Jan Sture Skouen Spesialist i nevrologi og i fysikalsk medisin og rehabilitering. Seksjonsoverlege, Nakke-og ryggpoliklinikken, Avdeling for fysikalsk medisin og rehabilitering, Haukeland universitetssykehus. Professor, dr.med., UiB.

Patogenese

• Prolaps

• Modic type 1,2

• Betydelig bukende skive hos unge Brinjikji W et al. 2015

Literature de Roos et al [de Roos, 1987] were the first to describe

endplate related signal changes

The most widely recognised classification of these signal changes was published in the following year by Modic et al., in which the authors described three types [Modic, 1988a, 1988b].

Modic Changes

T2 T1

6

Modic type 1 (ødem / granulasjonsvev)

T1 mørk T2 lys

7

Modic type 2 (fettvevserstatning)

T1 lys T2 lys / nøytral

8

Modic type 3 (sklerose)

T1 mørk T2 mørk

Vikane 2015 9

Modic type 1

(ødem)

Etter 1 år:

Modic type 2

(fett)

Modic og inflammasjon

jssk

Vertebrale endeplater fra pasienter med Modic type 1 or type 2 endeplateforandringer på MRI hadde signifikant flere PGP 9.5-immunoreaktive nerve fibre og TNF-immunoreaktive celler til sammenligning med normale endeplater

Ohtori S et al. 2006

Klinikk Smerter hele døgnet

Lokale smerter ved Springing test

Ofte støtsmerter

Lite myalgier

Sjelden psykososiale problemer

Ingen effekt av trening

Oppstår som oftest etter prolapser i samme nivå

Hvor hyppige er Modic forandringer, 58 studier

Modic changes A lumbar disc herniation is a strong risk factor for

developing Modic changes

Modic changes type 1 is more strongly related to LBP than type 2

Albert HB and Manniche C 2007

Literature

The association between MC and non-specific LBP has been investigated in three systematic reviews

Zhang YH, 2008; Jensen TS, 2008 and Brinjikji W, 2015

Siste systematiske review på modic og smerter Svakere sammenheng med smerter og modic enn

tidligere reviews

Ingen sammenheng med funksjon

Større sannsynlighet for sammenheng i de to nederste lumbale segmenter

Herlin C et al. Submitted PLOS ONE

Modic Changes (MCs) Visible on MRI-scans only

Classified into type I, II and III

Frequent finding in patients with LBP

The aetiology of the low graded inflammation is unclear

Mechanical? (the forces acting within the disc)

Nucleus tissue entering the vertebrae cause an autoimmune reaction?

MCs occur due to edema surrounding an infected disc?

infection with low virulent anaerobic organisms, mainly the propionibacterium acnes (P.acnes) is found in biopsies from nucleus material

i.e. the infection is in the disc and the MC is a secondary change in the bone due to cytokine and propionic acid production????

Background Albert et al treated a sub-group of chronic LBP patients with a

supposed biomedical source of LBP (Modic Changes) with Amoxicillin for 100 days

The effect was substantially greater than all currently established treatments for chronic LBP RMDQ during study (range 0-23): baseline, 100 days, 1 year

antibiotic 15, 11, 5.7

placebo 15, 14, 14

Leg pain during study (range 0 -10): baseline, 100 days, 1 y antibiotics 5.3, 3.0, 1.4

placebo 4.0, 4.3, 4.3

Lumbar pain during st. (range 0 – 10): baseline, 100 days, 1 y antibiotics 6.7, 5.0, 3.7

placebo 6.3, 6.3, 6.3

Hypothesis A current hypothesis is that MCs may occur due to

edema surrounding an infected disc; i.e. the infection is in the disc and the MC is a secondary change in the bone due to cytokine and propionic acid production

The AIM-study

Hence…. A new RCT should be performed to prevent

inappropriate use of antibiotics in a large group of patients based on a single trial!

Methods

Placebo-double blinded RCT

Multicenter

Haukeland

University

Hospital

St.Olavs Hospital

UNN

Oslo University

Hospital

Østfold Hospital

Drammen

Hospital

Prosjektets organisering

Kjersti Storheim

Ellen Årtun

Apotek Lab Radiolog Koordinator

PI Kragerø Tablettproduksjon Radiologi Haukeland Epigenetikk AFK

Datamanagement / Monitor

Sponsor

John-Anker Zwart

PI’s UNN Audny Anke St.Olav Øystein Nygaard HUS Jan Sture Skouen Drammen Anne Froholdt Østfold Lars Grøvle OUS Jens Ivar Brox

Ansgar

Espeland

Study interventions Antibiotic treatment:

Amoxicillin 750 mg x3 for 100 days

Versus placebo x3 for 100 days

Tilvirkes av Kragerø

Tablettproduksjon

Strata for

Modic type I / II

Tidligere discoperert: JA /

NEI

Inclusion criteria 18-65 years

LBP of > 6 months duration

NRS more and equal to 5 (current LBP, worst LBP last 2 weeks, mean LBP last 2 weeks)

MRI confirmed lumbar disc herniation within the preceding to years at the same level as

Modic changes 1,2.

If former surgery, the same level as Modic changes

Exclusion criteria Allergy to penicillin or cefalosporins

Allergy/hypersensitivity to any of the excipients of the study drug

Current pregnancy or lactation

Elevated kidney (creatinine) or hepatic (ALAT/ASAT) values outside normal range

Phenylketonuria (Følling disease)

Mononucleosis or leukaemia

Any specific diagnosis that may explain patient’s low back symptoms (e.g. tumor, fracture, spondyloarthritis, infection, spinal stenosis).

Former low back surgery (L1 – S1) for other reasons than disc herniation (e.g fusion, decompression, disc prosthesis).

Exclusion criteria (cont) Former surgery for disc herniation, but < 12 months have elapsed since surgery. Former surgery for disc herniation, but MC located at non-operated level(s)

only. Reservation against intake of gelatine (the capsules contains gelatine, which among other

things is produced by ingredients from pigs)

Regular use of glucocorticoids Regular use of opioids with the exception of codeine and tramadol Not understanding Norwegian language Unlikely to adhere to treatment and/ or complete follow-up (e.g ongoing serious

psychiatric disease, drug abuse, plans to move)

Antibiotic treatment within the preceding one month before treatment start Contraindications to MRI (e.g. cardiac pacemaker electrodes, metal implant in eye or brain,

claustrophobia).

Unwilling to participate

Outcome measures Primary outcome

Roland Morris Disability Questionnaire

Secondary outcomes Lumbar pain and leg pain measured by NRSs

Bothersomeness

Health-related quality of life (EuroQoL-5D)

Days with sick leave

Patient’s satisfaction

Radiological outcomes

Gene expression

Cost-effectiveness

Data will be collected at baseline, during treatment, post-treatment, during follow-up and at 1-year follow-up

Main

endpoint

Tidslinje

Screening

Alle som

tilfredsstiller

alle inkl/ekskl

krit og som

henvises til

nytt MR:

MR-studier

Ny MR

Inklusjon =

dag 0

Behandlingsperiode

Behandling

slutt = dag

100

Klinisk ktr

Dag 33

Klinisk ktr

Dag 66

Ukentlig: Smertemonitorering og Compliance

Follow-up

slutt

1 år etter

beh.start

Månedlig helseøkonomi

Estimert antall inkluderte per senter OUS 40

Tromsø 20

Trondheim 30

Bergen 35

Drammen 35

Østfold 40

Oppsummering Trolig en lavgradig inflammasjonstilstand som oftest

etter prolaps

Asymptomatiske Modic forandringer finnes

Lokale langvarige og meget plagsomme smerter

Ingen effekt av trening

Best av å være i moderat bevegelse

Kan ha effekt av kraftige anti-inflammatoriske midler