Friday, May 10, 2013

Can Antibiotics Cure Chronic Back Pain?

Back PainConsiderable excitement was recently generated by newly-reported research finding that a significant percentage of patients with chronic lower-back pain could be helped by a 100-day course of antibiotic therapy. While this was hailed as a major medical breakthrough, potentially sparing millions of patients from suffering and major back surgery, some caution seems warranted until this approach is more adequately tested and validated.

Pain specialists have suspected that infections might be involved in certain back pain conditions, but these cases were thought to be exceptional. That thinking has been overturned by scientists at the University of Southern Denmark who found that a third of select chronic lower-back pain cases may be associated with bacterial infection. “This [discovery] will not help people with normal back pain, those with acute or sub-acute pain,” said Hanne Albert, who led the Danish research team, “only those with chronic lower back pain, but it returns those patients to a form of normality they had never expected.”

The research, funded by 6 Danish foundations and the Danish Rheumatism Association, took more than 10 years to complete. Results were finally reported in 2 separate papers that appeared in the April 2013 edition of the European Spine Journal.

Study 1: Bacterial Infection & Modic Changes

In the first study, Albert and colleagues investigated how bacterial infections in the nucleus material of slipped discs might cause painful inflammation and tiny fractures in the surrounding vertebrae [Albert, Lambert, et al. 2013]. More specifically, they assessed whether herniated nucleus material infected with anaerobic bacteria was also associated with painful Modic changes in adjacent vertebrae.

[Author’s note] Modic changes relate to degenerative processes primarily affecting the end plates of vertebrae. The classification system used to describe these was developed by Michael Modic in the late 1980s, and they are detected by signal changes in the vertebral end plates seen on Magnetic Resonance Imaging (MRI), but not on regular x-rays [Modic et al. 1988]. The first stage is referred to as Type 1, which reflects hypervascularity in the vertebrae, probably as a result of inflammation and edema. Type 2 consists of fatty replacements of the red bone marrow in the vertebrae. Type 3 Modic changes are characterized by sclerotic thickening of end plates.

Modic changes often appear to be associated with low-back pain and might constitute a pathoanatomical cause of the condition [Kjaer et al. 2006]. A systematic review by Jensen et al. [2008] showed a median prevalence of Modic changes in 43% of patients with nonspecific chronic low-back pain, in contrast to a median prevalence of 6% in general populations without such pain. However, the pathologic mechanisms underlying Modic changes themselve have not been completely understood.

It has been suggested that a possible cause of Modic changes is disc degeneration causing increased shear forces on the lumbar vertebral end plates leading to microfractures. Modic changes also might be initialized by end plate edema causing microfracture and exacerbation by an inflammatory response to proinflammatory chemicals seeping from the nucleus pulposus through the fracture fissures [Albert et al. 2008].

In this latest journal article, Albert, Lambert, et al. note that several prior studies on nuclear tissue from herniated discs have demonstrated the presence of low-virulence anaerobic microorganisms, predominantly Propionibacterium acnes, in 7% to 53% of patients. Normally the microbes cause little harm; but, at the time of a disc herniation, they may enter the nucleus and give rise to an insidious infection. Local inflammation and Modic changes in adjacent bone may be a secondary effect due to cytokine and propionic acid production.

For this study, Albert and colleagues enrolled 61 patients who were undergoing primary surgery at a single spinal level for lumbar disc herniation. Selected cases had annular fibers penetrated by visible nuclear tissue, and this nucleus material was removed under stringent sterile protocols for culturing.

Results indicated that microbiological cultures were positive in 28 patients (46%). Anaerobic cultures were positive in 26 patients (43%) and, of these, 4 (7%) had dual microbial infections, containing both 1 aerobic and 1 anaerobic culture. No specimens had more than 2 types of bacteria identified, and 2 cultures (3%) only had aerobic bacteria isolated.

In patients having discs with nucleus material infected by anaerobic bacteria, 80% developed Modic changes in vertebrae adjacent to the disc herniation. In contrast, none of those with aerobic bacteria and only 44% of patients with negative cultures developed new Modic changes. The association between an anaerobic infection and Modic changes was statistically significant (p=0.0038), with an odds ratio of 5.60 (95% CI, 1.51–21.95).

Albert, Lambert, et al. conclude that these findings support the theory that the occurrence of type 1 Modic changes in the vertebrae adjacent to a previously herniated disc may be due to edema surrounding an infected disc. Furthermore, discs infected with anaerobic bacteria were much more likely to foster painful Modic changes in adjacent vertebrae than those in which no bacteria or only aerobic bacteria were found.

Study 2: Antibiotic Treatment of Chronic Low-Back Pain

In their second study, Albert and colleagues tested the efficacy of antibiotic treatment in patients with chronic low-back pain [Albert, Sorensen, et al. 2013]. In a double-blind, randomized controlled trial (RCT) they enrolled 162 patients whose only known illness was chronic lower-back pain of greater than 6 months duration. In all cases the pain occurred after a previous disc herniation and subjects also had bone edema demonstrated via MRI as Modic type 1 changes in the vertebrae adjacent to the herniation. The actual presence of bacterial infection was not directly determined.

Study participants were blindly randomized to either 100 days of oral antibiotic treatment (amoxicillin-clavulanate/500 mg-125mg; n=90) or placebo (n=72), and were blindly evaluated at baseline, end of treatment, and at 1-year follow-up. The primary outcome measure was disease-specific disability, lumbar pain. Secondarily, leg pain, number of hours with pain during last 4 weeks, global perceived health, and other pain-related measures were assessed.

The 2 groups were similar at baseline and improvements in the antibiotic group were statistically significant on all outcome measures at the end of treatment and there were continuing improvements observed at the 1-year follow-up. For outcome measures where a clinically important effect size was defined, improvements in most antibiotic group patients exceeded the thresholds. For example, on a “general improvement” measure there was a large (Cohen’s d=1.06, calculated from study data) and statistically significant (p=0.0001) effect size at 1-year favoring antibiotic treatment.

The treatment was relatively safe, although 4 patients dropped out of the study primarily due to gastrointestinal adverse effects. Overall, the researchers conclude that, compared with placebo, the antibiotic protocol in this select subgroup of patients with chronic low-back pain was significantly more effective on all primary and secondary outcome measures. They suggested that this discovery may merit the establishment of a new disease category, called Modic-related low-back pain.

COMMENTARY:
These studies were novel and provocative; suggesting strong benefits of a noninvasive, uncomplicated, and cost-effective approach for helping many persons with chronic lower-back pain (CLBP) in whom other remedies have failed. In their report, the researchers were careful to note that this was only the first RCT studying antibiotic therapy for CLBP, that it would not work for all back pain, and that further confirmatory work in other populations with improved treatment protocols should be supported.

Unfortunately, mass media reporters, as they often do, got carried away. There were claims that 80% of patients with CLBP had reduced pain as a result of therapy and that “up to 40% of patients with chronic back pain could be cured with a course of antibiotics rather than surgery.” In one news article, an eminent spinal surgeon was noted as saying the discovery was the greatest he had witnessed in his professional life and that its impact on medicine was “worthy of a Nobel prize” [eg, The Guardian here and Bloomberg News here].

We could not find those 80% or 40% figures relating to pain-relief and “cure” mentioned anywhere in the published trial report. In fact, according to data in the first study (by Albert, Lambert, et al.) only about one-third of carefully selected patients with CLBP would even be good prospects for the antibiotic therapy protocol. That is, 43% of patients had anaerobic infection after disc herniation and 80% of those cases developed Modic type 1 changes in vertebral end plates (80% of 43% ≈ 34%).

And, in the clinical trial (second study), only a proportion of the qualifying patients with Modic changes benefitted from antibiotic therapy. At the 1-year followup about two-thirds (67.5%) of patients in the antibiotic group still had low-back pain (down from 100% at baseline). Furthermore, 19.5% of antibiotic-group patients still had persistent pain (down from 75.3% at baseline).

The lack of stronger results may point to difficulties in patient selection, since the presence of Modic changes alone is not necessarily a marker of infection that can be ameliorated by antibiotic therapy (as was found in the first study). Still, the present outcomes were substantial and far better than results in the placebo group; although, the numbers were nowhere near the 80% for reduced pain and 40% “cured” as stated in the news reports. There also is the nagging, unanswered question of whether favorable outcomes persist well beyond 1 year.

Another question unanswered in the clinical trial report involves possible effects of concurrent pain medication and medical care. Subjects were asked to avoid seeking any other treatment for CLBP during the 1-year followup, but they were allowed to take their usual anti-inflammatory and analgesic medications (treatment as usual) throughout the study. Randomized assignment to groups might have controlled for these factors, but the researchers make no mention of whether these potential confounders were examined or taken into account.

Although the clinical trial appeared to be adequately powered, well-designed, and properly executed, further replication and independent verification of outcomes seems essential. There always is a concern with new approaches to pain management — especially those that appear to be transformational — that they may turn out to be less effective in diverse clinical settings and populations than originally envisioned. Therefore, it is somewhat disturbing that Albert and a number of colleagues involved in the research have already founded an organization with the apparent intent of widely disseminating and commercializing their discoveries.

Called “MAST (Modic Antibiotics Spine Therapy) Medical,” the organization’s website — mastmedical.com — offers, for a fee, training and certification courses for healthcare providers (the MAST Medical Academy) and guidance for patients. They will even evaluate patients’ MRI scans (uploaded to the website, and for a fee of £75, $116 USD ) to determine if there are Modic changes present; as stated at the website…

“Do you have pain in your lower back which has not subsided with commonly used treatments such as exercises, spinal manipulation and injections? If this is the case, then it is possible that the cause of your back pain are Modic changes in the vertebrae of your spine. Unfortunately, Modic changes are not always described by radiologists due to the usually held belief that Modic changes do not cause pain. Recent scientific discoveries have proven this to be incorrect. To have a painful condition which is unrecognised and therefore untreated is a difficult situation to be in. We therefore offer this service of providing independent MRI information as part of the services offered on this website.”

With only a single RCT of the “MAST” protocol published to date, this venture seems rather aggressive and premature. Besides the much-needed replication and verification of trial results, it appears that there is still much to learn about patient diagnosis and selection for best outcomes, whether the approach is applicable in diverse patient populations and settings, if it will help for pain in other areas of the back and neck, how the antibiotic regimen can be maximized for safety and efficacy, the durability of benefits beyond 1 year, and other considerations.

REFERENCES:
> Albert HB, Kjaer P, Jensen TS, et al. Modic changes, possible causes and relation to low back pain. Med Hypoth. 2008;70(2):361-368.
> Albert HB, Lambert P, Rollason J, et al. Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebrae? Eur Spine J. 2013;22(4):690-696 [
abstract here].
> Albert HB, Sorensen JS, Christensen BS, Manniche C. Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized clinical controlled trial of efficacy. Eur Spine J. 2013;22(4):697-707 [
abstract here].
> Jensen TS, Karppinen J, Sorensen JS, et al. Vertebral endplate signal changes (Modic change): a systematic literature review of prevalence and association with non-specific low back pain. Eur Spine J. 2008;17(11):1407-1422.
> Kjaer P, Korsholm L, Bendix T, et al. Modic changes and their associations with clinical findings. Eur Spine J. 2006;15(9):1312-1319.
> Modic MT, Steinberg PM, Ross JS, et al. Degenerative Disk Disease: Assessment of Changes in Vertebral Body Marrow with MR Imaging. Radiology. 1988;166(1 Pt 1):193-199.

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