ARTICLE IN BRIEF
A therapy already used to treat rheumatoid arthritis and several other autoimmune diseases was not found to be an effective alternative to epidural steroids for treating lumbosacral radiculopathy. But the steroids were effective on a short-term basis only.
Standard steroid injections are better for treating certain lower back and leg pain than injections with a newer anti-inflammatory drug, but even the steroid treatment offers only short-term relief for some patients, according to a study based out of Walter Reed Army Medical Center.
Researchers had hoped that etanercept (Enbrel), a genetically engineered anti-inflammatory drug that inhibits tumor necrosis factor, an inflammatory cytokine, might be an effective alternative to steroids for patients with acute or sub-acute lumbosacral radiculopathy.
The drug, already used to treat rheumatoid arthritis and several other autoimmune diseases, showed potential for treating lumbrosacral radiculopathy in animal testing, and some recent small studies done in the US and Japan showed favorable results, lead study author Steven P. Cohen, MD, associate professor of anesthesiology and critical care medicine at Johns Hopkins University, told Neurology Today. But that expectation did not hold up when the randomized trial compared epidural steroids to injections with etanercept or saline.
“The results of our study suggest short-term superiority but limited long-term benefits for epidural steroids compared with epidural saline,” Dr. Cohen and colleagues wrote. “At the low doses administered in this study, epidural etanercept seemed to provide no advantages over epidural saline.”
The dose of etanercept used in the study was low and probably sub-therapeutic, the researchers wrote in the April 17 Annals of Internal Medicine, and it's possible the drug could prove beneficial at higher doses.
This latest study was conducted at three US military medical centers, two pain centers that serve active and retired military personnel and their families, a military hospital in Germany and two civilian hospitals. The participants were between the ages of 18 and 70, with an average age of about 42.
To be included, subjects had to have been diagnosed with lumbosacral radiculopathy for more than four weeks but less than six months; have leg pain that was as severe or more severe than back pain; show evidence on MRI of a pathologic disc condition, such as herniated disc or annular tear, that correlated with symptoms. Patients with other unstable medical or psychiatric conditions and those who had previous spinal surgery or epidural injections were excluded.
The 84 participants were randomized to one of three epidural injections: 60 mg of methylprednisolone acetate plus 0.5 ml. of saline; 4 mg of etanercept reconstituted in 2 ml. of sterile water; or 2 ml. of normal saline. The treating physician and patient were unaware of the treatment given. The procedure was repeated two weeks later unless a patient declined further treatment either because of complete alleviation of pain or worsening of symptoms.
The first follow-up occurred one month after the second injection or month after the first injection in the 10 patients who received one dose. The primary outcome measure was a numeric rating scale score of 1 to 10 for leg pain at one month, reflecting the average pain experienced by the patient for one week before follow-up. Secondary outcome measures included the Oswestry Disability Index (ODI) version 2, a numeric rating scale of 0 to 10 for back pain during the proceeding week; reduction in analgesic medications; and global perceived effect (GPE), which involved asking patients if they felt better or worse.
In addition, researchers calculated a “positive categorical outcome,” defined as a reduction of 50 percent or more in leg pain with a positive GPE, negating the need for further treatment. Follow-up visits also took place at three and six months, and no added treatment was permitted during the study period.
At one month, leg and back pain had improved in all groups, with the largest reduction in leg pain in the steroid group, although the differences did not reach statistical significance. Based on the primary outcome measure — a score of 0 to 10 for leg pain at one month — pain scores in the steroid group decreased to 2.14 on average, compared with 3.63 for the etanercept group and 3.83 for the saline group. At the start of the study, participants had scored in the high to moderate range on the 0–10 leg pain scale, with the average score being 6.21.
ODI scores were improved in the saline and steroid groups, but not in the etanercept group. Seventy-five percent of the steroid group had a positive categorical outcome at one month, compared with 50 percent of the saline group and 42 percent of the etanercept group, but the advantage of steroids diminished over time. The majority of patients in all three groups needed less analgesic medicine at six months, with the steroid group faring the best.
The researchers offered various explanations. “We believe that the most probable explanation is that the analgesic effects of steroids are short-lived and that spontaneous improvement resulted in sustained beneficial effects in all treatment groups,” they wrote. They noted that “the natural course of a herniated disc is resorption and symptom resolution,” so many patients get better no matter what. The researchers said it's possible all treatments are over time fairly equal, but that the steroids do a better job up front.
Dr. Cohen said the disappointing performance of etanercept in this study did not mean the drug should be ruled out, but rather that further research is needed to address the dosing issue. The researchers also noted other limitations of the study: small sample size, relying on patient recall to record pain on follow-up visits, performing injections on a set rather than as-needed basis, and allowing patients to drop out of the study if they did not have a successful outcome after the first injection. They said larger studies with longer follow-ups are needed.
Charles Argoff, MD, professor of neurology at Albany Medical Center and director of its Comprehensive Pain Center, said the study's findings regarding the limited benefits of steroids for lumbosacral radiculopathy are consistent with the AAN guidelines issued by the Therapeutics and Technology Assessment Subcommittee and published in the March 6, 2007 issue of Neurology. The subcommittee offered a tempered recommendation for epidural steroids, noting that they “may result in some improvement in radicular lumbrosacral pain when assessed two and six weeks following the treatment.”
They noted that steroid injections, in general, do “not impact average impairment of function, need for surgery, or provide long-term pain relief beyond 3 months.”
Dr. Argoff, who helped write the guidelines, said better treatments are bound to come along as scientists gain more understanding of the mechanisms involved in pain, in particular the inflammatory response.
Gary Franklin, MD, MPH, a neurologist and medical director for the Washington State Department of Labor and Industries, added that for epidural injections, “the story is pretty thin and the data are pretty flimsy.” He noted that in a 2011 evidence-based report, a Washington State committee of 11 clinicians found the overall strength of evidence is low based on individual trial limitations and inconsistent results. The state does cover the use of epidural injections for radicular pain, he noted, if these and other conditions are met: conservative therapies have failed and there have been no more than two treatments without clinically meaningful improvement in pain and function.
Epidural steroid injections carry some risks, including the remote possibility of a spinal cord infarction, Dr. Franklin pointed out. Coming up with better treatments for low back pain could have a huge payoff as the estimated associated economic costs of addressing it in the US exceeds $100 billion annually, he said.