CHAPTER 83 Injection Procedures
PATHOPHYSIOLOGY OF RADICULAR LUMBAR PAIN
Lumbar radicular pain, i.e. sciatica, in this context is defined as pain referred from the back into the dermatome of the affected nerve root along the femoral or sciatic nerve trunk. This has to be differentiated from nonradicular pain, which refers symptoms into the leg in a nondermatomal pattern.1 Radicular pain is shooting and bandlike, whereas somatic referred pain is usually constant in position but poorly localized and diffuse, and is aching in quality. True radiculopathy is defined as radicular pain in the presence of a neurological deficit.2 The prevalence of lumbar disc syndrome (herniated disc or typical sciatica) was studied as part of the Mini-Finland Health Survey.3 A diagnosis of lumbar disc syndrome was made for 5.1% of men and 3.7% of women aged 30 years or over. In a Finnish longitudinal birth cohort study, symptomatic lumbar disc disease (herniated nucleus pulposus or sciatica) appeared around the age of 15 years, and the incidence rose more sharply from the age of 19 years.4
Tissue origin of lumbar radicular pain
The tissue origin of sciatic pain has been studied during decompression operations performed with local anesthesia. In these studies, sciatic pain could be produced only by pressure on the compressed, swollen nerve root, or on the dorsal root ganglion (DRG). Pressure on normal nerve roots or on other tissue did not produce sciatica.5,6
Intervertebral disc
Disc herniation is the single most common cause of radicular pain.2 Mixter and Barr7 discovered that soft tissue ‘tumours’ were actually derived from the intervertebral discs, and that their surgical removal relieved sciatica symptoms. The causal link between herniated nucleus pulposus (HNP) and radicular pain is, however, not so straightforward since (1) HNP can be found in 20–36%, depending on the age, of asymptomatic subjects,8–11 and (2) internal disc ruptures (without HNP) may also induce disabling radicular pain,12,13 indicating the existence of an alternative mechanism to neural compression. Even though this chapter does not cover the clinical diagnosis of lumbar radicular pain, the authors stress that nerve root tension signs, assessed by the straight leg-raising test, can be positive in sciatica patients without HNP in MRI.14
Central and lateral stenosis
Spinal stenosis is a condition associated with degenerative changes of the disc and zygapophyseal joints at multiple levels, which may include degenerative spondylolisthesis.15 Spinal stenosis has both structural and dynamic components. When the spinal canal is structurally narrowed, slight extension can cause compression of the nerves.16,17 Extension can also cause an increase in epidural pressure.18 Flexion has the reverse effect, widening the spinal canal and foramina and reducing the epidural pressure. These typical features can be used in the practical clinical diagnosis of spinal stenosis and also in the algorithm of radicular pain.
Lateral lumbar spinal stenosis due to osteoarthritis can be divided into entrance zone, midzone and exit zone stenosis.19 When a nerve root is laterally entrapped, it gives unilateral pain that is worse on walking. When central canal is narrow, pain radiates to one or both legs while walking and is relieved with flexion postures.20,21
Midzone stenosis is clinically the most relevant entity, because the DRG occupies a large part of the midzone.19 Recent experimental data also support the critical role played by the DRG in the pathophysiology of painful stenosis.22 The authors found that neither demyelinization nor axonal degeneration in the cauda equina induced mechanical allodynia, i.e. neuropathic pain, whereas lesions distal or immediately proximal to it are painful. They concluded that DRG apoptosis may be important for the production and maintenance of mechanical allodynia.22
Pathophysiological mechanisms of radicular pain
Evidence of other mechanisms that can elicit lumbar radicular pain other than nerve root compression comes from many directions. We have already cited the findings of experimental surgery in anesthesia, existence of HNP in asymptomatics, and on the other hand, sciatica syndromes in those without an HNP. Additional evidence comes from animal experiments. McCarron et al.23 demonstrated that nuclear material of the intervertebral disc is chemically inflammatory and neurotoxic. Olmarker et al. showed that nuclear material – without any compression – can induce structural and functional changes in porcine nerve roots.24 The functional changes included focal degeneration of myelinated fibers and focal Schwann cell damage in nondegenerated axons. The damage to the Schwann cells resulted in a disintegration of Schmidt-Lantermann incisures, which represent connections of Schwann cell cytoplasm inside and outside the myelin sheath.25 Additional evidence supporting inflammation comes from the finding that nucleus pulposus is chemotactic, attracting leukocytes, and it may also induce macromolecular leakage and spontaneous firing of axons in vitro.26 Inflammation-induced capillary leakage increases endoneural pressure and reduces blood flow, thereby causing a ‘compartment syndrome’ in the DRG.27 A similar decrease in blood flow has been observed also in the canine nerve root. This reduction correlated with decrease in nerve conduction velocity, and was maximal within 1 week and recovered within 1 month. The pattern of nucleus-exposed DRG was, however, different, showing no clear recovery.28 These findings suggest that DRG irritation may lead into a different – perhaps more conservative treatment-resistant – radicular pain entity than nerve root involvement only. An additional, important landmark study is that of Kawakami et al.29 They nicely showed that leukocytes are essential in experimental radicular pain. In a rat model of mechanical hyperalgesia induced by application of nucleus pulposus to nerve roots, depletion of leukocytes with nitrogen mustard inhibited the generation of hyperalgesia. This indicated that the leukocytes are important in the production of pain-related behavior. The cells first appearing in and around the HNP on nerve–nuclear interface were polymorphonuclear leukocytes. Macrophages, originating from monocytes, did predominate a few days later and then remain in the affected region until the inflammation subsided.29 The implication of the observations is that lumbar radicular pain is a systemic disease, at least in the early stages of the disease.
What is the leukotactic signal(s) of extruded nuclear material? Many substances, including hydrogen ions and glycoproteins, have been suspected of causing chemical radiculitis.30–32 A crucial finding was the one reported by Olmarker et al.33 They noted that the neurotoxicity of the nucleus seems to be associated with disc cells, as freezing prevented the neuronal damage. This observation limited the number of possible inflammatory candidates, but several were still ‘without alibi.’
Phospholipase A2 (PLA2) was a promising suspect, as it is the rate-limiting enzyme in the synthesis of proinflammatory lipid mediators (prostaglandins, leukotrienes, lipoxenies, and platelet-activating factor). It is calcium-dependent, adsorbing tightly to plasma membranes and intact cells. PLA2 liberates arachidonic acid from the membrane phospholipids, and is secreted extracellularly by activated phagocytes in response to cytokines.34 Additionally, it is released from rabbit chondrocytes in response to interleukin (IL)-1.35 It was found in extraordinarily high concentrations in herniated and painful discs,36 although this finding has since been questioned.37 It is also itself inflammatory38 and neurotoxic.39 When PLA2 was injected epidurally, motor weakness, demyelinization, and increased sensitivity of dorsal roots to mechanical stimulation were observed 3 days after the injection, but not beyond 3 weeks.40
Tumor necrosis factor alpha (TNF-α) is another potential candidate in HNP-induced nerve root irritation. TNF-α is a cytokine produced mainly by activated macrophages and T cells in response to inflammation, and by mast cells and Schwann cells in response to peripheral nerve injury.41,42 It activates the transcription factors NF-κB and AP-1 by binding to its p55 TNF-receptor (TNFR1), thereby inducing the production of proinflammatory and immunomodulatory genes.43 Endoneurial TNF-α causes demyelinization, axonal degeneration, and hyperalgesic pain states.44 In thermal hyperalgesia, two peaks have been associated with Wallerian degeneration, and can be reproduced in chronic injury to peripheral nerves.45 These peaks are also related to changes in TNF-α expression. It seems that the first peak, 6 hours after the nerve injury, is due to the local expression of the cytotoxic transmembrane 26 kDa TNF-α protein released by the resident Schwann cells. The second peak occurs 5 days after the injury, and may represent TNF-α protein released by hematogenously recruited macrophages.45 It has been shown immunohistochemically that TNF-α is expressed in the porcine nucleus pulposus.46 In a rat model, the concentration of TNF-α was found to be approximately 0.5 ng per herniated rat disc.47 Moreover, exogenous TNF-α produced neuropathological and behavioral changes (Wallerian degeneration of nerve fibers, macrophage recruitment to phagocytoze the debris, splitting of the myelin sheath) that mimicked those of the nucleus pulposus.47 Application of TNF-α on porcine nerve roots induced a reduction of the nerve conduction velocity that was even more pronounced than for nucleus pulposus, whereas application of IL-1β and IFNδ induced slight reductions of conduction velocity compared with fat, but they were not statistically significant.48 Additional evidence for a crucial role of TNF-α comes from an animal study in which soluble TNF-α receptor (etanercept, Enbrel™) reversed nucleus pulposus-induced nerve conduction block and nerve root edema.49 However, TNF-α is not just a ‘bad guy’ as it also has an important role in the resorption of disc herniations. Macrophages secrete matrix metalloproteinase (MMP)-7 (=matrilysin) enzyme, which liberates soluble TNF-α from macrophage cell membranes. Soluble TNF-α induces disc chondrocytes to secrete MMP-3 (stromelysin), required for the release of a macrophage chemoattractant and subsequent macrophage infiltration of the disc.50,51
In addition to TNF-α, other inflammatory mediators may take part in the inflammatory component of radicular pain. These mediators could be either proximal to TNF-α, i.e. increase the expression of TNF-α, or distal to TNF-α, i.e. they are upregulated by TNF-α. Kang et al.52 observed increased matrix metalloproteinase activity, and increased levels of nitric oxide, prostaglandin E2, and IL-6 in HNP culture media compared with the control discs. Similarly, Burke et al.53 also detected increased levels of IL-6 in disc extracts from patients undergoing fusion for discogenic pain. They found additionally increased levels of a chemokine, IL-8. Interleukin-6 is an interesting interleukin, as it regulates to a large extent the hepatic acute phase and cachectic responses to an acute inflammatory stimulus.54 Recently, it was found that sciatica patients have an elevated acute phase response.55 Mean sensitized C-reactive protein (CRP) levels were significantly higher in sciatica patients compared to age- and sex-matched controls (1.68 versus 0.74 mg/L; p=0.002). We have genotyped sciatica patients with regard to some inflammatory genes and compared these patients to asymptomatic subjects. A genotype leading to increased production of IL-6 was overexpressed in sciatica patients.56
Additionally, in the HNP homogenates IL-1α, IL-1β and granulocyte-macrophage colony stimulating factor are detectable.57 The exact role of IL-1 in HNP-induced radicular pain is not known but it may have separate activity as it has in experimental arthritis.58
Natural course of lumbar radicular pain
The long-term prognosis of lumbar radicular pain is considered to be good59 although in one study only one-third of sciatica patients recovered fully within 1 year, whereas one-third underwent surgery and one-third had residual symptoms.60 This study by Balague60 is in concordance with a systematic review on the long-term course of low back pain (LBP).61 Sixty-two percent of LBP patients still experienced pain at 12 months, 16% were sick-listed 6 months after inclusion into the study, and 60% experienced relapses of pain. A cohort of primary care patients with sciatica was followed in the Netherlands.62 An unfavorable outcome was predicted by a disease duration of more than 30 days, increased pain on sitting, pain upon coughing, and straight leg raising restriction.
Magnetic resonance imaging (MRI) follow-up examinations have shown that HNP tends to regress over time, with partial to complete resolution after 6 months in two-thirds of people.63 We have recently rescanned 21 patients with HNP-induced severe sciatica at 2 weeks, 3 months, and 6 months in an intervention trial. Significant resorption seemed to occur already as early as 3 months in most patients.64 There is a predilection for large extrusions to resorb well.65,66 The resorption process seems to associate with HNP-encircling rim enhancement,67 which is thought to represent a neovascularized zone with macrophage infiltration.68 Neovascularization probably remains high in extrusions, as these have ruptured the posterior longitudinal ligament and entered the epidural space, allowing small vessels to penetrate the disc tissue more easily, whereas subligamentous herniations are more or less immunoprivileged.69 This is supported by the higher resorption rate for extrusion-type disc herniations.70 We have recently analyzed determinants of HNP resorption.71 In the final model, the only significant determinants for resorption were thickness of rim enhancement and Komor classification, i.e. herniation extending above or below 67% of the adjacent vertebra.72
INTERVENTIONAL TREATMENT OPTIONS FOR LUMBAR RADICULAR PAIN
Evidence on substantiating the best method to achieve successful treatment of lumbar radicular pain is still sparse. A recent systematic review found only 19 randomized, controlled trials (RCTs), of which eight met the three major requirements (comparability of groups, observer blinding, and intention-to-treat analysis).73 From the perspective of this review, no significant effect was demonstrated for nonsteroidal antiinflammatory agents (NSAIDs), traction, or intramuscular steroids. Considering the, at least partial, inflammatory nature of lumbar radicular pain, blocking of the cytokine cascade by local or systematic corticosteroids might, however, be effective. It is known from animal experiments that methylprednisolone injected within 2 days after the application of the nucleus pulposus inhibits the nucleus-induced vascular permeability and functional impairment, i.e. decrease of nerve conduction velocity.74 Any clinically useful intervention for radicular pain should be (1) effective in pain alleviation, (2) safe (i.e. no harmful complications), and (3) the technical details of the procedure or the equipment used should not be too complicated so that the intervention can be used widely in clinical practice. Moreover, if two different interventions are found equally effective and safe on radicular pain, the more cost-effective procedure should be chosen. When designing and using interventions for radicular pain, one should not tamper with the benign natural course of sciatica. In the ensuing, epidural injections, selective nerve root blocks, and anticytokine therapy are discussed in more extensive detail.
Epidural injections
Epidural injections in the cervical, thoracic, and lumbosacral spine have been used for both diagnostic and therapeutic purposes in modern interventional spine practice. Epidural injections should preferably be combined with other therapeutic modalities, e.g. physical training and musculoskeletal rehabilitation. Epidural injection of medication allows a concentrated amount of the treatment agents (i.e. mostly corticosteroids) to be deposited and retained, thereby exposing the nerve roots to the medication for a prolonged period of time. The ability of steroids injected through an epidural route to reach their target in the anterior or anterolateral epidural compartment has been questioned. Indeed, even in experienced hands 25–45% of blind interlaminar or caudal epidural needle placements may be incorrect.75–77
Technical procedure
There are two different routes to perform epidural injections: a caudal route through the sacral hiatus, and a lumbar interlaminar route. Epidural injection can be done with fluoroscopy or without it. Many specialists recommend fluoroscopy, because without fluoroscopy the needle is not always placed in the epidural space. Additionally, fluoroscopy prevents accidental intravascular injection. The incidence of intravascular uptake during lumbar spinal injection procedures was found to be approximately 8.5%. Absence of flashback of blood upon preinjection aspiration did not predict extravascular needle placement.78 Recently, fluoroscopic guidance has evolved into the standard approach in the US, although some clinicians stubbornly perform blind injections (Curtis Slipman, personal communication). Typically, blind injections are reserved for pregnant women and heavy patients who exceed the weight limits of the fluoroscopy table. It is easiest and safest to insert the needle at L2–3 or L3–4, close to the superior spinous process. The standard technique used in epidural injections is the loss of resistance technique, where a controlled and well-defined loss of resistance occurs upon entering the epidural space through the ligamentum flavum. One study found that in the non-obese patient, lumbar interlaminar injections can be accurately placed without X-ray screening, in contrast to caudal injections, which require X-ray screening independent of the weight of the patient.79 In the caudal epidural injection, the quantity of corticosteroid that is possible to apply near to the inflamed nerve root is usually small. As well, the precise application is always uncertain, because anatomical structures such as septas may interfere with the flow of the injectate. However, caudal epidural route is useful in cases when the lesion is at L5–S1, but the interspinous route is preferable if the lesion is located at L4–5 or above.
Efficacy
Epidural steroid injections are found to have a high success rate when evaluated in terms of long-term alleviation of radicular symptoms due to lumbar HNP.80,81 One published meta-analysis concluded that epidural corticosteroids are effective in both the short and long term in low back pain and sciatica.82 In contrast, the systematic review by Koes et al. that included higher-quality trials, found at most a short-term effect on sciatica.83 To further complicate the matter, the systematic review by Vroomen et al. on treatment of sciatica concluded that epidural steroids may produce a short-term benefit for lumbar radicular pain.73 Following these aforementioned studies, two RCTs on epidural steroids for sciatica have been published. In the trial of Buchner et al.,84 patients with lumbar radicular pain consequent to a confirmed HNP were randomized into the epidural group (3 injections of 100 mg methylprednisolone in 0.25% bupivacaine; n=17) and control group (n=19). At 2 weeks, patients receiving methylprednisolone injection showed a significant improvement in straight leg raising test results and a tendency for a greater pain relief. At 6 weeks and 6 months, no significant differences were observed in any of the outcomes. In the trial of Valat and colleagues,85 three epidural injections of 50 mg prednisolone acetate (n = 43) were compared to epidural saline injections (n = 42) in HNP-induced sciatica. A significant improvement was observed in both groups, but epidural steroid injections provided no additional benefit over saline. Our conclusion, which stems from the reviews and subsequent RCTs, is that epidural steroids may have, at best, a short-term beneficial effect on lumbar radicular pain. Additionally, cost minimization analysis suggests that epidural injections under fluoroscopy may not be justified on the basis of the current literature.86 The authors’ personal preference is to use selective nerve root blocks (SNRB) in lieu of interlaminar epidurals for lesions at L4–5 or above. At L5–S1, our present view is to prefer computed tomography (CT)-guided SNRBs over caudal epidurals, and caudal epidurals over fluoroscopy-guided SNRBs. We do acknowledge that there is no uniform consensus regarding the approach at L5–S1.
Safety
A major concern when administrating anesthetics into the epidural space is systemic toxicity. There is the theoretical risk of cardiovascular toxicity and central nervous system (CNS) effects. These complications can be avoided by adhering to careful technique and using lower doses of less concentrated anesthetics as discussed in the spinal injections technique chapter (Ch. 23). The maximum epidural dose recommended for a single injection is 500 mg for lidocaine and 225 mg for bupivacaine. The amount of local anesthetic agent used for SNRBs is much less.
Epidural injections are usually considered to be extremely safe when performed with the proper technique.87 Nevertheless, the interlaminar route may be prone to complications, which include dural puncture-caused spinal headache, transient hypotension, Cushing’s syndrome, bacterial meningitis, chemical meningitis, epidural abscess, sinus arrhythmia, respiratory distress from spinal anesthesia, transiently increasing back or leg pain, numbness, transient dizziness, and cardiopulmonary arrest.88 In the meta-analysis of Watts and Silagy, which was based on seven trials with 431 patients, 2.5% suffered from dural taps, 2.3% transient headache, 1.9% transient increase in pain, and 0.2% irregular menstrual cycle.82 Long-term complications were not covered in the original reports, but, according to data from the American Society of Anesthesiologists Closed Claims Project database (1970–1999), epidural steroid injections accounted for 40% of all chronic pain management claims. Serious injuries, involving brain damage or death, occurred, especially with local anesthetics and/or opioids.89
Selective nerve root blocks
Derby et al.90 have postulated that the transforaminal approach may get corticosteroid more reliably in the anterior epidural space, where most of the pain-sensitive structures are located. In the procedure, the pharmaceutical agents are injected between the nerve root and the epidural sheath, depicting the nerve root in tubular fashion.91 Hereafter, we use the term selective nerve root block (SNRB), but synonymous terms include selective nerve root injection, periradicular infiltration, transforaminal injection, and perineural injection. The mechanism of therapeutic effect is postulated to rely on mainly on the antiinflammatory effect of corticosteroid, which blocks the afferent impulses from the periphery.91 However, the anesthetic component may have an effect on its own, as lidocaine has been shown to increase intraradicular blood flow identical to the responses of a sympathetic ganglion block.92
SNRBs are useful in the diagnosis of radicular pain in atypical presentations. They have an accuracy of 85–94% in identifying a single symptomatic root, sensitivity of 100%, and a positive predictive value of 93–95% has been presented for root blocks.1,91,93,94 Indications are: (1) atypical extremity pain; (2) when imaging studies and clinical presentation do not correlate; (3) when electromyography and MRI do not correlate; (4) anomalous innervations, such as conjoint nerve roots or furcal nerves; (5) failed back surgery syndrome with atypical extremity pain; and (6) transitional vertebrae.88 A diagnostic SNRB is usually done without any antiinflammatory drug such as steroid in order to confirm the identity of the affected nerve root, whereas in therapeutic injections the ultimate goal is a therapeutic effect (typically achieved with a corticosteroid with or without local anesthetic). See the algorithm on diagnostic SNRBs and treatment of lumbar radicular pain, Figures 83.1A and 83.1B, respectively.
Technical procedure
Fluoroscopy-guided SNRB is typically the simplest, most rapid, and cost-effective technique. The details of this procedure have been thoroughly explained in Chapter 23. There are, however, two other techniques to confirm the proper needle insertion and placement: CT and MRI guidance.
