The recent publication in this journal of papers by Albert and colleagues [1, 2] from Denmark suggesting that low grade anaerobic bacterial infection may be the underlying cause of significant persistent chronic back pain in a well-defined group of patients has precipitated an unprecedented response in the medical and lay media. In the midst of claim and counterclaim, these studies represent a significant and substantial change in our understanding of the pathophysiology of back pain in some patient groups, and the importance of this should not be lost amidst the negative, unstructured and unscientific response to this study.
The facts
The story starts in 2001 with the publication of a research letter in the Lancet by a group from Birmingham [3] demonstrating that 31 % of patients with sciatica tested positive to a newly developed serological test, which diagnosed deep-seated infections caused by virulent Gram-positive microorganisms. In addition, intervertebral disc material excised during microdiscectomy in a different group of patients, which was cultured in a specialist anaerobic environment, had positive cultures after long-term incubation in 53 % of patients and of this group 84 % grew Propionibacterium acnes.
Following the ISSLS 2006 meeting, a collaboration developed between the Birmingham group and the group from Southern Denmark. This led to publication of a pilot study in 2008 [4] where 32 chronic low back pain patients with Modic type 1 endplate changes and a previous lumbar herniated disc were treated with amoxicillin and clavulanate for 90 days. In this uncontrolled trial, there was a clinically important and statistically significant difference in outcome at 10-month follow-up following antibiotic treatment.
In the meantime, the evidence was accumulating about the significant correlation between Modic endplate changes and back pain. Albert and Manniche [5] identified a strong association between Modic changes and non-specific low back pain, a stronger association with Modic type 1 than type 2, and that a lumbar disc herniation is a strong risk factor for developing Modic changes, especially type 1, during the following year and that these changes are strongly associated with low back pain.
A systematic review from Southern Denmark in 2008 [6] identified the prevalence of vertebral endplate signal changes as 43 % in patients with non-specific low back pain and/or sciatica, and 6 % in a non-clinical population, demonstrating that endplate changes are associated with pain. A further systematic review in the same year from Shanghai [7] identified two possible pathophysiological mechanisms for Modic changes—one biomechanical and one biochemical. A biomechanical pathway for development of Modic changes was supported by a large population MRI scan study in 2011 [8].
Against this background two key papers were then published in this journal in 2013. In one study [2] Albert and colleagues established a strong relationship between Modic changes type 1 adjacent to a previously herniated disc and positive microbiological culture in 46 % of patients undergoing discectomy procedures for disc herniation. Finally, the study which has triggered all of the controversy [1] was a double-blinded randomised control trial. Patients with persistent low back pain following a disc herniation in the previous year with Modic type 1 changes improve significantly following a 100-day course of antibiotic treatment.
The hype
The spinal community has significant previous experience of the outcome following lay media and commercial marketing of new treatments before these treatments are fully scientifically validated, and ultimately long-term results did not live up to the hype. Intravenous high dose corticosteroids were trumpeted in the press as a treatment for spinal cord injury shortly after the publication of the NASCIS II study [9], and this more than the scientific evidence rapidly led to corticosteroids being the standard of care for managing spinal cord injuries. The passage of time, analysis of benefits and a proper understanding of the risks led to a marked decline in the use of steroids and now recommendations are that these should not be used in spinal cord injury [10].
More recently, there has been significant controversy regarding the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) augmenting spinal fusion, leading to hostile interchanges between protagonists and antagonists both in the scientific literature [11–14] and in the lay media.
A recent Yale University open data access project led to the publication of two systematic reviews on patient level data from all clinical trials conducted by Medtronic [15, 16]. These demonstrate that there is no significant difference in pain or functional outcome for patients being treated with rhBMP-2.
Against this background, it seems that a mass media launch in the United Kingdom, Europe, and North America with the story rapidly being taken up around the world, offering a “cure” for back pain propagated from a private clinic in London, should be considered unwise (for examples see http://www.dailymail.co.uk/health/article-2321665/From-cripple-action-man-Briton-proves-end-lifetime-pain-antibiotics.html, http://www.telegraph.co.uk/health/healthnews/10042211/Antibiotics-could-cure-40pc-of-chronic-back-pain-patients.html, http://www.express.co.uk/news/health/397889/Miracle-cure-for-back-pain-Agony-ended-by-everyday-antibiotics, http://www.abc.net.au/pm/content/2013/s3754841.htm). One of the authors of the Southern Denmark papers has a commercial link with this organisation and addresses this conflict of interest elsewhere in this edition of the European Spine Journal.
It is hard to measure the negative impact on the substantial group of chronic low back pain patients worldwide from reading in their newspaper and seeing on the television news that a new cure for back pain is available. If they understood the real outcomes from the paper [1], they would understand that at 1-year follow-up 67.5 % of the treatment group still has back pain. The treatment effect reduces the VAS for back pain from 6.7 to 3.7. This is an impressive real treatment effect, but would not be considered “a cure” by any standard. How many patients’ pain decreased to 0–2?
This mass media launch has led to a very widespread and negative feedback in the lay and specialist medical media. Obviously, this is an unregulated, opinionated repository for often extreme opinions, but there must be significant reputational risk both to the scientists, the commercial organisation in London and to the spinal community in general from some of these widely read internet resources (see http://ferretfancier.blogspot.co.uk/2013/05/antibiotics-for-back-pain-conflicts-of.html, and http://theconversation.com/zit-bacteria-causing-back-pain-a-spotty-hypothesis-14060). In addition, there has been a cynical response from the respected medical press [17] although a subsequent article gave a slightly more tempered response [18].
Response
We believe that the surgical and scientific communities should have a tempered and objective response to these publications. There was clearly a very significant and important treatment effect in this very small subgroup of patients who receive antibiotics within 1 year from a symptomatic disc herniation who develop persistent continuous back pain. It seems unlikely, however, at this stage that the majority of patients with Modic type 1 changes in the lumbar spine have an underlying infection. The tempered response in the editorial [19] in this journal flags up the need for further research.
The study of Albert [1] needs to be replicated in a different clinical and scientific setting. It was arguably underpowered and a larger study is essential. Have we satisfied Koch’s postulates or the updated criteria of Fredricks and Relman [20] for demonstrating a link between infection and the disease process? The use of Roland and Morris rather than the Oswestry Disability Index precludes comparisons with the major spinal surgery outcome studies [21–24]. We need stronger evidence that bacterial infection producing discitis and endplate changes is the cause of chronic low back pain in a significant number of patients. Much more research is required before these results can be extrapolated to a general population of patients with chronic back pain and underlying Modic type 1 changes. On the basis of a significant but not complete resolution of back pain in the treatment group, alternative antibiotic regimens and protocols need to be explored and we need understanding of why there was no spontaneous change in clinical outcome measures in this study in the control group. It would also be interesting to see if the results could be replicated in back pain sufferers who have Modic type 1 changes, but have not had a documented disc prolapse. If we genuinely believe that there is low grade infection in Modic type 1 endplates and discs then it logically follows that we should perform biopsy and culture with subsequent treatment dictated by the results. What should our position be for patients who would normally be offered anterior lumbar interbody fusion (or similar) for discogenic back pain and Modic type 1 changes on MRI? Should conservative treatment now include 100 days of antibiotics?
At the moment, the only patients that should be considered for a course of antibiotics outside the environment of a clinical trial are those with
-
1.
Low back pain of more than 6 months duration and has not responded to exercise therapy.
-
2.
A symptomatic disc herniation within the previous year.
-
3.
Modic type 1 changes at the same level as the disc herniation.
A period of reflective and scientific analysis with further high quality research may well lead to a new treatment for a small subgroup of low back pain patients being established, but it would be very wrong at this stage to give hope to the wider group of patients with chronic disabling low back pain.
References
Albert HB, Sorensen JS, Christensen BS, Manniche C (2013) 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 22(4):697–707
Albert HB, Lambert P, Rollason J, Sorensen JS, Worthington T, Pedersen MB, Nørgaard HS, Vernallis A, Busch F, Manniche C, Elliott T (2013) Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebrae? Eur Spine J 22(4):690–696
Stirling A, Worthington T, Rafiq M, Lambert PA, Elliott TS (2001) Association between sciatica and Propionibacterium acnes. Lancet 23:357(9273):2024–2025
Albert HB, Manniche C, Sorensen JS, Deleuran BW (2008) Antibiotic treatment in patients with low-back pain associated with Modic changes Type 1 (bone oedema): a pilot study. Br J Sports Med 42(12):969–973
Albert HB, Manniche C (2007) Modic changes following lumbar disc herniation. Eur Spine J 16(7):977–982
Jensen TS, Karppinen J, Sorensen JS, Niinimäki J, Leboeuf-Yde C (2008) Vertebral endplate signal changes (Modic change): a systematic literature review of prevalence and association with non-specific low back pain. Eur Spine J 17(11):1407–1422
Zhang YH, Zhao CQ, Jiang LS, Chen XD, Dai LY (2008) Modic changes: a systematic review of the literature. Eur Spine J 17(10):1289–1299
Albert HB, Briggs AM, Kent P, Byrhagen A, Hansen C, Kjaergaard K (2011) The prevalence of MRI-defined spinal pathoanatomies and their association with Modic changes in individuals seeking care for low back pain. Eur Spine J 20(8):1355–1362
Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings M, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL Jr, Piepmeier J, Sonntag VK, Wagner F, Wilberger JE, Winn HR, Young W (1997) Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 28:277(20):1597–1604
Bydon M, Lin J, Macki M, Gokaslan ZL, Bydon A (2013) The current role of steroids in acute spinal cord injury. World Neurosurg. pii S1878–8750
Carragee EJ, Ghanayem AJ, Weiner BK, Rothman DJ, Bono CM (2011) A challenge to integrity in spine publications: years of living dangerously with the promotion of bone growth factors. Spine J 11(6):463–468
Carragee EJ, Hurwitz EL, Weiner BK (2011) A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J 11(6):471–491
Spengler DM (2011) Resetting standards for sponsored research: do conflicts influence results? Spine J 11(6):492–494
Carragee EJ, Baker RM, Benzel EC, Bigos SJ, Cheng I, Corbin TP, Deyo RA, Hurwitz EL, Jarvik JG, Kang JD, Lurie JD, Mroz TE, Oner FC, Peul WC, Rainville J, Ratliff JK, Rihn JA, Rothman DJ, Schoene ML, Spengler DM, Weiner BK (2012) A biologic without guidelines: the YODA project and the future of bone morphogenetic protein-2 research. Spine J (10):877–880
Simmonds MC, Brown JVE, Heirs MK, Higgins JPT, Mannion RJ, Rodgers MA, Stewart LA (2013) Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion. A meta-analysis of individual-participant data. Ann Intern Med 158(12):877–889
Fu R, Selph S, McDonagh M, Peterson K, Tiwari A, Chou R, Helfand M (2013) Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion. A systematic review and meta-analysis. Ann Intern Med 158(12):890–902
McCartney M (2013) Antibiotics for back pain: hope or hype? BMJ 14(346):f3122
Wise J (2013) Study proposes antibiotics as possible new treatment for some types of chronic low back pain. BMJ 9(346):f2988
Aebi M (2013) (2013) Is low back pain after disc herniation with Modic Type 1 changes a low-grade infection? Eur Spine J 22(4):689
Fredericks DN, Relman DA (1996) Sequence-based identification of microbial pathogens: a reconsideration of Koch’s postulates. Clin Microbiol Rev 9(1):18–33
Fritzell P, Hägg O, Wessberg P, Fredericks A, Swedish Lumbar Spine Study Group (2001) Volvo award winner in clinical studies: lumbar fusion versus nonsurgical treatment for chronic low back pain: a multicenter randomized controlled trial from the Swedish Lumbar Spine Study Group. Spine 26(23):2521–2532
Brox JI, Sørensen R, Friis A, Nygaard Ø, Indahl A, Keller A, Ingebrigtsen T, Eriksen HR, Holm I, Koller AK, Riise R, Reikerås O (2003) Randomized clinical trial of lumbar instrumented fusion and cognitive intervention and exercises in patients with chronic low back pain and disc degeneration. Spine 28(17):1913–1921
Fairbank J, Frost H, Wilson-MacDonald J, Yu LM, Barker K, Collins R (2005) Randomised controlled trial to compare surgical stabilisation of the lumbar spine with an intensive rehabilitation programme for patients with chronic low back pain: the MRC spine stabilisation trial. Spine Stabilisation Trial Group. BMJ 330(7502):1233
Brox JI, Reikerås O, Nygaard Ø, Sørensen R, Indahl A, Holm I, Keller A, Ingebrigtsen T, Grundnes O, Lange JE, Friis A (2006) Lumbar instrumented fusion compared with cognitive intervention and exercises in patients with chronic back pain after previous surgery for disc herniation: a prospective randomized controlled study. Pain 122(1–2):145–155
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
O’Dowd, J., Casey, A. Antibiotics a cure for back pain, a false dawn or a new era?. Eur Spine J 22, 1694–1697 (2013). https://doi.org/10.1007/s00586-013-2893-3
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00586-013-2893-3