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Antitumor Necrosis Factor-α Drugs and Disease-Modifying Antirheumatic Drugs for Low Back Pain
C H A P T E R
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Antitumor Necrosis Factor-α Drugs and Disease-Modifying Antirheumatic Drugs for Low Back Pain Khalid Malik, MD, FRCS
INTRODUCTION Low back pain (LBP) is a major source of pain and suffering in industrialized nations.1,2 The collective cost of LBP, comprising both direct and incidental expenses, exceeds billions of dollars every year in the United States alone.3 Despite the vast resources utilized, treatments for LBP continue to be suboptimal, and substantial dissatisfaction exists among both patients and treating physicians. A comprehensive assessment of novel and innovative treatments for LBP is therefore imperative. In recent years, a range of potent antiinflammatory drugs, including diseasemodifying antirheumatic drugs (DMARDs), have become available. In this chapter, a broader range of antiinflammatory drugs, outside of the more commonly utilized nonsteroidal antiinflammatory drugs (NSAIDs) and steroids, is explored.
ROLE OF INFLAMMATION IN LOW BACK PAIN Among the myriad causes of LBP, syndromes affecting the various spinal elements are the most prevalent. Most notable of these spinal pain syndromes are herniated and degenerated discs and stenosis and arthritic changes of the spine.4 These spinal lesions can cause pain either directly or indirectly by affecting the neural components housed within the spine.4,5 First described in 1934, compression of the contiguous nerve root by a herniated disc has traditionally been regarded as a prominent cause of LBP.6 However, substantial evidence (listed as follows) has accumulated recently that implicates local inflammation as a key factor in LBP.7,8 l A herniated nucleus pulposus is highly inflammatory in nature.9,10 l Intervertebral discs that cause pain (i.e., are positive for concordant pain on discography), produce high levels of inflammatory mediators.11,12 l Tumor necrosis factor-α (TNF-α), a major inflammatory cytokine, is found in high concentrations at the site of the nucleus pulposus-induced nerve injury.13,14 l In animal studies, TNF-α is known to cause nerve damage15 and neuropathic pain behavior,16 and its blockade at the nerve injury site reduces pain, local edema, and thrombus formation.17 l A significant number of patients with LBP have no demonstrable compressive lesion on imaging studies. l A number of LBP patients continue to have pain despite relief of the presumptive injurious lesion.18 Based on these observations, it can be concluded that chronic inflammation plays a key role in the etiology of LBP, and antiinflammatory drugs may have an important role in its treatment.
A BRIEF INTRODUCTION TO ANTIINFLAMMATORY DRUGS Plant extracts have been used for the treatment of fever and aches since ancient Egyptian and Roman times. The era of antiinflammatory drugs, however, began with the extraction of aspirin from willow bark in the early 19th century.19,20 The second wave of innovation for the treatment of inflammatory diseases came in the mid-20th century with the discovery of phenylbutazone, indomethacin, and ibuprofen—a group of drugs commonly referred to as NSAIDs.19,20 Although aspirin and NSAIDs successfully alleviated pain and fever, they were ineffective in preventing disease progression. Glucocorticoids, introduced in the 1950s, had disease-modifying characteristics and revolutionized the treatment of numerous chronic inflammatory conditions. However, long-term glucocorticoid therapy at high doses, often required to treat these chronic disabling conditions, can lead to major metabolic and nonmetabolic adverse effects.19–21 Consequently, an extensive search for safer antiinflammatory and disease-modifying drugs ensued, and a range of biological and nonbiological DMARDs were introduced.19–21 Biological DMARDs, often referred to as “biologics,” are a homogenous group of recombinant monoclonal peptides or fusion proteins. However, a large group of nonbiological DMARDs are diverse in structure and characteristics, and include drugs such as sulfasalazine, cyclosporine, levamisole, and methotrexate, among others. Normal inflammatory response is mediated by an array of cytokines, which are peptides released by a variety of cells in order to augment the function of other similar cells.20,21 The various cytokines typically act synergistically at extremely low concentrations; therefore blockade of one can interrupt the entire inflammatory cascade.20,21 Biological DMARDs are antibodies to several cytokines, specifically TNF-α, interleukin-1 (IL-1), and IL-6, and their antiinflammatory properties are due to the targeted inhibition of these key cytokines.20,21 Given that their targets are primarily extracellular, biological DMARDs have few metabolic consequences, and their primary side effect is increased susceptibility to infections. In comparison, nonbiological DMARDs have diverse mechanisms of action. They are frequently potent antimetabolites and suppress cellular replication and inflammatory response. Consequently, nonbiological DMARDs often cause serious immunosuppressive and metabolic adverse effects in a dose-dependent manner. DMARDs are being used increasingly for the treatment of a host of chronic inflammatory and autoimmune conditions such as rheumatoid arthritis, Crohn disease, inflammatory bowel disease, psoriasis, and ankylosing spondylitis. DMARD use in these conditions is 585
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characterized by a protocol-driven approach, and a typical DMARD regimen often consists of a combination of one or two biological drugs along with a nonbiological DMARD.22
ANTITUMOR NECROSIS FACTOR-α DRUGS AND DISEASE-MODIFYING ANTIRHEUMATIC DRUGS FOR LOW BACK PAIN The use of antiinflammatory drugs for LBP is not novel. Aspirin and NSAIDs are routinely given orally, parenterally, or applied topically for several LBP syndromes. Steroids, given orally or injected into the epidural space, have been a mainstay of treatment for LBP for the past several decades.23 However, despite a range of antiinflammatory drugs and DMARDs becoming available in recent years, their use for LBP has exclusively been investigational in nature and limited to only four drugs (Table 64.1). Of these, only two biological drugs (etanercept and infliximab) have been used with any regularity, and the use of two remaining drugs (adalimumab and tocilizumab) is limited only to one study group each (see Table 64.1).
ETANERCEPT There are six randomized controlled trials (RCTs) evaluating etanercept use for LBP,24–29 of which four involved epidural route of administration (see Table 64.1).24–27 Three such trials were in patients with lumbar radicular pain secondary to disc herniation.24–26 l A trial of 24 patients (four groups in 3:1 ratio) compared two epidural injections, given 2 weeks apart, of escalating etanercept doses (2, 4 or 6 mg) to placebo (normal saline). It reported efficacy of epidural etanercept at all three doses compared with placebo.24 This was a well-randomized and blinded trial; however, unblinding occurred at 4 weeks, and therefore only short-term results could be ascertained. l A trial of 49 patients received two epidural injections 2 weeks apart of either etanercept (0.5, 2.5, or 12.5 mg) or placebo.25 The results reported efficacy of etanercept relative to placebo for up to 6 months, but only in patients receiving the lowest etanercept dose (0.5 mg). Almost 40% of the randomized patients were excluded from the final analysis, and the results of this trial were therefore not robust. l The third trial compared epidural etanercept to similarly administered steroids and placebo.26 Eighty-four patients in three equal groups received two epidural injections 2 weeks apart of etanercept (4 mg), methylprednisolone (60 mg), or placebo (normal saline). One month posttreatment, the steroid group experienced better pain relief and functional improvement than the etanercept and saline groups (the results were similar for the etanercept and the saline groups), with no significant differences reported at 3 months. Even though this study was well conducted and followed patients out to 6 months, those that failed to derive benefit were unblinded after 1 month. Consequently, with these conflicting results, no valid conclusions can be drawn regarding the efficacy of epidural etanercept in
patients with lumbar radicular pain from a herniated disc. Only one trial involving epidural etanercept examined its efficacy in patients with radicular pain from spinal stenosis, comparing it with similarly administered steroids.27 Eighty patients in two equal groups received a single epidural injection of etanercept (10 mg) or dexamethasone (3.3 mg), and relative efficacy of etanercept was reported at 4 weeks. This trial was not blinded, was inadequately randomized, and based on its results, routine use of epidural etanercept in patients with radicular pain from spinal stenosis could not be recommended. Intradiscal etanercept was studied in a single trial of patients with LBP from suspected intervertebral disc pathology.28 Thirty-six patients in six groups received either escalating doses of etanercept (0.1, 0.25, 0.5, 0.75, 1.0, 1.5 mg) or placebo (sterile water). No difference was observed between the groups at 1 month, so this study did not provide evidence to substantiate the use of intradiscal etanercept for LBP. Subcutaneous etanercept administration has been studied in a single trial of 15 patients with lumbar radicular pain due to herniated disc.29 Either a single subcutaneous “perispinal” injection of etanercept (25 mg, n = 8) or placebo (saline, n = 7) was given. No difference in outcomes between the groups was reported at 3 months. The trial was inadequately randomized, not blinded, and only 15 patients were recruited over a 4-year period, with a dropout rate of nearly 20%. It therefore provides no evidence to substantiate the use of subcutaneous “perispinal” etanercept in patients with lumbar radicular pain from herniated disc. Overall, etanercept as used in the treatment of LBP is most frequently administered by epidural injection. The dose used has been substantially lower than the typical subcutaneously administered recommended dose for rheumatologic conditions of 25 mg twice-weekly injections. The doses administered in these LBP studies ranged from 0.1 to 25 mg, usually less than 5 mg, and often only one or a maximum of two injections were given. A typical justification for this substantially lower epidural etanercept dose is the lower dose of epidural opioids compared with their parenteral dosage,24,26 even though no relationship exists between opioids and biological DMARDs. When administered by the recommended subcutaneous route, etanercept was still usually given well below the recommended frequency, oftentimes only as a single injection.29
INFLIXIMAB Infliximab, normally given by intravenous infusion of 3–5 mg/kg, repeated at 2, 6, and 8 weeks, is the second most commonly used DMARD for LBP. It has been administered exclusively by the intravenous route in all studies examining its effect on LBP, and almost always via a single infusion. The controlled study of infliximab use for LBP is limited to one clinical trial involving a single group of patients with lumbar radicular pain from a herniated disc. The results of this study cohort are reported at 3 months and 1 year in two separate publications.30,31 Forty patients received a single intravenous infusion of infliximab (5 mg/kg given over 2 hours, n = 21) or placebo (saline, n = 19). No differences in outcomes were reported at 3 months30 or 1 year.31 The results of this trial therefore did not support the use of intravenous infliximab in patients with lumbar radicular pain from herniated disc.
CHAPTER 64 Antitumor Necrosis Factor-α Drugs and Disease-Modifying Antirheumatic Drugs for Low Back Pain
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TABLE 64.1 Randomized Controlled Trials of Disease-Modifying Antirheumatic Drugs for Low Back Pain
Study
Methodology
Outcomes
Limitations
24 patients with radicular pain from herniated disc in four groups received two epidural injections of either escalating doses (2, 4, or 6 mg) of etanercept or saline in 3:1 ratio
Significant improvement in all etanercept groups compared to saline injections at 1 and 6 months
Not blinded after 1 month. Small trial of 24 patients with four study groups.
Freeman et al. 201325
49 patients with radicular pain from herniated disc in four groups received two epidural injections of either etanercept (0.5, 2.5, or 12.5 mg) or placebo
Significant pain relief in only 0.5 mg etanercept group at 2 weeks to 6 months
Etanercept efficacious in only 1 group with lowest etanercept dose. Multiple small groups. High dropout rate of almost 40%.
Cohen et al. 201226
84 patients with radicular pain from herniated disc in three equal groups received two epidural injections of either 60 mg methylprednisolone, 4 mg etanercept, or saline
Pain and disability scores lower at 1 month in steroid group but results not statistically significant
Inconclusive results. Short-term follow-up.
Ohtori et al. 201227
80 patients with radicular pain from spinal stenosis in two equal groups received epidural injection of either 10 mg etanercept or 3.3 mg of dexamethasone
Significant improvement in pain and disability scores in etanercept group at 4 weeks
Nonblinded. Short follow-up.
Cohen et al. 200728
36 patients with back pain from disc pathology received intradiscal injection of escalating doses (0.1, 0.25, 0.5, 0.75, 1.0, or 1.5 mg) of etanercept or sterile water in 5:1 ratio
No difference in pain and disability between the groups at 1 month
Not blinded after 1 month. Shortterm results. Small trial of 36 patients with six study groups.
Okoro et al. 201029
15 patients with radicular pain from herniated disc received subcutaneous injection of either 25 mg etanercept (n = 8) or saline (n = 7) in perispinal area
No difference in pain and disability between the groups at 3 months
15 patients recruited over 4 years. High dropout rate of 20%. Poorly randomized. Nonblinded.
Korhonen et al. 200530
40 patients with radicular pain from herniated disc received one intravenous infusion, over 2 h, of either infliximab 5 mg/kg (n = 21) or saline (n = 19)
No significant difference between the groups at 3 months
Inadequate randomization and blinding. Small-sized trial.
Korhonen et al. 200631
40 patients with radicular pain from herniated disc received one intravenous infusion, over 2 h, of either infliximab 5 mg/kg (n = 21) or saline (n = 19)
No significant difference between the groups at 1 year
Inadequate randomization and blinding. Small-sized trial.
Genevay et al. 201032
61 patients with radicular pain from herniated disc received two subcutaneous injections 1 week apart of either adalimumab 40 mg (n = 31) or placebo (n = 30)
Lower pain scores in adalimumab group but only at 6 months
No difference in pain scores between the groups except at 6 months
Ohtori et al. 201233
60 patients with radicular pain from spinal stenosis in two equal groups received epidural injection of either 80 mg to cilizumab or 3.3 mg of dexamethasone
Significant improvement in pain and disability scores in tocilizumab group at 4 weeks
Inadequate randomization. Nonblinded. Short-term results at 4 weeks.
Cohen et al.
200924
ADALIMUMAB There is only one published controlled trial of adalimumab use for LBP. Sixty-one patients with lumbar radicular pain from herniated disc received two subcutaneous injections, 1 week apart, of either adalimumab (40 mg, n = 31) or placebo (saline, n = 30).32 The primary outcome (pain score in the leg) was similar in both groups at all time points, with the exception of the 6-month time point, at which point the pain scores were lower for patients in the adalimumab group. Although the trial was well conducted, it provided inconsistent evidence of the efficacy of subcutaneous adalimumab in this group of patients. Additionally, the recommended
dosing of adalimumab is 40–80 mg, given indeterminately by subcutaneous injection every 2 weeks, but the investigators in this study administered a course of only two 40-mg subcutaneous injections separated by 1 week.
TOCILIZUMAB Tocilizumab was also evaluated in only one trial involving patients with radicular pain from lumbar spinal stenosis.33 Sixty patients in two equal groups received either a single epidural injection of tocilizumab (80 mg in 2 cc of lidocaine) or dexamethasone (3.3 mg). The patients in the
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tocilizumab group had lower pain and disability scores for up to 4 weeks. This trial was not blinded and inadequately randomized. Based on this, despite the positive results, tocilizumab is not considered an approved treatment for patients with radicular pain from lumbar spinal stenosis. Overall, the current use of DMARDs for LBP can be summarized as follows34: l Use for investigational purposes only l Exceedingly narrow empiric selection of the drugs l Significant variation from the recommended drug doses, frequency, and routes of administration l Lack of any nonbiological DMARD use l Use of substantially lower cumulative drug dosages l Lack of any studies evaluating combination drug therapy
EPIDURAL DMARD ADMINISTRATION FOR LOW BACK PAIN The epidural route has been a frequent choice of DMARD administration for LBP. This selection naturally follows common practice of epidural steroid injections for LBP.23 However, notwithstanding steroids, only biological DMARDs were administered in the epidural space. It should also be noted that biological DMARDs are highly soluble and biodegradable drugs that do not have a depot formulation, which may limit their duration of action. It is unclear if administration of these exceedingly watersoluble drugs in the highly vascular epidural space has any added advantage over their intravenous administration. Frequent administration of biological DMARDs in the epidural space, as would be necessitated by their pharmacokinetic profile, is impractical. In contrast, steroids given in the epidural space are often in the form of sustained release formulations that prolong their local antiinflammatory activity, and the epidural dose is similar to their parenteral dose.23 In addition, steroids are potent antiinflammatory drugs that inhibit genetic expression of almost all proinflammatory cytokines. It is therefore unclear if epidural injection of biological DMARDs, especially in small doses or as a monotherapy, would be superior to epidural steroid injections.34 Epidural steroid injections are generally well tolerated, and the safety of this route of administration is well established.23 In one randomized study that compared epidurally administered steroids to etanercept and saline, steroids resulted in better outcomes on some measures than the etanercept and control groups.26 Despite the fact that no serious adverse effects of epidural injection of biological DMARDs have been reported, their potential for neurotoxicity, especially if given in larger doses, or more frequently and if nonbiological DMARDs are used, remains unknown.
SYSTEMIC DMARD USE FOR LOW BACK PAIN Similar to epidural DMARD use, systemic use of DMARDs for LBP has been characterized by: (1) isolated use of single biological drugs, (2) low cumulative doses, (3) absence of any nonbiological drug use, and (4) lack of combination DMARD therapy.34 Consequently, the lack of benefit reported in many of the studies evaluating systemic
DMARD use for LBP may have been due to inadequate treatment. Combinations of biological and nonbiological DMARDs, despite the significant risk of side effects, is regularly offered early in the course of many rheumatologic conditions in order to prevent the progressive deformities that often characterize the natural history of the disease.22 Patients undergoing combination DMARD therapy should be monitored for systemic infections, blood dyscrasias, and metabolic abnormalities. In contrast to the many progressively disabling rheumatologic disorders, chronic LBP is often self-limiting, with only a small percentage of patients progressing to a debilitated state.35 Therefore the routine use of potent combination DMARD therapy is likely unwarranted, and the prudent pain physician should only use this strategy in patients with disabling LBP unresponsive to traditional therapies. If used, systemic DMARD therapy should be modeled after well-established treatment protocols for other rheumatologic disorders, using recommended drug doses and a combination of both biological and nonbiological DMARDs.22
ADVERSE EFFECTS OF DMARD USE FOR LOW BACK PAIN As a result of their primarily extracellular site of action, biological DMARDs have minimal metabolic adverse side effects, and their major limitation is increased susceptibility to infection.21,22 Biological DMARDs are therefore contraindicated in patients with known infections and those who are otherwise immunocompromised, and their longterm use requires surveillance for chronic indolent infections such as tuberculosis. There are minimal to no adverse effects reported in the literature from the use of biological DMARDs for LBP patients. The likely explanation for this is the low cumulative drug doses, lack of concomitant or prior treatment with other DMARDs, and the fact that LBP patients otherwise possess normal immune function. It is possible that if combination DMARD therapy is used for LBP, the incidence of infections and other complications would rise, and monitoring for chronic infections may become necessary.
CONCLUSION The current use of DMARDs for LBP, excluding steroids, is exceedingly narrow in scope and nonadherent to standardized protocols. The evidence for the efficacy of the drugs used is either inconclusive or has demonstrated only short-term benefit. Consequently, until further evidence is available, the use of DMARDs for LBP remains largely experimental in nature.
KEY POINTS l
l
hronic inflammation plays a robust role in the etiolC ogy of many LBP syndromes. Despite the availability of a range of potent antiinflammatory drugs and DMARDs in the past few decades, the use of these drugs for LBP syndromes is limited predominantly to the administration of steroids and NSAIDs.
CHAPTER 64 Antitumor Necrosis Factor-α Drugs and Disease-Modifying Antirheumatic Drugs for Low Back Pain
l
l
l
he current use of nonsteroidal DMARDs for LBP is T exceedingly narrow in scope and nonadherent to standardized protocols. Current evidence for the efficacy of these drugs is either inconclusive or demonstrates only short-term benefit. Until further evidence is available, the use of DMARDs (except steroids) for LBP remains largely experimental in nature.
REFERENCES Access the reference list online at ExpertConsult.com.
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REFERENCES 1. Martin BI, Deyo RA, Mirza SK, et al: Expenditures and health status among adults with back and neck problems. JAMA 299:656–664, 2008. 2. Andersson GB: Epidemiological features of chronic low-back pain. Lancet 354:581–585, 1999. 3. Nachemson A: Newest knowledge of low back pain. Clin Orthop Rel Res 279:8–20, 1992. 4. Malik KM, Cohen SP, Walega DR, et al: Diagnostic criteria and treatment of discogenic pain: a systematic review of the recent clinical literature. Spine J 13:1675–1689, 2013. 5. Malik K, Joseph NJ: Intervertebral disc a source of pain? Low back pain: problems and future directions—case reports. Middle East J Anesthesiol 19:683–692, 2007. 6. Mixter WB, Barr JS: Rupture of the intervertebral disk with involvement of the spinal canal. N Engl J Med 211:210–215, 1934. 7. Marshall LL, Trethewie ER: Chemical irritation of nerve-root in disc prolapse. Lancet 2:320, 1973. 8. McCarron RF, Wimpee MW, Hudkins PG, et al: The inflammatory effect of nucleus pulposus: a possible element in the pathogenesis of low back pain. Spine 12:760–764, 1987. 9. Olmarker K, Blomquist J, Stromberg J, et al: Inflammatogenic properties of nucleus pulposus. Spine 20:665–669, 1995. 10. Olmarker K, Rydevik B, Nordborg C: Autologous nucleus pulposus induces neurophysiologic and histologic changes in porcine cauda equina nerve roots. Spine 18:1425–1432, 1993. 11. Burke JG, Watson RW, McCormack D, et al: Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators. J Bone Joint Surg Br 84:196–201, 2002. 12. Burke JG, Watson RW, McCormack D, et al: Spontaneous production of monocyte chemoattractant protein-1 and interleukin-8 by the human lumbar intervertebral disc. Spine 27:1402–1407, 2002. 13. Olmarker K, Larsson K: Tumor necrosis factor-alpha and nucleus-pulposus induced nerve root injury. Spine 23:2538–2544, 1998. 14. Igarashi T, Kikuchi S, Shubayev V, et al: Exogenous tumor necrosis factoralpha mimics nucleus pulposus induced neuropathology: molecular, histologic and behavioral comparisons in rats. Spine 25:2975–2980, 2000. 15. Aoki Y, Rydevik B, Kikuchi S, et al: Local application of disc-related cytokines on spinal nerve roots. Spine 27:1614–1617, 2002. 16. Wagner R, Myers RR: Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport 7:2897–2901, 1996. 17. Olmarker K, Rydevik B: Selective inhibition of tumor necrosis factor prevents nucleus pulposus induced thrombus formation, intraneural edema, and reduction of nerve conduction velocity: possible implications of future pharmacologic treatment strategies of sciatica. Spine 26:863–869, 2001. 18. Anderson VC, Israel Z: Failed back surgery syndrome. Curr Rev Pain 4:105–111, 2000. 19. Fleischmann R: Don’t forget traditional DMARDs. Rheumatology 50:429–430, 2011.
20. Dinarello CA: Anti-inflammatory agents: present and future. Cell 140:935–950, 2010. 21. Rainsford KD: Anti-inflammatory drugs in the 21st century. Subcell Biochem 42:3–27, 2007. 22. Singh JA, Furst DE, Bharat A, et al: 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biological agents in the treatment of rheumatoid arthritis. Arthritis Care Res 64:625–639, 2012. 23. Kozlov N, Benzon HT, Malik K: Epidural steroid injections: update on efficacy, safety, and newer medications for injection. Minerva Anestesiol 81:901–909, 2015. 24. Cohen SP, Bogduk N, Dragovich A, et al: Randomized, double-blind, placebocontrolled, dose response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology 110:1116–1126, 2009. 25. Freeman BJC, Ludbrook GL, Hall S, et al: Randomized, double-blind, placebo-controlled, trial of transforaminal epidural etanercept for the treatment of symptomatic lumbar disc herniation. Spine 38:1986–1994, 2013. 26. Cohen SP, White RL, Kurihara C, et al: Epidural steroids, etanercept, or saline in subacute sciatica: a multicenter, randomized trial. Ann Intern Med 156:551–559, 2012. 27. Ohtori S, Miyagi M, Eguchi Y, et al: Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for treatment of sciatica in patients with lumbar spinal stenosis. Spine 37:439–444, 2012. 28. Cohen SP, Wenzell D, Hurley RW, et al: A double-blind, placebo-controlled, dose–response pilot study evaluating intradiscal etanercept in patients with chronic discogenic low back pain or lumbosacral radiculopathy. Anesthesiology 107:99–105, 2007. 29. Okoro T, Tafazal SI, Longworth S, et al: Tumor necrosis α-blocking agent (etanercept): a triple blind randomized controlled trial of its use in treatment of sciatica. J Spinal Disord Tech 23:74–77, 2010. 30. Korhonen T, Karppinen J, Paimela L: The treatment of disc herniationinduced sciatica with infliximab: results of a randomized, controlled, 3-month follow-up study. Spine 30:2724–2728, 2005. 31. Korhonen T, Karppinen J, Paimela L, et al: The treatment of disc herniationinduced sciatica with infliximab: one-year follow-up results of FIRST II, a randomized controlled trial. Spine 31:2759–2766, 2006. 32. Genevay S, Viatte S, Finckh A, et al: Adalimumab in severe and acute sciatica: a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 62:2339–2346, 2010. 33. Ohtori S, Miyagi M, Eguchi Y, et al: Efficacy of epidural administration of anti-interleukin-6 receptor antibody onto spinal nerve for treatment of sciatica. Eur Spine J 21:2079–2084, 2012. 34. Malik K, Nelson A, Benzon HT: Disease modifying anti-rheumatic drugs for the treatment of low back pain: a systematic review of the literature. Pain Pract 16:629–641, 2016. 35. Benoist M: The natural history of the lumbar disc herniation and radiculopathy. Joint Bone Spine 69:155–160, 2002.
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Antitumor Necrosis Factor-α Drugs and Disease-Modifying Antirheumatic Drugs for Low Back Pain Khalid Malik, MD, FRCS
INTRODUCTION Low back pain (LBP) is a major source of pain and suffering in industrialized nations.1,2 The collective cost of LBP, comprising both direct and incidental expenses, exceeds billions of dollars every year in the United States alone.3 Despite the vast resources utilized, treatments for LBP continue to be suboptimal, and substantial dissatisfaction exists among both patients and treating physicians. A comprehensive assessment of novel and innovative treatments for LBP is therefore imperative. In recent years, a range of potent antiinflammatory drugs, including diseasemodifying antirheumatic drugs (DMARDs), have become available. In this chapter, a broader range of antiinflammatory drugs, outside of the more commonly utilized nonsteroidal antiinflammatory drugs (NSAIDs) and steroids, is explored.
ROLE OF INFLAMMATION IN LOW BACK PAIN Among the myriad causes of LBP, syndromes affecting the various spinal elements are the most prevalent. Most notable of these spinal pain syndromes are herniated and degenerated discs and stenosis and arthritic changes of the spine.4 These spinal lesions can cause pain either directly or indirectly by affecting the neural components housed within the spine.4,5 First described in 1934, compression of the contiguous nerve root by a herniated disc has traditionally been regarded as a prominent cause of LBP.6 However, substantial evidence (listed as follows) has accumulated recently that implicates local inflammation as a key factor in LBP.7,8 l A herniated nucleus pulposus is highly inflammatory in nature.9,10 l Intervertebral discs that cause pain (i.e., are positive for concordant pain on discography), produce high levels of inflammatory mediators.11,12 l Tumor necrosis factor-α (TNF-α), a major inflammatory cytokine, is found in high concentrations at the site of the nucleus pulposus-induced nerve injury.13,14 l In animal studies, TNF-α is known to cause nerve damage15 and neuropathic pain behavior,16 and its blockade at the nerve injury site reduces pain, local edema, and thrombus formation.17 l A significant number of patients with LBP have no demonstrable compressive lesion on imaging studies. l A number of LBP patients continue to have pain despite relief of the presumptive injurious lesion.18 Based on these observations, it can be concluded that chronic inflammation plays a key role in the etiology of LBP, and antiinflammatory drugs may have an important role in its treatment.
A BRIEF INTRODUCTION TO ANTIINFLAMMATORY DRUGS Plant extracts have been used for the treatment of fever and aches since ancient Egyptian and Roman times. The era of antiinflammatory drugs, however, began with the extraction of aspirin from willow bark in the early 19th century.19,20 The second wave of innovation for the treatment of inflammatory diseases came in the mid-20th century with the discovery of phenylbutazone, indomethacin, and ibuprofen—a group of drugs commonly referred to as NSAIDs.19,20 Although aspirin and NSAIDs successfully alleviated pain and fever, they were ineffective in preventing disease progression. Glucocorticoids, introduced in the 1950s, had disease-modifying characteristics and revolutionized the treatment of numerous chronic inflammatory conditions. However, long-term glucocorticoid therapy at high doses, often required to treat these chronic disabling conditions, can lead to major metabolic and nonmetabolic adverse effects.19–21 Consequently, an extensive search for safer antiinflammatory and disease-modifying drugs ensued, and a range of biological and nonbiological DMARDs were introduced.19–21 Biological DMARDs, often referred to as “biologics,” are a homogenous group of recombinant monoclonal peptides or fusion proteins. However, a large group of nonbiological DMARDs are diverse in structure and characteristics, and include drugs such as sulfasalazine, cyclosporine, levamisole, and methotrexate, among others. Normal inflammatory response is mediated by an array of cytokines, which are peptides released by a variety of cells in order to augment the function of other similar cells.20,21 The various cytokines typically act synergistically at extremely low concentrations; therefore blockade of one can interrupt the entire inflammatory cascade.20,21 Biological DMARDs are antibodies to several cytokines, specifically TNF-α, interleukin-1 (IL-1), and IL-6, and their antiinflammatory properties are due to the targeted inhibition of these key cytokines.20,21 Given that their targets are primarily extracellular, biological DMARDs have few metabolic consequences, and their primary side effect is increased susceptibility to infections. In comparison, nonbiological DMARDs have diverse mechanisms of action. They are frequently potent antimetabolites and suppress cellular replication and inflammatory response. Consequently, nonbiological DMARDs often cause serious immunosuppressive and metabolic adverse effects in a dose-dependent manner. DMARDs are being used increasingly for the treatment of a host of chronic inflammatory and autoimmune conditions such as rheumatoid arthritis, Crohn disease, inflammatory bowel disease, psoriasis, and ankylosing spondylitis. DMARD use in these conditions is 585
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characterized by a protocol-driven approach, and a typical DMARD regimen often consists of a combination of one or two biological drugs along with a nonbiological DMARD.22
ANTITUMOR NECROSIS FACTOR-α DRUGS AND DISEASE-MODIFYING ANTIRHEUMATIC DRUGS FOR LOW BACK PAIN The use of antiinflammatory drugs for LBP is not novel. Aspirin and NSAIDs are routinely given orally, parenterally, or applied topically for several LBP syndromes. Steroids, given orally or injected into the epidural space, have been a mainstay of treatment for LBP for the past several decades.23 However, despite a range of antiinflammatory drugs and DMARDs becoming available in recent years, their use for LBP has exclusively been investigational in nature and limited to only four drugs (Table 64.1). Of these, only two biological drugs (etanercept and infliximab) have been used with any regularity, and the use of two remaining drugs (adalimumab and tocilizumab) is limited only to one study group each (see Table 64.1).
ETANERCEPT There are six randomized controlled trials (RCTs) evaluating etanercept use for LBP,24–29 of which four involved epidural route of administration (see Table 64.1).24–27 Three such trials were in patients with lumbar radicular pain secondary to disc herniation.24–26 l A trial of 24 patients (four groups in 3:1 ratio) compared two epidural injections, given 2 weeks apart, of escalating etanercept doses (2, 4 or 6 mg) to placebo (normal saline). It reported efficacy of epidural etanercept at all three doses compared with placebo.24 This was a well-randomized and blinded trial; however, unblinding occurred at 4 weeks, and therefore only short-term results could be ascertained. l A trial of 49 patients received two epidural injections 2 weeks apart of either etanercept (0.5, 2.5, or 12.5 mg) or placebo.25 The results reported efficacy of etanercept relative to placebo for up to 6 months, but only in patients receiving the lowest etanercept dose (0.5 mg). Almost 40% of the randomized patients were excluded from the final analysis, and the results of this trial were therefore not robust. l The third trial compared epidural etanercept to similarly administered steroids and placebo.26 Eighty-four patients in three equal groups received two epidural injections 2 weeks apart of etanercept (4 mg), methylprednisolone (60 mg), or placebo (normal saline). One month posttreatment, the steroid group experienced better pain relief and functional improvement than the etanercept and saline groups (the results were similar for the etanercept and the saline groups), with no significant differences reported at 3 months. Even though this study was well conducted and followed patients out to 6 months, those that failed to derive benefit were unblinded after 1 month. Consequently, with these conflicting results, no valid conclusions can be drawn regarding the efficacy of epidural etanercept in
patients with lumbar radicular pain from a herniated disc. Only one trial involving epidural etanercept examined its efficacy in patients with radicular pain from spinal stenosis, comparing it with similarly administered steroids.27 Eighty patients in two equal groups received a single epidural injection of etanercept (10 mg) or dexamethasone (3.3 mg), and relative efficacy of etanercept was reported at 4 weeks. This trial was not blinded, was inadequately randomized, and based on its results, routine use of epidural etanercept in patients with radicular pain from spinal stenosis could not be recommended. Intradiscal etanercept was studied in a single trial of patients with LBP from suspected intervertebral disc pathology.28 Thirty-six patients in six groups received either escalating doses of etanercept (0.1, 0.25, 0.5, 0.75, 1.0, 1.5 mg) or placebo (sterile water). No difference was observed between the groups at 1 month, so this study did not provide evidence to substantiate the use of intradiscal etanercept for LBP. Subcutaneous etanercept administration has been studied in a single trial of 15 patients with lumbar radicular pain due to herniated disc.29 Either a single subcutaneous “perispinal” injection of etanercept (25 mg, n = 8) or placebo (saline, n = 7) was given. No difference in outcomes between the groups was reported at 3 months. The trial was inadequately randomized, not blinded, and only 15 patients were recruited over a 4-year period, with a dropout rate of nearly 20%. It therefore provides no evidence to substantiate the use of subcutaneous “perispinal” etanercept in patients with lumbar radicular pain from herniated disc. Overall, etanercept as used in the treatment of LBP is most frequently administered by epidural injection. The dose used has been substantially lower than the typical subcutaneously administered recommended dose for rheumatologic conditions of 25 mg twice-weekly injections. The doses administered in these LBP studies ranged from 0.1 to 25 mg, usually less than 5 mg, and often only one or a maximum of two injections were given. A typical justification for this substantially lower epidural etanercept dose is the lower dose of epidural opioids compared with their parenteral dosage,24,26 even though no relationship exists between opioids and biological DMARDs. When administered by the recommended subcutaneous route, etanercept was still usually given well below the recommended frequency, oftentimes only as a single injection.29
INFLIXIMAB Infliximab, normally given by intravenous infusion of 3–5 mg/kg, repeated at 2, 6, and 8 weeks, is the second most commonly used DMARD for LBP. It has been administered exclusively by the intravenous route in all studies examining its effect on LBP, and almost always via a single infusion. The controlled study of infliximab use for LBP is limited to one clinical trial involving a single group of patients with lumbar radicular pain from a herniated disc. The results of this study cohort are reported at 3 months and 1 year in two separate publications.30,31 Forty patients received a single intravenous infusion of infliximab (5 mg/kg given over 2 hours, n = 21) or placebo (saline, n = 19). No differences in outcomes were reported at 3 months30 or 1 year.31 The results of this trial therefore did not support the use of intravenous infliximab in patients with lumbar radicular pain from herniated disc.
CHAPTER 64 Antitumor Necrosis Factor-α Drugs and Disease-Modifying Antirheumatic Drugs for Low Back Pain
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TABLE 64.1 Randomized Controlled Trials of Disease-Modifying Antirheumatic Drugs for Low Back Pain
Study
Methodology
Outcomes
Limitations
24 patients with radicular pain from herniated disc in four groups received two epidural injections of either escalating doses (2, 4, or 6 mg) of etanercept or saline in 3:1 ratio
Significant improvement in all etanercept groups compared to saline injections at 1 and 6 months
Not blinded after 1 month. Small trial of 24 patients with four study groups.
Freeman et al. 201325
49 patients with radicular pain from herniated disc in four groups received two epidural injections of either etanercept (0.5, 2.5, or 12.5 mg) or placebo
Significant pain relief in only 0.5 mg etanercept group at 2 weeks to 6 months
Etanercept efficacious in only 1 group with lowest etanercept dose. Multiple small groups. High dropout rate of almost 40%.
Cohen et al. 201226
84 patients with radicular pain from herniated disc in three equal groups received two epidural injections of either 60 mg methylprednisolone, 4 mg etanercept, or saline
Pain and disability scores lower at 1 month in steroid group but results not statistically significant
Inconclusive results. Short-term follow-up.
Ohtori et al. 201227
80 patients with radicular pain from spinal stenosis in two equal groups received epidural injection of either 10 mg etanercept or 3.3 mg of dexamethasone
Significant improvement in pain and disability scores in etanercept group at 4 weeks
Nonblinded. Short follow-up.
Cohen et al. 200728
36 patients with back pain from disc pathology received intradiscal injection of escalating doses (0.1, 0.25, 0.5, 0.75, 1.0, or 1.5 mg) of etanercept or sterile water in 5:1 ratio
No difference in pain and disability between the groups at 1 month
Not blinded after 1 month. Shortterm results. Small trial of 36 patients with six study groups.
Okoro et al. 201029
15 patients with radicular pain from herniated disc received subcutaneous injection of either 25 mg etanercept (n = 8) or saline (n = 7) in perispinal area
No difference in pain and disability between the groups at 3 months
15 patients recruited over 4 years. High dropout rate of 20%. Poorly randomized. Nonblinded.
Korhonen et al. 200530
40 patients with radicular pain from herniated disc received one intravenous infusion, over 2 h, of either infliximab 5 mg/kg (n = 21) or saline (n = 19)
No significant difference between the groups at 3 months
Inadequate randomization and blinding. Small-sized trial.
Korhonen et al. 200631
40 patients with radicular pain from herniated disc received one intravenous infusion, over 2 h, of either infliximab 5 mg/kg (n = 21) or saline (n = 19)
No significant difference between the groups at 1 year
Inadequate randomization and blinding. Small-sized trial.
Genevay et al. 201032
61 patients with radicular pain from herniated disc received two subcutaneous injections 1 week apart of either adalimumab 40 mg (n = 31) or placebo (n = 30)
Lower pain scores in adalimumab group but only at 6 months
No difference in pain scores between the groups except at 6 months
Ohtori et al. 201233
60 patients with radicular pain from spinal stenosis in two equal groups received epidural injection of either 80 mg to cilizumab or 3.3 mg of dexamethasone
Significant improvement in pain and disability scores in tocilizumab group at 4 weeks
Inadequate randomization. Nonblinded. Short-term results at 4 weeks.
Cohen et al.
200924
ADALIMUMAB There is only one published controlled trial of adalimumab use for LBP. Sixty-one patients with lumbar radicular pain from herniated disc received two subcutaneous injections, 1 week apart, of either adalimumab (40 mg, n = 31) or placebo (saline, n = 30).32 The primary outcome (pain score in the leg) was similar in both groups at all time points, with the exception of the 6-month time point, at which point the pain scores were lower for patients in the adalimumab group. Although the trial was well conducted, it provided inconsistent evidence of the efficacy of subcutaneous adalimumab in this group of patients. Additionally, the recommended
dosing of adalimumab is 40–80 mg, given indeterminately by subcutaneous injection every 2 weeks, but the investigators in this study administered a course of only two 40-mg subcutaneous injections separated by 1 week.
TOCILIZUMAB Tocilizumab was also evaluated in only one trial involving patients with radicular pain from lumbar spinal stenosis.33 Sixty patients in two equal groups received either a single epidural injection of tocilizumab (80 mg in 2 cc of lidocaine) or dexamethasone (3.3 mg). The patients in the
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SECTION VIII Interventional Techniques for Pain Management
tocilizumab group had lower pain and disability scores for up to 4 weeks. This trial was not blinded and inadequately randomized. Based on this, despite the positive results, tocilizumab is not considered an approved treatment for patients with radicular pain from lumbar spinal stenosis. Overall, the current use of DMARDs for LBP can be summarized as follows34: l Use for investigational purposes only l Exceedingly narrow empiric selection of the drugs l Significant variation from the recommended drug doses, frequency, and routes of administration l Lack of any nonbiological DMARD use l Use of substantially lower cumulative drug dosages l Lack of any studies evaluating combination drug therapy
EPIDURAL DMARD ADMINISTRATION FOR LOW BACK PAIN The epidural route has been a frequent choice of DMARD administration for LBP. This selection naturally follows common practice of epidural steroid injections for LBP.23 However, notwithstanding steroids, only biological DMARDs were administered in the epidural space. It should also be noted that biological DMARDs are highly soluble and biodegradable drugs that do not have a depot formulation, which may limit their duration of action. It is unclear if administration of these exceedingly watersoluble drugs in the highly vascular epidural space has any added advantage over their intravenous administration. Frequent administration of biological DMARDs in the epidural space, as would be necessitated by their pharmacokinetic profile, is impractical. In contrast, steroids given in the epidural space are often in the form of sustained release formulations that prolong their local antiinflammatory activity, and the epidural dose is similar to their parenteral dose.23 In addition, steroids are potent antiinflammatory drugs that inhibit genetic expression of almost all proinflammatory cytokines. It is therefore unclear if epidural injection of biological DMARDs, especially in small doses or as a monotherapy, would be superior to epidural steroid injections.34 Epidural steroid injections are generally well tolerated, and the safety of this route of administration is well established.23 In one randomized study that compared epidurally administered steroids to etanercept and saline, steroids resulted in better outcomes on some measures than the etanercept and control groups.26 Despite the fact that no serious adverse effects of epidural injection of biological DMARDs have been reported, their potential for neurotoxicity, especially if given in larger doses, or more frequently and if nonbiological DMARDs are used, remains unknown.
SYSTEMIC DMARD USE FOR LOW BACK PAIN Similar to epidural DMARD use, systemic use of DMARDs for LBP has been characterized by: (1) isolated use of single biological drugs, (2) low cumulative doses, (3) absence of any nonbiological drug use, and (4) lack of combination DMARD therapy.34 Consequently, the lack of benefit reported in many of the studies evaluating systemic
DMARD use for LBP may have been due to inadequate treatment. Combinations of biological and nonbiological DMARDs, despite the significant risk of side effects, is regularly offered early in the course of many rheumatologic conditions in order to prevent the progressive deformities that often characterize the natural history of the disease.22 Patients undergoing combination DMARD therapy should be monitored for systemic infections, blood dyscrasias, and metabolic abnormalities. In contrast to the many progressively disabling rheumatologic disorders, chronic LBP is often self-limiting, with only a small percentage of patients progressing to a debilitated state.35 Therefore the routine use of potent combination DMARD therapy is likely unwarranted, and the prudent pain physician should only use this strategy in patients with disabling LBP unresponsive to traditional therapies. If used, systemic DMARD therapy should be modeled after well-established treatment protocols for other rheumatologic disorders, using recommended drug doses and a combination of both biological and nonbiological DMARDs.22
ADVERSE EFFECTS OF DMARD USE FOR LOW BACK PAIN As a result of their primarily extracellular site of action, biological DMARDs have minimal metabolic adverse side effects, and their major limitation is increased susceptibility to infection.21,22 Biological DMARDs are therefore contraindicated in patients with known infections and those who are otherwise immunocompromised, and their longterm use requires surveillance for chronic indolent infections such as tuberculosis. There are minimal to no adverse effects reported in the literature from the use of biological DMARDs for LBP patients. The likely explanation for this is the low cumulative drug doses, lack of concomitant or prior treatment with other DMARDs, and the fact that LBP patients otherwise possess normal immune function. It is possible that if combination DMARD therapy is used for LBP, the incidence of infections and other complications would rise, and monitoring for chronic infections may become necessary.
CONCLUSION The current use of DMARDs for LBP, excluding steroids, is exceedingly narrow in scope and nonadherent to standardized protocols. The evidence for the efficacy of the drugs used is either inconclusive or has demonstrated only short-term benefit. Consequently, until further evidence is available, the use of DMARDs for LBP remains largely experimental in nature.
KEY POINTS l
l
hronic inflammation plays a robust role in the etiolC ogy of many LBP syndromes. Despite the availability of a range of potent antiinflammatory drugs and DMARDs in the past few decades, the use of these drugs for LBP syndromes is limited predominantly to the administration of steroids and NSAIDs.
CHAPTER 64 Antitumor Necrosis Factor-α Drugs and Disease-Modifying Antirheumatic Drugs for Low Back Pain
l
l
l
he current use of nonsteroidal DMARDs for LBP is T exceedingly narrow in scope and nonadherent to standardized protocols. Current evidence for the efficacy of these drugs is either inconclusive or demonstrates only short-term benefit. Until further evidence is available, the use of DMARDs (except steroids) for LBP remains largely experimental in nature.
REFERENCES Access the reference list online at ExpertConsult.com.
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