Clinical effect modifiers of antibiotic treatment in patients with chronic low back pain and Modic changes - secondary analyses of a randomised, placebo-controlled trial (the AIM study)

Lars Christian Haugli Bråten, Lars Grøvle, Ansgar Espeland, Are Hugo Pripp, Margreth Grotle, Christian Helllum, Anne Julsrud Haugen, Anne Froholdt, Mads Peder Rolfsen, Øystein Petter Nygaard, Olav Lutro, Per Martin Kristoffersen, Audny Anke, Elina Iordanova Schistad, Jan Sture Skouen, Jens Ivar Brox, John-Anker Zwart, Kjersti Storheim, AIM-study group, Maja Wilhelmsen, Terese Fors, Guro Kjos, Ida Beate Østhus, Gunn Hege Marchand, Britt Elin Lurud, Fredrik Granvigen, Hege Andersen, Vidar Rao, Thomas Istvan Kadar, Siv Krüger Claussen, Erling Andersen, Nils Vetti, Jörg Aßmus, Sigrun Randen, Hilde Presberg, Monica Wigemyr, Linda Margareth Pedersen, Bendik Slagsvold Winsvold, Karianne Wiger Gammelsrud, Maria Dehli Vigeland, Benedicte Alexandra Lie, Siri Tennebø Flåm, Magnus Dehli Vigeland, Marianne Thorsø, Knut Morten Huneide, Veronica Sørensen, Thor Einar Holmgard, Lars Christian Haugli Bråten, Lars Grøvle, Ansgar Espeland, Are Hugo Pripp, Margreth Grotle, Christian Helllum, Anne Julsrud Haugen, Anne Froholdt, Mads Peder Rolfsen, Øystein Petter Nygaard, Olav Lutro, Per Martin Kristoffersen, Audny Anke, Elina Iordanova Schistad, Jan Sture Skouen, Jens Ivar Brox, John-Anker Zwart, Kjersti Storheim, AIM-study group, Maja Wilhelmsen, Terese Fors, Guro Kjos, Ida Beate Østhus, Gunn Hege Marchand, Britt Elin Lurud, Fredrik Granvigen, Hege Andersen, Vidar Rao, Thomas Istvan Kadar, Siv Krüger Claussen, Erling Andersen, Nils Vetti, Jörg Aßmus, Sigrun Randen, Hilde Presberg, Monica Wigemyr, Linda Margareth Pedersen, Bendik Slagsvold Winsvold, Karianne Wiger Gammelsrud, Maria Dehli Vigeland, Benedicte Alexandra Lie, Siri Tennebø Flåm, Magnus Dehli Vigeland, Marianne Thorsø, Knut Morten Huneide, Veronica Sørensen, Thor Einar Holmgard

Abstract

Background: Randomised trials on antibiotic treatment for patients with chronic low back pain and vertebral endplate changes visible on MRI (Modic changes) have shown mixed results. A possible explanation might be a real treatment effect in subgroups of the study populations. The purpose of the present study was to explore potential clinical effect modifiers of 3-months oral amoxicillin treatment in patients with chronic low back pain and type I or II Modic changes at the level of a previous lumbar disc herniation.

Methods: We performed analyses of effect modifiers on data from AIM, a double-blind parallel-group multicentre trial. One hundred eighty patients with chronic low back pain, previous disc herniation, Modic change type I (n = 118) or type II (n = 62) were randomised to 3-months oral treatment with 750 mg amoxicillin (n = 89) or placebo (n = 91) three times daily. The primary outcome was the Roland-Morris Disability Questionnaire (RMDQ) score (possible values 0-24) at 1-year follow-up in the intention-to-treat population. The predefined minimal clinically important between-group mean difference was 4 RMDQ points (not reached in the primary analysis of AIM). Predefined baseline characteristics were analysed as potential effect modifiers, four primary (type I Modic changes, previous disc surgery, positive pain provocation test, high CRP) and five exploratory (disturbed sleep, constant low back pain, short duration of low back pain, younger age, and male) using ANCOVA with interaction terms.

Results: None of the four primary potential effect modifiers had strong evidence of modifying the treatment effect. In patients younger than 40 years the difference in mean RMDQ score between the treatment groups was - 4.0 (95%CI, - 6.9 to - 1.2), compared to - 0.5 (95%CI, - 2.3 to 1.3) in patients 40 years or older, both in favour of amoxicillin treatment (exploratory analysis).

Conclusions: We did not find evidence for convincing clinical effect modifiers of antibiotic treatment in patients with chronic low back pain and Modic changes. Our results for younger age in these explorative analyses should not affect clinical treatment decisions without confirmation in future studies.

Trial registration: ClinicalTrials.gov NCT02323412 , First registered 23 December 2014.

Keywords: Antibiotic; Chronic low back pain; Effect modifier; Infection; Modic changes; Randomised; Subgroup.

Conflict of interest statement

Audny Anke, Anne Julsrud Haugen, Jan Sture Skouen, Mads Peder Rolfsen, Lars Christian Bråten, Anne Froholdt, Ansgar Espeland, Per Martin Kristoffersen, Are Hugo Pripp, Øystein Nygaard, Lars Grøvle, Jens Ivar Brox, Margreth Grotle, Olav Lutro, Christian Hellum, Elina Iordanova Schistad, John-Anker Zwart and Kjersti Storheim declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Forest plot with results for RMDQ (primary outcome). The difference in mean RMDQ score between the treatment groups (size of treatment effect) with 95% confidence interval is shown in black on the right for each of the two categories of each potential effect modifier. The difference in size of treatment effect between the two categories (estimated by the interaction term), with 95% confidence interval and p-values is shown in red. RMDQ Roland-Morris Disability Questionnaire. Score from 0 to 24. Higher scores indicate more severe pain and disability. CRP C-reactive protein. ODI Oswestry Disability Index. Score from 0 to 100. Higher scores indicate more severe pain and disability. LBP Low back pain
Fig. 2
Fig. 2
Forest plot with results for ODI (secondary outcomes). The difference in mean ODI score between the treatment groups (size of treatment effect) with 95% confidence interval is shown in black on the right for each of the two categories of each potential effect modifier. The difference in size of treatment effect between the two categories (estimated by the interaction term), with 95% confidence interval and p-values is shown in red. CRP C-reactive protein. ODI Oswestry Disability Index. Score from 0 to 100. Higher scores indicate more severe pain and disability. LBP Low back pain
Fig. 3
Fig. 3
Forest plot with results for low back pain intensity (secondary outcome). The difference in mean low back pain intensity score between the treatment groups (size of treatment effect) with 95% confidence interval is shown in black on the right for each of the two categories of each potential effect modifier. The difference in size of treatment effect between the two categories (estimated by the interaction term), with 95% confidence interval and p-values is shown in red. CRP C-reactive protein. ODI Oswestry Disability Index. Score from 0 to 100. Higher scores indicate more severe pain and disability. LBP Low back pain

References

    1. Maher C, Underwood M, Buchbinder R. Non-specific low back pain. Lancet. 2017;389(10070):736–747. doi: 10.1016/S0140-6736(16)30970-9.
    1. Dudli S, Fields AJ, Samartzis D, Karppinen J, Lotz JC. Pathobiology of Modic changes. Eur Spine J. 2016;25:3723-34.
    1. Albert HB, Kjaer P, Jensen TS, Sorensen JS, Bendix T, Manniche C. Modic changes, possible causes and relation to low back pain. Med Hypotheses. 2008;70(2):361–368. doi: 10.1016/j.mehy.2007.05.014.
    1. 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. doi: 10.1007/s00586-013-2675-y.
    1. Bråten LCH, Rolfsen MP, Espeland A, Wigemyr M, Aßmus J, Froholdt A, et al. Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial. BMJ. 2019;367:l5654. doi: 10.1136/bmj.l5654.
    1. Bell KJ, Irwig L, Craig JC, Macaskill P. Use of randomised trials to decide when to monitor response to new treatment. Bmj. 2008;336(7640):361–365. doi: 10.1136/bmj.39476.623611.25.
    1. Capoor MN, Birkenmaier C, Wang JC, McDowell A, Ahmed FS, Brüggemann H, et al. A review of microscopy-based evidence for the association of Propionibacterium acnes biofilms in degenerative disc disease and other diseased human tissue. Eur Spine J. 2019;28:2951-71.
    1. Kent P, Keating JL, Leboeuf-Yde C. Research methods for subgrouping low back pain. BMC Med Res Methodol. 2010;10:62. doi: 10.1186/1471-2288-10-62.
    1. Storheim K, Espeland A, Grøvle L, Skouen JS, Aßmus J, Anke A, et al. Antibiotic treatment In patients with chronic low back pain and Modic changes (the AIM study): study protocol for a randomised controlled trial. Trials. 2017;18(1):596.
    1. Moher D, Hopewell S, Schulz K, Montori V, G?Tzsche P, Devereaux P, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. 2010.
    1. Thompson K, Dagher A, Eckel T, Clark M, Reinig J. Modic changes on MR images as studied with provocative diskography: clinical relevance--a retrospective study of 2457 disks. Radiology. 2009;250:849–855. doi: 10.1148/radiol.2503080474.
    1. Dudli S, Liebenberg E, Magnitsky S, Miller S, Demir-Deviren S, Lotz JC. Propionibacterium acnes infected intervertebral discs cause vertebral bone marrow lesions consistent with Modic changes. J Orthopaedic Res. 2016:n/a–a.
    1. Chen Z, Zheng Y, Yuan Y, Jiao Y, Xiao J, Zhou Z, et al. Modic changes and disc degeneration caused by inoculation of Propionibacterium acnes inside intervertebral discs of rabbits: a pilot study. Biomed Res Int. 2016;2016:9612437.
    1. Palazzo C, Ferrari M, Lefevre-Colau M-M, Nguyen C, Rannou F, Poiraudeau S. Lack of effectiveness of antibiotics in chronic low back pain with Modic 1 changes. Joint Bone Spine. 2017;84(4):507.
    1. Gouliouris T, Aliyu SH, Brown NM. Spondylodiscitis: update on diagnosis and management. J Antimicrob Chemother. 2010;65(suppl 3):iii11–iii24.
    1. Kjaer P, Korsholm L, Bendix T, Sorensen JS, Leboeuf-Yde C. Modic changes and their associations with clinical findings. Eur Spine J. 2006;15(9):1312–1319. doi: 10.1007/s00586-006-0185-x.
    1. Capoor MN, Ruzicka F, Schmitz JE, James GA, Machackova T, Jancalek R, et al. Propionibacterium acnes biofilm is present in intervertebral discs of patients undergoing microdiscectomy. PLoS One. 2017;12(4):e0174518. doi: 10.1371/journal.pone.0174518.
    1. Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ. 2010;340:c117.
    1. Bråten LCH SK, Espeland A, Aßmus J, Zwart J. Statistical analysis plan for clinical predictor analysis in the AIM-study. . 2018. Available from: .
    1. Bråten LC RM, Espeland A, Storheim K, Zwart JA, Hellum C, Aßmus J. Statistical analysis plan (SAP) for clinical outcomes in the AIM-study. . 2018. Available from: .
    1. Group IEW . International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 1998. ICH Harmonised tripartite guideline – Statistical principles for clinical trials E9.
    1. Brookes ST, Whitely E, Egger M, Smith GD, Mulheran PA, Peters TJ. Subgroup analyses in randomized trials: risks of subgroup-specific analyses;: power and sample size for the interaction test. J Clin Epidemiol. 2004;57(3):229–236. doi: 10.1016/j.jclinepi.2003.08.009.
    1. Takatalo J, Karppinen J, Niinimäki J, Taimela S, Näyhä S, Mutanen P, et al. Does lumbar disc degeneration on magnetic resonance imaging associate with low back symptom severity in young Finnish adults? Spine. 2011;36(25):2180-89.
    1. Hernán MARJ. Causal Inference. In: Boca Raton: Chapman & Hall/CRC f, editor. Causal Inference. 2019.
    1. Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet. 2000;355(9209):1064–1069. doi: 10.1016/S0140-6736(00)02039-0.
    1. Albert HB, Lambert P, Rollason J, Sorensen JS, Worthington T, Pedersen MB, 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. doi: 10.1007/s00586-013-2674-z.
    1. Rajasekaran S, Tangavel C, SVA KS, DCR S, Nayagam SM, Matchado MS, et al. Inflammaging determines health and disease in lumbar discs—evidence from differing proteomic signatures of healthy, aging, and degenerating discs. Spine J. 2020;20(1):48–59. doi: 10.1016/j.spinee.2019.04.023.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere