variations in symptoms, historical, imaging and physical examination information may be helpful.

To establish a consensus among interventional pain management specialists in the diagnosis and management of spinal pain, particularly specifics of treatment techniques (treatment modality, medication, frequency of administration), an algorithmic approach for the clinical management of chronic spinal pain based on evidence-based guidelines has been suggested.⁶⁵

In facetogenic pain, diagnostic blocks targeting suspected painful joints can identify sources of lumbar, thoracic, and cervical pain. Medial branch blocks can also aid in the selection of patients who might respond to facet radiofrequency denervation. For LBP, a systematic review⁶⁶ of 122 studies, leading to the inclusion of 11 randomized trials and observational studies concluded that the evidence is good for radiofrequency neurotomy and fair to good for lumbar facet joint nerve blocks for short- and long-term improvement. Evidence for intraarticular injections and pulsed radiofrequency neurotomy is limited.

In the cervical region, a systematic review⁶⁷ including four randomized trials and six observational studies concluded that evidence for cervical radiofrequency neurotomy and medial branch blocks is fair, and evidence for cervical intraarticular injections with local anesthetic and steroid is limited. However, the study noted a paucity of published literature for cervical facet joint injections. In the thoracic region, there is evidence that the facet joints are responsible pain generators for thoracic pain⁶⁸ and that the diagnostic accuracy of controlled facet joint blocks is strong for cervical and lumbar facet joints and moderate for thoracic facet joints.⁶⁹

OVERVIEW

Corticosteroids are steroid hormones produced in the adrenal cortex, and this class consists of glucocorticoids and mineralocorticoids. Mineralocorticoids, such as aldosterone, are responsible for regulation of electrolyte and fluid balance.⁷⁰ Glucocorticoids (named for their modulation of the metabolism of carbohydrates) exert their action via the glucocorticoid receptor (GR).⁷¹

With respect to their use in pain management, corticosteroids can be compared pharmacologically with focus on each medication’s mineralocorticoid and glucocorticoid potency, duration of action, and particulate size.

Glucocorticoids have been useful in the treatment of inflammatory diseases for more than 50 years, but their usefulness has been limited by complications and side effects. These include, but are not limited to, suppression of the hypothalamic–pituitary–adrenal (HPA) axis and the immune system, exacerbation of diabetes, hypertension, and osteoporosis.^72–78 Pharmacologic research has focused on modifying the chemical structure of glucocorticoids in hopes of increasing their potency while decreasing the likelihood of side effects. The separation of anti-inflammatory activity from the systemic side effects of glucocorticoids has been difficult. The anti-inflammatory potency of steroids is related to the GR binding affinity.⁷⁹ While steroid preparations are typically injected in proximity to regions of inflammation, they cross into the systemic circulation and affect every major organ system in the body.⁸⁰

STEROID MECHANISM OF ACTION

The mechanism of action of the glucocorticoids is complex but in part involves the inhibition of phospholipase A2 activity with a resulting reduction in the release of arachidonic acid from membrane phospholipids.⁸¹ Arachidonic acid is the precursor for the synthesis of eicosanoids (including prostaglandins, thromboxanes, leukotrienes, and lipoxins), which mediate a wide range of inflammatory responses. Additionally, methylprednisolone has been shown in the rat to suppress transmission in thin unmyelinated C-fibers but not in myelinated A-β fibers, suggesting a direct membrane effect of the steroid per se.⁸² Thus, inhibiting phospholipase A2 reduces the presence of inflammatory mediators, some of which cause hyperalgesia,⁸³ edema, and decreased blood flow.

STEROID PREPARATIONS USED FOR INJECTIONS

Although adverse events relating to neuraxially administered steroid medications are rare, their severity, especially with regard to brain and spinal cord infarction with regard to transforaminal administration, has prompted numerous reviews.⁸⁴ Studies have investigated particulate size, route of administration, and the use of sedation because embolic phenomena have resulted in spinal cord injuries, stroke, and deaths.^85–89 Etiologies for the sequelae have been postulated to include embolic infarction secondary to particulate injection into an arterial vessel; direct vascular injury causing spasm, trauma, or compression; or neurotoxicity from medications injected or the vehicle or additives to the preparation.⁹⁰

Corticosteroids used for injection that are commercially available in the United States can be categorized as soluble, insoluble, or a combination of both. Insoluble corticosteroid preparations (methylprednisolone, triamcinolone) are typically corticosteroid esters and offer theoretical advantages in their longer duration of action because they require hydrolysis by cellular esterases for the active steroid moiety to be released.⁹¹ Additionally, preparations of insoluble crystalline powder in aqueous suspensions are less likely to be absorbed soon after injection in comparison with soluble preparations.⁹² Soluble steroid preparations (dexamethasone, betamethasone) are taken up rapidly by cells and have a quicker onset but reduced duration of action.⁹³ Betamethasone is unique in its availability as a water-soluble ester, betamethasone sodium phosphate, or as the practically water-insoluble salt, betamethasone phosphate. One formulation containing both betamethasone ester and salt (Celestone Soluspan; Schering, Kenilworth, NJ) may offer both a rapid onset and longer duration of action.

There are substantial variations in the size of the crystals found in insoluble corticosteroid preparations, and this has been demonstrated in numerous in vitro studies.^94–98 Ester corticosteroid preparations tend to contain larger particulate sizes, and because of variations in crystal concentrations and physical characteristics and with mixture with other injected medications or with plasma,⁹⁹ crystals may aggregate into larger particles. This phenomenon is of extreme importance given the potential for these particles, injected intravascularly, to cause distal embolization and tissue injury.

STEROID PARTICULATE SIZE AND MECHANISMS FOR SERIOUS ADVERSE EVENTS

Infarction of central nervous system (CNS) tissue has been postulated to be secondary to embolic occlusion by particulate steroid.^100–102 Particulate size may influence the degree of arterial occlusion and size and variability of particles in the injectate have been investigated,^103–106 as well as their dilution or mixture with other medications.¹⁰⁷ In comparison to the red blood cell, particles larger than the lumen of an arteriole may occlude arterioles, however collateral blood supply may decrease the likelihood of tissue damage.^108,109

Particles smaller than an arteriole but greater than the size of a red blood cell may occlude terminal arterial vessels and cause infarction. The diameter of an arteriole ranges from 100 to 500 µm, and that of vertebral arteries ranges from 600 to 2600 µm. The size of corticosteroid ester particles can exceed 500 µm, and particles can aggregate or precipitate in the vascular space or in blood to form larger particles.

Use of nonparticulate steroid preparations (pure betamethasone, dexamethasone) may decrease the risk of embolic phenomena and may strengthen the postulate that embolic occlusion is the source of CNS damage. Ongoing investigations are looking at the incidence and clinical presentations of major complications associated with cervical transforaminal epidural steroid injections to make evidence-based recommendations.¹¹⁰ Based on animal studies of the serious CNS sequelae after injection of insoluble methylprednisolone acetate versus no noticeable deficits after the injection of soluble dexamethasone phosphate,¹¹¹ MacMahon et al. suggest no longer performing transforaminal epidural steroid injections in the cervical, thoracic, or lumbar regions with insoluble corticosteroid preparations and believe that this reduces, if not removes, the risk of CNS embolization during the procedure.¹¹²

Additionally, two case reports describe significant CNS injury (bilateral lower extremity paralysis with neurogenic bowel and bladder) after a fluoroscopically guided (left L3–L4) lumbar transforaminal epidural steroid injection with betamethasone and a computed tomography–guided (right L3–L4) transforaminal injection of methylprednisolone, with MR images consistent with spinal cord infarction without evidence of intraspinal mass or hematoma.¹¹³ In each of these cases, the use of particulate corticosteroid with embolization in a radicular artery is asserted as a likely mechanism of injury, and statements discuss reducing or eliminating this risk by the utilization of particulate-free steroids and testing for intraarterial injection with digital subtraction angiography and a preliminary injection of local anesthetic.

An alternative mechanism of injury suggests retrograde flow into a common arterial trunk with subsequent antegrade flow into vulnerable arteries and should be considered as a possible mechanism by which spinal cord or brain injury may occur.¹¹⁴ Spinal cord infarction has also been reported after a (right L2–L3) transforaminal epidural steroid injection with spinal angiography demonstrating occlusion of the right L2 segmental artery with reconstitution of the radicular branch from collaterals. The artery of Adamkiewicz was presumably occluded by steroid injection.¹¹⁵

Numerous case reports and reviews describe and attempt to quantify both minor and devastating neurologic complications of epidural steroid injections and their mechanisms. Although embolic phenomena may be responsible for tissue infarction, direct injury to the vessel may also be problematic. Perineural hematoma after lumbar transforaminal steroid injection was described in a case report and demonstrated by MRI after the observation of progressive motor and sensory loss.¹¹⁶ Although digital subtraction angiography (DSA) has been suggested as an adjunct to aid in the identification of vascular compromise during interventional neuraxial procedures, irreversible paraplegia was reported after a lumbar transforaminal epidural steroid injection despite the administration of a local anesthetic test dose and the use of DSA.¹¹⁷