Friday, April 27, 2012

Treatments for Sciatica Pain Disappointing

Sciatica Sciatica is a term often used to describe any low back and leg pain, but it more specifically applies to lumbosacral radiculopathy due to the impingement of nerve roots as they emerge from the spinal canal. Up to half of all cases of spinal pain may be neuropathic in origin, meaning they are caused by nerve compression, inflammation, and/or injury. A pair of recent studies examined treatments for sciatica and found that very few are helpful and they confer only modest and temporarily relief.

The most commonly affected nerve roots in sciatica are at L4/L5 and L5/S1, so pain typically radiates below the knee, and leg pain may be more pronounced than accompanying low back pain. Intervertebral disk herniation is a typical cause, but others include spondylolisthesis (vertebral displacement) and foraminal stenosis. The lack of reliable treatments for sciatica has been problematic: analgesics may be modestly effective but accompanied by adverse effects, invasive surgery can be effective when disk herniation is present but long-term benefits are unproven, and epidural injections may be effective for only modest periods of time and are not without risks.

Epidural Injections Helpful, Somewhat

The first study, reported in the Annals of Internal Medicine, compared transforaminal epidural injections of saline (placebo control), steroids, and etanercept for the improvement of pain and function in adults with sciatica [Cohen et al. 2012]. Etanercept (Embrel®) is a biologic drug approved for subcutaneous injection in treating autoimmune diseases by interfering with tumor necrosis factor — TNF; a soluble inflammatory cytokine — by acting as a TNF inhibitor. The drug is approved in the United States for treating rheumatoid, juvenile rheumatoid, and psoriatic arthritis, plaque psoriasis, and ankylosing spondylitis.

This 3-group, randomized, placebo-controlled trial was conducted from 2008 to 2011 at 8 military and civilian centers. In total, 84 adults with lumbosacral radiculopathy of less than 6 months’ duration were randomized to receive 2 epidural injections of either steroid (60 mg methylprednisolone, n=28), etanercept (4 mg, n=26), or saline (2 mL, n=26); each injection separated by 2 weeks. The primary outcome measure was leg pain at 1 month after the second injection, as assessed on a 1-to-10 numeric rating scale (NRS). At the 1-month follow-up visit, those whose condition improved remained blinded for up to a 6–month followup period.

The group receiving epidural steroids had greater reductions in leg pain than those administered saline or etanercept; however, NRS pain reduction measures represented small effect sizes and were not statistically significant between groups. For back pain, as a secondary outcome measure, there were smaller improvements favoring steroids compared with saline and etanercept; again, between group NRS differences were not statistically significant.

The largest differences were noted for functional capacity, in which etanercept fared significantly worse than the other two treatments. However, on categorical outcome measures at 1 month, more patients treated with epidural steroids (75%) reported ≥50% leg pain relief and a positive global perceived effect than those who received saline (50%) or etanercept (42%). However, these success rates declined steadily at 3 month and 6 month followup assessments. By the end of the study, 17%, 21%, and 23% of patients in the saline, steroid, and etanercept groups, respectively, had proceeded to have surgery for their condition.

The authors concluded that epidural steroid injections may provide modest short-term pain relief for some adults with lumbosacral radiculopathy, as compared with saline injections. At the low doses used in this study, etanercept has no advantage over saline. Whether the limited long-term effects observed across all treatment groups was due to treatment effects or spontaneous improvement remains uncertain. Larger trials of longer duration are needed to establish benefits of epidural steroids for sciatica.

Pharmacologic Approaches Inadequate

The second study was a systematic review and meta-analysis to investigate the efficacy and tolerability of analgesic and adjuvant pain drugs typically prescribed in primary care setting for the management of sciatica [Pinto et al. 2012]. Writing in the British Medical Journal, a team of investigators reported a literature search from earliest records to March 2010 looking for randomized controlled trials assessing the efficacy and tolerability of drugs versus placebo or other pharmacotherapy for sciatica.

They identified 23 published reports meeting inclusion criteria and assessing the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antidepressants, anticonvulsants, muscle relaxants, and opioid analgesics. Study quality ranged from moderate to low, and most of the pooled estimates did not favor the active treatment over placebo. That is, none of the trials demonstrated robust and clearly significant beneficial effects of any pharmacotherapy, even when compared with placebo.

Two trials of corticosteroids and a single trial of the anticonvulsant gabapentin for chronic sciatica showed some benefits, but only in the short term. Similarly, 2 trials of the NSAID meloxicam and 1 trial of diclofenac demonstrated some immediate overall pain relief, but statistical significance was marginal. Overall, the median rate of adverse events was 17% for the active drugs and 11% for placebo.

The researchers concluded that there is “insufficient evidence to confidently guide the use of any analgesic or adjuvant pain medicine for the effective management of pain and disability in patients with sciatica.” At present, there is only low-quality evidence to judge the efficacy and tolerability of pharmacotherapy for sciatica pain and, until this changes, they advise practitioners treating patients exhibiting clinical features of neuropathic pain to consider evidence based guidelines for treating neuropathic pain. For other patients with sciatica, therapeutic recommendations from current guidelines for the management of non-specific low back pain might be consulted.

COMMENTARY: Many Research Limitations to Consider

InjectionThere were numerous limitations in the first study, examining epidural injections [Cohen et al. 2012], including small group sizes that barely met the number needed to achieve 80% power for demonstrating significant differences between groups, lack of a control group not receiving injections to assess the natural course of the disorder, and relying on retrospective patient recall of pain at followup visits. Also, having 84 subjects spread across 8 different research centers may have interjected variability into the protocol and data collection that diminished statistical precision.

The researchers seemed most disappointed that etanercept was not more effective, while conceding that this off-label use of the drug might have been at a subtherapeutic dose. In all, however, all 3 drugs demonstrated favorable effects in achieving ≥50% pain relief, at least short term, and the beneficial effect of steroids was quite pronounced. Of interest were benefits afforded by saline, which was expect to serve as a placebo control but performed more as an active therapy.

The researchers speculate that saline solution might have had a washout effect on inflammatory cytokines and other pain mediators, reduced inflammatory adhesions, and enhanced blood flow to ischemic nerve roots. Although, on the other hand, saline might have exerted a true placebo effect, or the results in this group could have been due to remission of sciatica in some patients as a natural course of the disease. An effect that was exaggerated by small group size.

The most troubling aspect of this study was that, although subjects had presumably failed more conservative therapies, most or all of them continued to take analgesic medications after the injections. The authors state that subjects received instructions about how to increase or decrease those drugs “based on their response to therapy,” plus they could be provided rescue analgesics as needed. There is no other discussion of this — eg, how many subjects were taking the medications, or the type, dose, or frequency — but this certainly could have confounded the data and skewed outcomes in more favorable directions.

Epidural injections have become a popular modality in pain management but are not without risks; particularly, transforaminal injections as used in this trial. As previously discussed in an UPDATE [here], a long list of potential complications has been noted, including dural puncture, nausea and vomiting, fever, nerve root injury, epidural hematoma, subdural hematoma, paresthesias, infection, paralysis, spinal cord injury, and others. There can be delayed reactions and complications after the procedure that often go unreported in research studies.

The second study, assessing pharmacotherapy for sciatica [Pinto et al. 2012], was disappointing on a number of levels. Most prominently was the poor state of the evidence base for analyses; both in terms of quantity and quality of studies. A limited range of agents has been studied and the vast majority of trials were underpowered to produce meaningful results either statistically or clinically. For each agent or combination of agents there were too few studies to conduct scrupulous meta-analyses and, in most studies, outcome measures were inadequate and/or there was a lack of adequate followup.

Still, conservative pharmacotherapy would be a starting place for most practitioners, and they are left with the dilemma of choosing what might work best. In an editorial accompanying the Pinto et al. article, Roger Chou — of the Oregon Health and Science University, Portland — suggests looking at evidence from trials of drugs for related conditions and making assumptions about generalizability of the results [Chou 2012].

For example, it might be expected that sciatica might respond to drugs demonstrating efficacy for other types of neuropathic pain. However, Chou concedes that for sciatica expressing features inconsistent with neuropathy there is no specific evidence to guide drug choices. So, ultimately, practitioners are left to rely on empirical prescribing based more on experience, trial-and-error, and hope than on guidance from strong evidence.

> Chou R. Treating sciatica in the face of poor evidence [editorial]. BMJ 2012(Feb);344:e487 [
> Cohen SP, White RL, Kurihara C, et al. Epidural Steroids, Etanercept, or Saline in Subacute Sciatica: A Multicenter, Randomized Trial. Ann Int Med. 2012(Apr);156(8):551-559 [
abstract here].
> Pinto RZ, Maher CG, Ferreira ML, et al. Drugs for relief of pain in patients with sciatica: systematic review and meta-analysis. BMJ. 2012(Feb);344:e497 [

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