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Sciatica: a review of history, epidemiology, pathogenesis, and the role of epidural steroid injection in management

2007; Elsevier BV; Volume: 99; Issue: 4 Linguagem: Inglês

10.1093/bja/aem238

1471-6771

Mai Stafford, Philip Peng, David A. Hill,

Anesthesia and Pain Management

Radicular pain in the distribution of the sciatic nerve, resulting from herniation of one or more lumbar intervertebral discs, is a frequent and often debilitating event. The lifetime incidence of this condition is estimated to be between 13% and 40%. Fortunately, the majority of cases resolve spontaneously with simple analgesia and physiotherapy. However, the condition has the potential to become chronic and intractable, with major socio-economic implications. This review discusses the history, epidemiology, pathophysiology, and natural history of sciatica. A Medline search was performed to obtain the published literature on the sciatica, between 1966 and 2006. Hand searches of relevant journals were also performed. Epidemiological factors found to influence incidence of sciatica included increasing height, age, genetic predisposition, walking, jogging (if a previous history of sciatica), and particular physical occupations, including driving. The influence of herniated nucleus pulposus and the probable cytokine-mediated inflammatory response in lumbar and sacral nerve roots is discussed. An abnormal immune response and possible mechanical factors are also proposed as factors that may mediate pain. The ongoing issue of the role of epidural steroid injection in the treatment of this condition is also discussed, as well as potential hazards of this procedure and the direction that future research should take. Radicular pain in the distribution of the sciatic nerve, resulting from herniation of one or more lumbar intervertebral discs, is a frequent and often debilitating event. The lifetime incidence of this condition is estimated to be between 13% and 40%. Fortunately, the majority of cases resolve spontaneously with simple analgesia and physiotherapy. However, the condition has the potential to become chronic and intractable, with major socio-economic implications. This review discusses the history, epidemiology, pathophysiology, and natural history of sciatica. A Medline search was performed to obtain the published literature on the sciatica, between 1966 and 2006. Hand searches of relevant journals were also performed. Epidemiological factors found to influence incidence of sciatica included increasing height, age, genetic predisposition, walking, jogging (if a previous history of sciatica), and particular physical occupations, including driving. The influence of herniated nucleus pulposus and the probable cytokine-mediated inflammatory response in lumbar and sacral nerve roots is discussed. An abnormal immune response and possible mechanical factors are also proposed as factors that may mediate pain. The ongoing issue of the role of epidural steroid injection in the treatment of this condition is also discussed, as well as potential hazards of this procedure and the direction that future research should take. Sciatic neuralgia is defined as 'pain in the distribution of the sciatic nerve due to pathology of the nerve itself'.72Merskey H Bokduk N Classification of Chronic Pain. 2nd Edn. IASP Press, 1994: 13-15Google Scholar Radicular pain is defined as 'pain perceived as arising in a limb or the trunk caused by ectopic activation of nociceptive afferent fibres in a spinal nerve or its roots or other neuropathic mechanisms'.72Merskey H Bokduk N Classification of Chronic Pain. 2nd Edn. IASP Press, 1994: 13-15Google Scholar According to these definitions, sciatic neuralgia is clearly a form of radicular pain, and is described as a disease of the peripheral nervous system.72Merskey H Bokduk N Classification of Chronic Pain. 2nd Edn. IASP Press, 1994: 13-15Google Scholar The term 'sciatica' may cause confusion as it has been used to describe any pain, including referred, felt in the leg along the distribution of the sciatic nerve. Indeed, the term has been described as 'an anachronism and should be abandoned'.72Merskey H Bokduk N Classification of Chronic Pain. 2nd Edn. IASP Press, 1994: 13-15Google Scholar Nevertheless, the term 'sciatica' remains in common usage both in clinical practice and in publications. Indeed, a Medline search from 1996 to 2006 reveals 1204 papers using 'sciatica' as a key word. The use of the term sciatica, however, should only be in the context of the above definitions and as such, be distinguished from any or all other forms of pain felt in the leg, particularly referred pain. Sciatica is a relatively common condition with a lifetime incidence varying from 13% to 40%. The corresponding annual incidence of an episode of sciatica ranges from 1% to 5%.35Frymoyer J Lumbar disc disease: epidemiology.Instr Course Lect. 1992; 41: 217-223PubMed Google Scholar 36Frymoyer JW Back pain and sciatica.N Engl J Med. 1988; 318: 291-300Crossref PubMed Scopus (939) Google Scholar This review assesses current knowledge of the epidemiology, pathogenesis, and natural history of sciatica. The ongoing debate about the role of epidural steroid injection in the management of this condition is also discussed. Although this is a fairly safe procedure where hazards are usually mild and transient, serious complications can occur and so the patients should be fully aware of the balance between risk and benefit before giving informed consent. Despite a large number of clinical trials of epidural steroid injections for sciatica, the most important question remains unanswered, and indeed, unasked. Is the effect of epidural steroid injection due to a direct action on lumbar nerve roots or simply due to systemic uptake from the vascular epidural space? The ancient Greeks were familiar with sciatic neuralgia and used the term 'sciatica', to describe pains or 'ischias' felt around the hip or thigh. Hippocrates himself referred to 'ischiatic' pain affecting men between 40 and 60 yr. He observed that young men described pain that lasted about 40 days before resolving spontaneously. He also noted that pain radiating to the foot was a good prognostic sign, whereas localized hip pain was less likely to resolve.51Hippocrates (460–370 BC) The Genuine Works of Hippocrates. Sydenham Society, London1849Google Scholar The Italian anatomist Domenico Cotugno (1736–1822) wrote the first book on sciatica in 1764 and for many years it was known as Cotugno's disease.30Delaney TJ Rowlingson JC Carron H Butler A Epidural steroid effect in nerves ad meninges.Anesth Analg. 1980; 59: 610-614PubMed Google Scholar He was the first to distinguish sciatica due to nervous disease from the aching pain associated with low back pain. He observed that sciatica could be continuous or intermittent and noted that continuous pain could become intermittent, but not vice versa. By the 19th century, sciatica was thought to be due to a variety of rheumatic conditions causing inflammation of the sciatic nerve. However, early frustrations with difficulties in identifying a cause of and treating sciatica were expressed by Fuller in his book Rheumatism, Rheumatic Gout and Sciatica (1852). He stated 'the history of sciatica is, it must be confessed, the record of pathological ignorance and therapeutic failure'.37Fuller HW On Rheumatism, Rheumatic Gout and Sciatica: The Pathology, Symptoms and Treatment. John Churchill, London1852Google Scholar There may be many pain management physicians who would agree with those sentiments today. The intervertebral disc was first implicated as a causative factor in sciatica in the early 20th century. Schmorl94Schmorl G Ueber Knorpelknotchen an der hinterflache der wirbelbandscheiben.Fortschr ad Geb d Rontgenstraglen. 1929; 40: 629-634Google Scholar and Andrae (1929)3Andrea A Ueber knorpelknotchen am hinteren ende der wirbelbandscheiben im bereich des spinalkanals.Beitr 2 Path Anat UZ Allg Path. 1929; 82: 464-474Google Scholar described posterior disc protrusions seen at post-mortem studies, but did not link these with sciatic pain and concluded they were probably asymptomatic in life. In an early surgical management of sciatica, the neurosurgeon Eslberg (1931)33Eleberg CA The extradural ventral on ondromas (eccondroses) their favourite sites, the spinal cord and root symptoms they produce and their surgical treatment.Bull Neurosurg Inst New York. 1931; 1: 350-366Google Scholar described removal of cartilaginous 'tumours' from the spinal canal, with subsequent improvement of symptoms. He considered the possibility that these 'tumours' could in fact be prolapsed disc material. This idea, however, was initially rejected. The concept of prolapsed disc material causing pain was later revisited by Mixter and Barr who reviewed the pathology of all excised chondromas of the spine held in the Harvard Medical School pathology museum, comparing them with normal disc material. Of 16 specimens reviewed, 10 were judged to contain normal disc material. They concluded that sciatica and neurological sequelae were due to protrusion of normal disc material. Six months later, the first patient with a preoperative diagnosis of 'ruptured intervertebral disc' was operated on in the Massachusetts General Hospital. This led to the landmark paper published in the New England Journal of Medicine74Mixter WJ Barr JS Rupture of the intervertebral disc with involvement of the spinal canal.N Engl J Med. 1934; 211: 210-215Crossref Google Scholar and since then, the prolapsed intervertebral disc has been irreversibly linked with the pathogenesis of sciatica. The presence of pain was initially ascribed to pressure on nerve roots. This idea was challenged by Kelly,59Kelly M Pain due to pressure on nerves. Spinal tumours and the intervertebral disc.Neurology. 1956; 6: 32-36Crossref PubMed Google Scholar who felt that pressure on a nerve would lead to loss of function rather than pain; therefore, pain must arise by a different mechanism. Around the same time, Lindahl and Rexed64Kotilainen E Sonninen P Kotilainen P Spinal epidural abscess: an unusual cause of scaitica.Eur Spine J. 1996; 5: 1-3Crossref Scopus (8) Google Scholar found evidence of an inflammatory response on lumbar nerve roots at laminectomy leading to the theory that prolapse of an intervertebral disc may provoke an inflammatory reaction in lumbar nerve roots, causing the sciatic type pain. This theory led to an active research programme that is still ongoing.2Allan DB Waddell G An historical perspective on low back pain and disability.Acta Orthop Scand. 1989; 60: 1-23Crossref PubMed Scopus (118) Google Scholar A number of environmental and inherent factors thought to influence the development of sciatica have been studied, including gender, body habitus, parity, age, genetic factors, occupation, and environmental factors (Table 1). A cross-sectional study of 2946 women and 2727 men showed neither gender nor body mass had an influence on the development of sciatica, although body mass may have been associated with low back pain.46Heliovaara M Makela M Knekt P Impivaara O Aromaa A Determinants of sciatica and low back pain.Spine. 1991; 16: 608-614Crossref PubMed Scopus (260) Google Scholar Body height may be a risk factor for sciatica, although this appears to be significant only in males in the 50–64 yr age group. Parity of up to six also has been identified as having no association with sciatica.46Heliovaara M Makela M Knekt P Impivaara O Aromaa A Determinants of sciatica and low back pain.Spine. 1991; 16: 608-614Crossref PubMed Scopus (260) Google Scholar, 47Heliovaara M Body height, obesity and risk of herniated lumbar intervertebral disc.Spine. 1987; 12: 469-472Crossref PubMed Scopus (138) Google Scholar, 48Heliovaara M Risk factors for low back pain and sciatica.Ann Med. 1989; 21: 257-264Crossref PubMed Scopus (131) Google Scholar The incidence of sciatica is related to age. Rarely seen before the age of 20, incidence peaks in the fifth decade and declines thereafter.35Frymoyer J Lumbar disc disease: epidemiology.Instr Course Lect. 1992; 41: 217-223PubMed Google Scholar This age distribution was also observed in those presenting for lumbar disc herniation surgery.98Spangfort EV The lumbar disc hernation: a computer aided analysis of 2504 operations.Acta Orthop Scand Suppl. 1972; 142: 1-95Crossref PubMed Scopus (405) Google Scholar The odds ratio (OR) of an episode of sciatica increased by 1.4 for every additional 10 yr of age, up to the age of 64.46Heliovaara M Makela M Knekt P Impivaara O Aromaa A Determinants of sciatica and low back pain.Spine. 1991; 16: 608-614Crossref PubMed Scopus (260) Google Scholar Interestingly, the site of disc herniation appears to change with age. Although the majority of disc herniations occur at the L4/5 or L5/S1 level, with advancing age, there appears to be a relatively increased incidence of herniation at the L3/4 or even L2/3 level.36Frymoyer JW Back pain and sciatica.N Engl J Med. 1988; 318: 291-300Crossref PubMed Scopus (939) Google ScholarTable 1Factors associated with development of sciaticaPositive influenceIncreasing height (older age groups only)AgeGenetic pre-dispositionWalkingJogging (pre-disposes to pain if previous history exists)Occupation (particularly if associated with physical activity, especially flexion/torsion of trunk, arms frequently raised above shoulder height, driving of motor vehicles)SmokingNo influenceGender, body mass, parityNegative influenceJogging (if no baseline history of sciatica) Open table in a new tab A genetic link with sciatica was first reported in a juvenile population.108Varlotta GP Brown MD Kelsey JL Golden AL Familial predisposition for herniation of a lumbar disc in patients who are less than twenty one years old.J Bone Joint Surg Am. 1991; 73: 124-128Crossref PubMed Scopus (120) Google Scholar This has also been observed in the adult population, where both retro- and prospective observational studies identified a higher incidence of sciatica or prolapsed disc among first-degree relatives than controls in a population of patients presenting for surgery on herniated lumbar discs.69Matsui H Kanamori M Ishihara H Yudoh K Naruse Y Tsuji H Familial predisposition for lumbar degenerative disc disease.Spine. 1998; 23: 1029-1034Crossref PubMed Scopus (127) Google Scholar 96Simmons ED Guntupalli M Kowalski JM Braun F Seidel T Familial predisposition for degenerative disc disease.Spine. 1996; 21: 1527-1529Crossref PubMed Scopus (57) Google Scholar A study of 9365 pairs of adult twins identified the lifetime incidence of sciatica in monozygotic and dizygotic twins as 17.7% and 12%, respectively. The estimated heritability was 20.8% for those reporting sciatica and 10.6% for those admitted to hospital with sciatica.45Heikkila JK Koskenvuo M Heliovaara M et al.Genetic and environmental factors in sciatica. Evidence from a nationwide panel of 9365 adult twin pairs.Ann Med. 1989; 21: 393-398Crossref PubMed Scopus (69) Google Scholar Recreational activities, such as walking and jogging, may influence incidence of sciatica. Regular walking was shown to almost double the incidence of sciatica in a group of 2077 workers who were pain free at baseline. This study also showed that jogging had a dual effect on the incidence of sciatica. Although joggers who were pain free at baseline had a decreased incidence of sciatica, those with a previous history of sciatica were more likely to experience more episodes.73Miranda H Viikari-Juntura E Martikainen R Takala EP Riihimaki H Individual factors, occupational loading and physical exercise as predictors of sciatica pain.Spine. 2002; 27: 1002-1009Crossref Scopus (127) Google Scholar Physical activity associated with occupation has also been shown to influence incidence of sciatica. Carpenters (OR 1.7) and machine operators (OR 1.6) were shown to be more likely to develop sciatica than sedentary office workers.88Riihimaki H Tola S Videman T Hanninen K Low back pain and occupation.Spine. 1989; 14: 204-209Crossref PubMed Scopus (135) Google Scholar 89Riihimaki H Viikari-Juntura E Moneta G Kuha J Videman T Tola S Incidence of sciatic pain among men in machine operating, dynamic physical work and sedentary work.Spine. 1994; 19: 138-142Crossref PubMed Scopus (131) Google Scholar Retired (OR 0.15) or part-time (OR 0.16) farmers were less likely to develop sciatica than full-time ones.68Manninen P Riihimaki H Heliovaara M Incidence and risk factors of low-back pain in middle aged farmers.Occup Med. 1995; 45: 141-146Crossref Scopus (95) Google Scholar Risk factors identified for sciatica associated with occupation included awkward working position, working in a flexed or twisted trunk position (OR 2.6),73Miranda H Viikari-Juntura E Martikainen R Takala EP Riihimaki H Individual factors, occupational loading and physical exercise as predictors of sciatica pain.Spine. 2002; 27: 1002-1009Crossref Scopus (127) Google Scholar or with the hand above the shoulder. Driving is also positively associated with sciatica or lumbar disc herniation.47Heliovaara M Body height, obesity and risk of herniated lumbar intervertebral disc.Spine. 1987; 12: 469-472Crossref PubMed Scopus (138) Google Scholar 60Kelsey JL Githens PB O'Connor T et al.Acute prolapsed lumbar intervertebral disc: an epidemiologic study with special reference to driving automobiles and cigarette smoking.Spine. 1984; 9: 608-613Crossref PubMed Scopus (223) Google Scholar It is possible that driving causes exposure to vibration at around 4–5 Hz which may coincide with resonant frequency of the spine in the seated position and so leading to a direct mechanical effect on the lumbar disc.35Frymoyer J Lumbar disc disease: epidemiology.Instr Course Lect. 1992; 41: 217-223PubMed Google Scholar Smoking has been linked with sciatica35Frymoyer J Lumbar disc disease: epidemiology.Instr Course Lect. 1992; 41: 217-223PubMed Google Scholar and several hypotheses, such as tobacco disturbing the metabolic balance of intervertebral discs, coughing causing marked elevations of intra-disc pressures, or a possible fibrinolytic effect of tobacco, have been proposed. An analysis of eight studies of smoking and sciatica revealed a positive correlation in only four of eight studies in men and one of five studies in women. Although there was a weak association between smoking and sciatica, these studies were cross-sectional and it was impossible to say that smoking preceded the sciatica.39Goldberg MS Scott SC Mayo NE A review of the association between cigarette smoking and the development of non specific back pain and related outcomes.Spine. 2000; 25: 995-1014Crossref PubMed Scopus (194) Google Scholar The intervertebral disc was implicated in the pathophysiology of sciatica,74Mixter WJ Barr JS Rupture of the intervertebral disc with involvement of the spinal canal.N Engl J Med. 1934; 211: 210-215Crossref Google Scholar and with the assumption that the protruding disc exerted pressure on sciatic nerve roots, the treatment was surgical removal of the disc. Any subsequent improvement in symptoms was attributed to relief of pressure on the nerve roots. Kelly, however, suggested that pressure on a nerve results in loss of function and is rarely associated with pain.59Kelly M Pain due to pressure on nerves. Spinal tumours and the intervertebral disc.Neurology. 1956; 6: 32-36Crossref PubMed Google Scholar There are several lines of evidence to support this. Disc pathology and stenosis with apparent neural compromise have been shown to be a relatively common finding in asymptomatic patients.11Boden SD Davis DO Dina TS Patronas NJ Wiesel SW Abnormal magnetic resonance scans of the lumbar spine in asymptomatic subjects: a prospective investigation.J Bone Joint Surg [Am]. 1990; 72: 403-408Crossref PubMed Scopus (1948) Google Scholar 14Boos N Semmer N Elfering E et al.Natural history of individuals with asymptomatic disc abnormalities in magnetic resonance imaging.Spine. 2000; 25: 1484-1492Crossref PubMed Scopus (184) Google Scholar 53Jensen MC Brant-Zawadzki MN Obuchowski N Modil MT Malkasian D Ross JS Magnetic resonance imaging of the lumbar spine in people without back pain.N Engl J Med. 1994; 331: 69-73Crossref PubMed Scopus (1852) Google Scholar Symptomatic patients with disc herniation may experience marked improvement in symptoms without any alteration of the original pathology,38Garfin SR Rydevik BL Brown RA Compressive neuropathy of spinal nerve roots.Spine. 1991; 16: 162-166PubMed Google Scholar whereas the removal of herniated disc material or other causes of nerve root compression does not always relieve pain. A positive correlation was noted between contact pressure and preoperative neurological impairment, suggesting that pressure led to loss of function rather than pain,104Takahashi K Shima I Porter RW Nerve root pressure in lumbar disc herniation.Spine. 1999; 24: 2003-2006Crossref PubMed Scopus (73) Google Scholar whereas chymopapain, a substance used for chemonucleolysis of herniated lumbar discs, may cause a rapid relief of leg pain that precedes any change in the size of the disc herniation or degree of nerve root impingement.57Kato F Mimatsu K Kawakami N Iwata H Miura T Serial changes observed by magnetic resonance imaging in the intervertebral disc after chemonucleolysis. A consideration of the mechanism of chemonucleolysis.Spine. 1992; 17: 934-939Crossref PubMed Scopus (29) Google Scholar These observations suggest that processes other than pressure on nerve roots are involved in the development of sciatic neuralgia. The evidence suggests that a complex interplay of inflammatory, immunological, and pressure-related processes may be involved. When Lindahl and Rexed67Lindahl O Rexed B Histological changes in spinal nerve roots of operated cases of sciatica.Acta Orthop Scand. 1951; 20: 215-225Crossref PubMed Scopus (86) Google Scholar found histological evidence of inflammation in posterior nerve roots examined during laminectomy, they postulated that inflammation rather than pressure was the source of nerve root pain. Support for this theory was provided when injection of autologous nucleus pulposus into canine epidural space provoked an intense inflammatory reaction involving the dura and nerve roots, with signs of epidural fibrosis present from as early as 2 weeks.70McCarron RF Wimpee MW Hudkins PG Laros GS The inflammatory effects of nucleus pulposus: a possible element in the pathogenesis of low back pain.Spine. 1987; 12: 760-764Crossref PubMed Scopus (518) Google Scholar High levels of phospholipase A2 (PLA2), an important enzyme in the inflammatory process, were demonstrated in herniated nuclear material of patients with radicular pain,92Saal JS Franson RC Dobrow R White AH Goldthwaite N High levels of inflammatory phospholipase A2 activity in lumbar disc herniations.Spine. 1990; 15: 674-678Crossref PubMed Scopus (526) Google Scholar whereas PLA2 isolated from human disc material was demonstrated to provoke an intense inflammatory reaction.34Franson RC Saal JS Saal JA Human disc phospholipase A2 is inflammatory.Spine. 1992; 17: 5129-5132Crossref Google Scholar PLA2 activity was noted to be higher in cases of sequestrated rather than bulging discs at the time of surgery, with a strong correlation between disc and plasma PLA2 levels.84Piperno M Hellio le Graverand MP Reboul P et al.Phospholipase A2 activity in herniated lumbar discs.Spine. 1997; 22: 2061-2065Crossref PubMed Scopus (53) Google Scholar Injection of PLA2 into rat epidural space caused motor weakness and altered sensation of the hind limbs, and sustained ectopic discharge of lumbar dorsal roots was provoked. Histological examination of nerve roots after 3 days revealed evidence of demyelination.26Chen C Cavanaugh JM Ozaktay C Kallakuri S King AI Effects of phospholipase A2 on lumbar nerve root structure and function.Spine. 1997; 22: 1057-1064Crossref PubMed Scopus (77) Google Scholar Chymopapain, used for chemonucleolysis of herniated intervertebral discs, has anti-inflammatory properties, reducing PLA2 activity around inflamed sciatic nerves.93Sawin PD Traynelis VC Rich G et al.Chymopapain-induced reduction of proinflammatory phospholipase A2 activity and amelioration of neuropathic behavioural changes in an in vivo model of acute sciatica.J Neurosurg. 1997; 86: 998-1006Crossref PubMed Scopus (13) Google Scholar This may explain why pain relief often precedes shrinkage of the herniated disc. Finally, PLA2 acting on cell membrane, releases arachadonic acid, a precursor of the inflammatory mediators leukotrienes, and thromboxanes (Fig. 1). Elevated levels of leukotriene B4 and thromboxane B2 have been demonstrated in human lumbar discs removed for relief of radicular pain.75Nygaard OP Mellgren SI Osterud B The inflammatory properties of contained and noncontained lumbar disc herniation.Spine. 1997; 22: 2484-2488Crossref PubMed Scopus (166) Google Scholar Further evidence for the inflammatory properties of nucleus pulposus was demonstrated by s.c. injection of autologous disc material in pigs. Titanium chambers containing autologous nucleus pulposus material attracted significantly more leucocytes than those containing fat or empty 'sham' chambers.76Olmarker K Blomquist J Stromberg J Hannmark U Thomsen P Rydevik B Inflammatogenic properties of nucleus pulposus.Spine. 1995; 20: 665-669Crossref PubMed Scopus (295) Google Scholar The injection of nucleus pulposus suspension also induced increased microvascular thrombosis and macromolecular leakage in hamster cheek pouch. Autologous nucleus pulposus applied to rat L5 nerve roots reduced blood flow to the dorsal root ganglion by up to 20%. This was a statistically significant reduction compared with controls. Endoneurial fluid pressure of the L5 nerve roots was also significantly raised compared with controls.115Yabuki S Kikuchi S Olmarker K Myers RR Acute effects of nucleus pulposus on blood flow and endoneurial fluid pressure in rat dorsal root ganglia.Spine. 1998; 23: 2517-2523Crossref PubMed Scopus (113) Google Scholar Cytokines have also been implicated in the genesis of this inflammatory response. Analysis of homogenates of 77 discs removed from patients with nerve root pain revealed the presence of the cytokines interleukin-1α (IL-1α), IL-1β, IL-6, and tumour necrosis factor-α (TNF-α).103Takahashi H Suguro T Okazima Y Motegi M Okada Y Kakiuchi T Inflammatory cytokines in the herniated disc of the lumbar spine.Spine. 1996; 21: 218-224Crossref PubMed Scopus (432) Google Scholar High levels of IL-6, IL-8, and prostaglandin E2 (PGE2) were found in discs removed from patients having surgery for sciatica and low back pain.21Burke JG Watson RWG McCormack D Dowling FE Walsh MG Fitzpatrick JM Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators.J Bone Joint Surg Br. 2002; 84-B: 196-201Crossref Scopus (559) Google Scholar Raised levels of IL-8 in preoperative samples of cerebrospinal fluid (CSF) and serum in patients undergoing discectomy, correlated with a more pronounced degree of disc herniation noted at surgery.17Brisby H Olmarker K Larsson K Nutu M Rydevic B Proinflammatory cytokines in cerebrospinal fluid and serum in patients with disc herniation and sciatica.Eur Spine J. 2002; 11: 62-66Crossref PubMed Scopus (136) Google Scholar Cytokines, particularly TNF, induce synthesis of nitric oxide (NO), a potent mediator of inflammation. Raised NO synthase activity was detected in rat nerve roots exposed to autologous nucleus pulposus, whereas aminoguanidine, an NO synthesase inhibitor, reduced the oedema and adverse effects on nerve conduction in pig nerve roots after exposure to nucleus pulposus.16Brisby H Byrod G Olmarker K Miller VM Aoki Y Rydevik B Nitric oxide as a mediator of nucleus pulposus-induced effects on spinal nerve roots.J Orthop Res. 2000; 18: 815-820Crossref PubMed Scopus (45) Google Scholar TNF-α appears to be the cytokine most strongly associated with the inflammatory properties of nucleus pulposus. This has been demonstrated to be present in pig nucleus pulposus, although the adverse effects of nucleus pulposus on nerve conduction were completely blocked by doxycycline, a compound that inhibits the effects of TNF-α.77Olmarker K Larsson K Tumor necrosis factor α and nucleus-pulposus-induced nerve root injury.Spine. 1998; 23: 2538-2544Crossref PubMed Scopus (297) Google Scholar The effects on porcine saccrococcygeal cauda equina were inhibited by the selective TNF-α inhibitors etanercept and infliximab. These drugs reduced effects on nerve conduction velocity, intracapillary thrombus formation, and intraneural oedema formation compared with enoxaparin and control.79Olmarker K Rydevik B Selective inhibition of tumor necrosis factor-α prevents nucleus pulposus-induced thrombus formation, intraneural oedema, and reduction of nerve conduction velocity.Spine. 2001; 26: 863-869Crossref PubMed Scopus (217) Google Scholar Monoclonal anti-TNF-α antibodies were shown to inhibit the enhanced activity that was seen in wide dynamic range neurons of the superficial dorsal horn when autologous nucleus pulposus was applied to the L5 nerve root.80Onda A Yabuki S Kikuchi S Effects of neutralizing antibodies to tumor necrosis factor-alpha on nucleus pulposus-induced abnormal nociresponses in rat dorsal horn neurons.Spine. 2003; 28: 967-972PubMed Google Scholar Finally, infusion of the monoclonal anti-TNF-α antibody infliximab in 10 patients with herniated disc-induced sciatica led to significant reductions in pain levels at 1 h, 2 weeks, and 3 months, compared with historical controls.55Karppinen J Korhonen T Malmivaara A et al.Tumor necrosis factor-α monoclonal antibody, infliximab, used to manage severe sciatica.Spine. 2003; 28: 750-754PubMed Google Scholar These studies all suggest that TNF-α plays an early and prominent role in the pathophysiological events that lead to nerve dysfunction and pain when nucleus pulposus is approximated to lumbar nerve roots. There is some evidence to suggest that the immune system also m