Background: Low back pain (LBP) is the number one cause of disability worldwide. Chronic
LBP (cLBP), also referred to as persisting low back pain, is defined as low back pain
lasting at least twelve weeks, with a lifetime prevalence of about 23%. It represents
extensive individual, societal, and financial burdens.
The etiology of cLBP is multifactorial with complex pathogenesis, and only a small
proportion of patients with disabling cLBP have a well-understood pathophysiological
cause. Over the last several decades, the biopsychosocial model of LBP has been the
standard approach. Accordingly, current clinical guidelines recommend treatments such as
advice to stay active, exercise, reassurance and coping strategies, analgesic
medications, and avoiding bed rest. The existing treatments, however, have only small to
moderate effects, and 85-90% of patients do not receive a pathoanatomical diagnosis
(National Institute for Health and Care Excellence (NICE)).
Many pathophysiological hypotheses for cLBP have been proposed (e.g., annular tear, disc
herniation, loss of disc height, facet joint degeneration, and Modic changes). For
example, it has been hypothesized that cLBP with Modic changes is caused by bacterial
infection. A Danish trial reported that antibiotic treatment was superior to placebo in
selected cLBP patients with focal vertebral bone marrow changes (Modic changes graded by
MRI of the lumbar spine). However, the Norwegian AIM (Antibiotic In Modic changes) study
did not support this finding. Nonetheless, intervertebral disc (IVD) degeneration is
generally accepted as a relevant cause of cLBP, especially among surgeons treating the
condition. An experimental study of cultured human nucleus pulposus cells showed that
acidic pH caused an increase in several pro-inflammatory, neurotrophic, and pain-related
factors. This upregulation of inflammatory substances may, in turn, induce the ingrowth
of nerve fibers into degenerative IVDs, possibly explaining how discs can become painful.
Therefore, one possible approach to diagnose painful IVDs could be to measure IVD pH
levels by MRI spectroscopy (MRS). The local inflammation in degenerative IVD is
correlated with a systemic inflammatory response that can be measured in serum samples
and is related to symptoms. Recent developments in diagnostics and biomarkers in the
field may improve patient selection and support an individually tailored treatment.
A few randomized controlled trials have compared lumbar spine fusion with non-operative
treatment, finding similar improvements in pain and disability for both treatment
alternatives. This has led to guidelines recommending non-operative treatment.
The researchers in the current project aim to improve treatment, develop refined
diagnostic assessments, and explore potential biomarkers in a multicenter randomized
controlled trial (RCT), adding level-one evidence to the subject.
The overall concept is to assess whether there is a difference in treatment effect
between modern lumbar interbody fusion (LIF) and multidisciplinary rehabilitation (MRE)
for patients with cLBP. The researchers aim to:
Evaluate the effect of LIF versus MRE at one-year follow-up (FU).
Evaluate the treatment effectiveness at two-year FU in the cohort of patients
crossing over from one treatment arm to the other at one-year FU. (Primary and
secondary outcome measures will be the same as those listed in sections 1 through 12
of the 'Outcome Measures' section.
Evaluate the effect of LIF versus MRE at one-year FU on physical activity, sleep
disturbances, and circadian rhythm.
Evaluate whether baseline MRS biomarkers are associated with treatment response
after LIF at one-year FU.
Evaluate whether baseline MRS biomarkers are associated with treatment response
after MRE at one-year FU.
Evaluate whether MRS biomarkers are associated with molecular biomarkers in blood
samples collected at three time points.
Evaluate if molecular biomarkers can identify patients with improvement after LIF at
one-year FU.
Evaluate if molecular biomarkers can identify patients with improvement after MRE at
one-year FU.
Evaluate, if feasible, the correlation between MRS biomarkers and perioperative pH
measurement of the IVD.
Evaluate the cost-effectiveness of LIF versus MRE from baseline to one-year FU The
spinal surgeons will screen participants for trial eligibility by predetermined
inclusion- and exclusion criteria and ensure that necessary imaging examinations
(MRI and X-ray) have been done per protocol.
Patients will be invited to trial participation if all the inclusion criteria and none of
the exclusion criteria are satisfied. Patients who may be relevant study candidates are
set up for a new appointment with another surgeon associated with the project so that
each potential participant receives an individual assessment by two different surgeons,
ensuring a thorough evaluation and sufficient reflection period for the patient. To avoid
undue pressure to participate in the study, one of the treating surgeons who have
assessed the patient at the outpatient clinic will provide information about the project,
and obtaining informed consent will be done by an independent third party, for example, a
study nurse, a representative from rehabilitation or another surgeon associated with the
project. To ensure comprehensive and unbiased information regarding both trial arms,
representatives from the MRE arm will also have a face-to-face or electronic meeting with
potential trial participants before their inclusion. General consent, as well as specific
consent to the neuroscientific biobank, will be obtained. However, consent to the
neuroscience biobank is not mandatory for study participation. The participant will be
issued copies of the letter informing about the trial and the signed informed consent(s).
Eligible patients will be allocated in a 1:1 ratio between LIF and MRE, using a computer
randomization procedure stratified by center. Block size and allocation sequence
generation details will be provided in a separate document unavailable to those who
enroll patients or assign treatment. Following screening, eligible participants will be
randomized in a continuous manner. Treatment initiation will occur within three months of
randomization for both treatment groups.
Baseline data collection will include sociodemographic variables (age, gender, BMI,
ethnicity, educational level, work status), as well as information on physical workload,
leisure activities, smoking habits, emotional distress (assessed with Hopkins Symptom
Checklist-25 [HSCL-25]), fear avoidance beliefs (FABQ), Örebro Musculoskeletal Pain
Screening Questionnaire (Short-form), and cLBP history (including duration and prior
treatments such as spinal surgery, physiotherapy, and chiropractic therapy). At baseline,
we will ask all participants to report their smallest worthwhile reduction of pain and
disability (in percent, not specified to measurement instrument), what treatment group
they hope to be randomized to, and how well they expect to be at one-year FU (Likert
scale (1-7)). We will further ask all investigators at baseline to report what treatment
allocation they think would be best for the individual participant if they were not
participating in a study and to rate (Likert scale (1-7)) how well they expect the
participant to be at one-year FU given the randomization.
Baseline sick listing and subsequent sick listing at each FU consultation will include
documentation of complete work absence and part-time absence.
Prospective participants must undergo radiological examinations before study inclusion,
including MRI and plain radiographs for measuring pelvic spine parameters. The MRI and
radiographs must be obtained within six months before the initiation of treatment.
Hematological parameters (leucocytes, thrombocytes, hemoglobin (Hb)), sedimentation rate,
CRP, electrolytes (Na and K), and measures of kidney (creatinine) and liver function
(ALAT) will be assessed and registered at baseline if allocated to LIF intervention.
Functional comorbidity index will be reported at screening and serve as a screening tool
for other relevant illnesses together with physical examination at baseline.
The study will be monitored by the Clinical Trial Unit at Oslo University Hospital
according to the standard by NorCRIN and Good Clinical Practice. Adverse events and
serious adverse events will be registered at all study FUs. The study will focus on
monitoring specific adverse events in individuals allocated to the LIF intervention.
These events include the following:
Deep and superficial wound infection and rupture of the surgical wound
Hardware mechanical complications with loosening of pedicle screws and interbody
implants before bony fusion of the addressed lumbar level are evidenced.
Improper hardware placement
Wrong-level surgery
Dural tears leading to spinal headaches and possibly a pseudo-meningocele
Nerve root injury possibly leading to chronic neuropathic pain, palsy, and
dysfunction of the muscles affected.
Postoperative spinal hematoma necessitating an acute surgical evacuation
Cauda equina compression that may lead to transient or permanent dysfunction of the
urinary bladder and bowel function.
Potentially life-threatening hemorrhage by iatrogenic injury to large pelvic vessels
Iatrogenic injury to the ureter necessitating additional urologic procedures
Bowel perforation in case of ALIF
Retrograde ejaculation due to iatrogenic injury to the lumbar autonomous nervous
system (ALIF) Monitoring for these adverse events will involve clinical examination,
blood sample analysis (including parameters such as Hb, CRP, and leukocytes), and
radiologic imaging such as CT scans and MRI.
Blood samples for DNA genotyping (Genomics), methylation (Epigenetics), and RNA
sequencing (Transcriptomics) will be collected at baseline, 6- and 12-months FU from
participants who have consented to participate in the genetic analysis component of the
study. Participation is optional. Participants who do not wish to participate in the
genetic research may still participate in the study.
The researchers will also, at baseline, 6- and 12 months, measure a panel of 40 cytokines
by duplicate serum analysis with a 40-plex Pro Human Chemokine multi-bead assay. Samples
that can be used to analyze suspected molecular biomarkers in the future will also be
collected.
For all participants throughout the study, the investigator and study site personnel will
collect data about healthcare resource utilization associated with medical encounters.
The cost-benefit analysis of LIF versus MRE will be assessed by QUALYs derived from
EQ-5D-5L and hospital and community treatment costs. The following data will be
collected:
LIF: Time in theatre, duration of surgery, blood loss and transfusions, number of
surgeons, anesthesiologists, and nurses, implant costs, length of sick leave, use of
non-operative treatment (i.e., physiotherapy, rehabilitation), additional visits to
the GP, additional follow-ups including imaging outside the study protocol.
MRE: Medical consultations at the general practitioner or other primary care
treatment, additional diagnostic tests (e.g., X-ray, MRI, CT, laboratory tests),
medications (e.g., pain relievers, muscle relaxants, anti-inflammatories,
antidepressants), time spent at treatment facilities, staffing costs, travel
expenses (for patients traveling to rehabilitation institution for every treatment
day or session), accommodation costs (for patients staying at the rehabilitation
institution during the treatment period) and sick leave.