Antitumor Necrosis Factor-α Drugs and Disease-Modifying Antirheumatic Drugs for Low Back Pain




Abstract


Low back pain is a major source of pain and suffering. A body of knowledge has accumulated over the years which suggests that many of the syndromes causing low back pain are inflammatory in nature. Corticosteroids, either orally or more commonly by epidural route, have been administered for the treatment of low back pain syndromes for the past several decades. In the interim, a wide range of antiinflammatory drugs, which typically fall in the realm of disease modifying antirheumatic drugs, have been introduced. In this chapter we briefly explore this class of antiinflammatory drugs and discern their current use and possible future role in the treatment of various low back pain disorders. My overall conclusion is that the current use of the various antiinflammatory drugs for low back pain, except corticosteroids, was exceedingly narrow in scope and largely experimental in nature, hence, presenting opportunities for further research and study.




Keywords

inflammatory nature of low back pain, limited and experimental use of these drugs for the low back pain syndromes, wide variety of available antiinflammatory drugs

 




Introduction


Low back pain (LBP) is a major source of pain and suffering in industrialized nations. The collective cost of LBP, comprising both direct and incidental expenses, exceeds billions of dollars every year in the United States alone. 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 disease-modifying 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. These spinal lesions can cause pain either directly or indirectly by affecting the neural components housed within the spine. First described in 1934, compression of the contiguous nerve root by a herniated disc has traditionally been regarded as a prominent cause of LBP. However, substantial evidence (listed as follows) has accumulated recently that implicates local inflammation as a key factor in LBP.




  • A herniated nucleus pulposus is highly inflammatory in nature.



  • Intervertebral discs that cause pain (i.e., are positive for concordant pain on discography), produce high levels of inflammatory mediators.



  • 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.



  • In animal studies, TNF-α is known to cause nerve damage and neuropathic pain behavior, and its blockade at the nerve injury site reduces pain, local edema, and thrombus formation.



  • A significant number of patients with LBP have no demonstrable compressive lesion on imaging studies.



  • A number of LBP patients continue to have pain despite relief of the presumptive injurious lesion.



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. 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. 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. Consequently, an extensive search for safer antiinflammatory and disease-modifying drugs ensued, and a range of biological and nonbiological DMARDs were introduced. 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. The various cytokines typically act synergistically at extremely low concentrations; therefore blockade of one can interrupt the entire inflammatory cascade. 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. 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 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.




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. 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 ).



TABLE 64.1

Randomized Controlled Trials of Disease-Modifying Antirheumatic Drugs for Low Back Pain



























































Study Methodology Outcomes Limitations
Cohen et al. 2009 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. 2013 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. 2012 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. 2012 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. 2007 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. Short-term results. Small trial of 36 patients with six study groups.
Okoro et al. 2010 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. 2005 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. 2006 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. 2010 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. 2012 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.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Sep 21, 2019 | Posted by in PAIN MEDICINE | Comments Off on Antitumor Necrosis Factor-α Drugs and Disease-Modifying Antirheumatic Drugs for Low Back Pain

Full access? Get Clinical Tree

Get Clinical Tree app for offline access