Efficacy of naproxen in patients with sciatica: multicentre, randomized, double-blind, placebo-controlled trial.

ABSTRACT: This trial assessed the efficacy of naproxen in patients with sciatica in outpatient clinics across 4 Norwegian hospitals. A total of 123 adults with radiating pain below the knee (≥4 on a 0-10 numeric rating scale) and signs consistent with nerve root involvement were included. Participants were randomized to receive either naproxen 500 mg or a placebo twice daily for 10 days. The primary outcome, daily leg pain intensity measured on a 0 to 10 numeric rating scale throughout the treatment period, revealed a statistically significant difference in favor of naproxen, with an adjusted mean difference of -0.5 (95% CI -0.8 to -0.1, P = 0.015). In the naproxen group, the treatment effect was significantly related to time, and over the whole 10-day period, the average adjusted difference was -0.6 (95% CI -0.8 to -0.5). Mean numbers needed to treat for 30% and 50% improvement were 9.9 (95% CI 4.7-15.0) and 20.7 (8.7-32.7), respectively. The adjusted mean difference for back pain was -0.4 (95% CI -0.8 to 0.0), and for Roland Morris Disability Questionnaire for Sciatica, it was -1.5 (95% CI -3.0 to 0.0). No differences were found for sciatica bothersomeness or consumption of rescue medication or opioids. Participants in the naproxen group exhibited an adjusted odds ratio of 4.7 (95% CI 1.3-16.2) for improvement by 1 level on the global perceived change scale. In conclusion, naproxen treatment showed small, likely clinically unimportant benefits compared with placebo in patients with moderate-to-severe sciatica.

The terminologies of transient, migratory, or localized osteoporosis, and bone marrow edema syndrome: a scoping review.

There is no formally defined terminology for the related entities transient osteoporosis of the hip (TOH), localized or regional migratory osteoporosis (RMO) and bone marrow edema syndrome (BMES). This study aimed to map the diversity and frequency of diagnostic terms and vocabulary utilized in the literature. A comprehensive search of electronic databases and reference lists was conducted. Publications that reported on patients with TOH, RMO, BMES, or related variants were eligible for inclusion. The terminologies were categorized based on the wording of the titles, abstracts, or texts. We included 561 publications, of which 423 were case reports, involving 2921 patients. Overall, TOH was the most commonly used term, occurring in 257 (45.8%). RMO was used in 34 (6.1%) and BMES in 57 (10.2%). The remaining used various combinations of transient, migratory, and regional in conjunction with either osteoporosis or bone marrow edema. Localized osteoporosis was not used. We identified three different terms related to pregnancy. In 76.3% of the publications, the terminology was related to osteoporosis and in 18.2% to bone marrow edema, although terminology did not correspond to actual findings. Bone marrow edema occurred as often as osteoporosis, and osteoporosis was generally ascertained by visual inspection of radiographs, seldom by bone densitometry. Many publications used osteoporosis-related terms without evidence that osteoporosis had been detected. The terminology of these closely related entities is confusing and unstandardized. The lack of formal definitions impedes accurate diagnosis, research on disease mechanisms, and effective treatment.

Longitudinal Relationship Between Reduced Modic Change Edema and Disability and Pain in Patients With Chronic Low Back Pain.

STUDY DESIGN: Secondary analyses of a randomized trial [Antibiotics In Modic changes (MCs) study]. OBJECTIVE: To assess whether or not reduced MC edema over time is related to reduced disability and pain in patients with chronic low back pain (LBP). SUMMARY OF BACKGROUND DATA: It is not clear whether or not reduced MC edema implies improved clinical outcomes. PATIENTS AND METHODS: Linear regression was conducted separately in 2 subgroups with MC edema at baseline on short tau inversion recovery (STIR) or T1/T2-weighted magnetic resonance imaging, respectively. Independent variable: reduced edema (yes/no) at 1 year on STIR or T1/T2-series, respectively. Dependent variable: 1-year score on the Roland-Morris Disability Questionnaire (RMDQ), Oswestry Disability Index (ODI), or 0 to 10 numeric rating scale for LBP intensity, adjusted for the baseline score, age, smoking, body mass index, physical workload, and baseline edema on STIR (STIR analysis only). Post hoc, we, in addition, adjusted all analyses for baseline edema on STIR, treatment group (amoxicillin/placebo), and prior disc surgery-or for disc degeneration. RESULTS: Among patients with MC edema on STIR at baseline (n = 162), reduced edema on STIR was not significantly related to the RMDQ ( B : -1.0, 95% CI: -2.8, 0.8; P = 0.27), ODI ( B :-1.4, 95% CI: -5.4, 2.6; P = 0.50), or LBP intensity scores ( B : -0.05, 95% CI: -0.8, 0.7; P = 0.90) after 1 year. Among patients with MC edema on T1/T2-series at baseline (n = 116), reduced edema on T1/T2 ( i.e ., reduced volume of the type 1 part of MCs) was not significantly related to RMDQ ( B: -1.7, 95% CI: -3.8, 0.3; P = 0.10) or ODI score ( B : -2.3, 95% CI: -7.1, 2.5; P = 0.34) but was significantly related to LBP intensity at 1 year ( B : -0.9, 95% CI: -1.8, -0.04; P = 0.04; correlation coefficient: 0.24). The post hoc analyses supported these results. CONCLUSION: Reduced MC edema over 1 year was not significantly associated with pain-related disability but was (on T1/T2-series) significantly but weakly related to reduced LBP intensity. LEVEL OF EVIDENCE: Level 3.

Cytokine Patterns as Predictors of Antibiotic Treatment Effect in Chronic Low Back Pain with Modic Changes: Subgroup Analyses of a Randomized Trial (AIM Study).

Objective: Randomized trials testing the effect of antibiotics for chronic low back pain (LBP) with vertebral bone marrow changes on MRI (Modic changes) report inconsistent results. A proposed explanation is subgroups with low grade discitis where antibiotics are effective, but there is currently no method to identify such subgroups. The objective of the present study was to evaluate whether distinct patterns of serum cytokine levels predict any treatment effect of oral amoxicillin at one-year follow-up in patients with chronic low back pain and Modic changes at the level of a previous lumbar disc herniation. Design: We used data from an overpowered, randomized, placebo-controlled trial (the AIM study) that tested 100 days of oral 750 mg amoxicillin vs placebo three times daily in hospital outpatients with chronic (>6 months) LBP with pain intensity ≥5 on a 0-10 numerical rating scale and Modic changes type 1 (oedema type) or 2 (fatty type). We measured serum levels of 40 inflammatory cytokines at baseline and analysed six predefined potential predictors of treatment effect based on cytokine patterns in 78 randomized patients; three analyses with recursive partitioning, one based on cluster analysis and two based on principal component analyses. The primary outcome was the Roland-Morris Disability Questionnaire score at one-year follow-up in the intention to treat population. The methodology and overall results of the AIM study were published previously. Results: The 78 patients were 25-62 years old and 47 (60%) were women. None of the three recursive partitioning analyses resulted in any suggested subgroups. Of all main analyses, the largest effect estimate (mean difference between antibiotic and placebo groups) was seen in a subgroup not predefined as of main interest (Cluster category 3+4; -2.0, 95% CI: -5.2-1.3, RMDQ points; p-value for interaction 0.54). Conclusion: Patterns of inflammatory serum cytokine levels did not predict treatment effect of amoxicillin in patients with chronic LBP and Modic changes. Clinical Trial Registration Number: ClinicalTrials.gov (identifier: NCT02323412).

Amoxicillin Did Not Reduce Modic Change Edema in Patients With Chronic Low Back Pain: Subgroup Analyses of a Randomised Trial (the AIM Study).

STUDY DESIGN: Exploratory subgroup analyses of a randomised trial [Antibiotics in Modic changes (AIM) study]. OBJECTIVE: The aim was to assess the effect of amoxicillin versus placebo in reducing Modic change (MC) edema in patients with chronic low back pain. SUMMARY OF BACKGROUND DATA: The AIM study showed a small, clinically insignificant effect of amoxicillin on pain-related disability in patients with chronic low back pain and MC type 1 (edema type) on magnetic resonance imaging (MRI). MATERIALS AND METHODS: A total of 180 patients were randomised to receive 100 days of amoxicillin or placebo. MC edema was assessed on MRI at baseline and one-year follow-up. Per-protocol analyses were conducted in subgroups with MC edema on short tau inversion recovery (STIR) or T1/T2-weighted MRI at baseline. MC edema reductions (yes/no) in STIR and T1/T2 series were analyzed separately. The effect of amoxicillin in reducing MC edema was analyzed using logistic regression adjusted for prior disk surgery. To assess the effect of amoxicillin versus placebo within the group with the most abundant MC edema on STIR at baseline ("STIR3" group), we added age, STIR3 (yes/no), and STIR3×treatment group (interaction term) as independent variables and compared the marginal means (probabilities of edema reduction). RESULTS: Compared to placebo, amoxicillin did not reduce MC edema on STIR (volume/intensity) in the total sample with edema on STIR at baseline (odds ratio 1.0, 95% CI: 0.5, 2.0; n=141) or within the STIR3 group (probability of edema reduction 0.69, 95% CI: 0.47, 0.92 with amoxicillin and 0.61, 95% CI: 0.43, 0.80 with placebo; n=41). Compared with placebo, amoxicillin did not reduce MC edema in T1/T2 series (volume of the type 1 part of MCs) (odds ratio: 1.0, 95% CI: 0.5, 2.3, n=104). Edema declined in >50% of patients in both treatment groups. CONCLUSIONS: From baseline to one-year follow-up, amoxicillin did not reduce MC edema compared with placebo. LEVEL OF EVIDENCE: 2.

Symptom descriptors and patterns in lumbar radicular pain caused by disc herniation: a 1-year longitudinal cohort study.

OBJECTIVE: The objective of the present study was to explore the diversity, quality, severity and distribution of symptoms in patients with radicular pain and a lumbar disc herniation. DESIGN: Longitudinal cohort study. SETTING: Hospital-based back clinic. PARTICIPANTS: Ninety patients referred to secondary healthcare with (a) low back-related leg pain, (b) age between 18 and 65 years and (c) MRI confirmed lumbar disc herniation at a relevant side and level. OUTCOME MEASURES: Neuropathic pain symptoms were assessed using the Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) and the painDETECT Questionnaire. In a subsample classified with neuropathic pain, in-depth interviews were performed, and symptomatic areas were drawn on standardised body charts. RESULTS: At baseline, the most frequently used painDETECT symptom descriptor was numbness sensation, reported by 94%, followed by sudden pain attacks and tingling or prickling. The mean (SD) SF-MPQ-2 score (0-10) for aching pain was 5.9 (2.8); numbness 4.3 (3.3); tingling 4.0 (3.4); burning 2.6 (3.1); pain caused by light touch 1.5 (2.6). Leg pain was rated as extremely bothersome by 73%, numbness and tingling by 38%, weakness by 24% and back pain by 17%. In the subsample (n=52), deep-lying pain and non-painful abnormal sensations were frequent, at 71% and 85%. Drawings demonstrated substantial overlap between symptoms from compromised L5 and the S1 nerve roots. Painful and non-painful symptoms improved at approximately the same rate. At the 1-year follow-up, 45% (14/31) of patients who had received disc surgery, and 34% (18/53) of those who had received conservative treatment reported no bothersome back pain, leg pain, numbness/tingling or weakness. CONCLUSION: Patients reported several highly bothersome symptoms, but not all are described as painful. The overall symptom profile of lumbar disc-related radicular pain differs from other neuropathic pain conditions with limited allodynia and thermal hyperalgesia. Symptomatic areas for the L5 and S1 nerve roots have a large overlap.

Minimal important change was on the lower spectrum of previous estimates and responsiveness was sufficient for core outcomes in chronic low back pain.

OBJECTIVES: The objective of this study was to estimate the minimal important change (MIC) and responsiveness of core patient reported outcome measures for chronic low back pain (LBP) and Modic changes. STUDY DESIGN AND SETTING: In the Antibiotics in Modic changes (AIM) trial we measured disability (RMDQ, ODI), LBP intensity (NRS) and health-related quality of life (EQ5D) electronically at baseline, three- and 12-month follow-up. MICs were estimated using Receiver Operating Curve (ROC) curve and Predictive modeling analyses against the global perceived effect. Credibility of the estimates was assessed by a standardized set of criteria. Responsiveness was assessed by a construct and criterion approach according to COSMIN guidelines. RESULTS: The MIC estimates of RMDQ, ODI and NRS scores varied between a 15-40% reduction, depending on including "slightly improved" in the definition of MIC or not. The MIC estimates for EQ5D were lower. The credibility of the estimates was moderate. For responsiveness, five out of six hypotheses were confirmed and AUC was >0.7 for all PROMs. CONCLUSION: When evaluated in a clinical trial of patients with chronic LBP and Modic changes, MIC thresholds for all PROMs were on the lower spectrum of previous estimates, varying depending on the definition of MIC. Responsiveness was sufficient.

Apparent diffusion coefficient values in Modic changes - interobserver reproducibility and relation to Modic type.

BACKGROUND: Modic Changes (MCs) in the vertebral bone marrow were related to back pain in some studies but have uncertain clinical relevance. Diffusion weighted MRI with apparent diffusion coefficient (ADC)-measurements can add information on bone marrow lesions. However, few have studied ADC measurements in MCs. Further studies require reproducible and valid measurements. We expect valid ADC values to be higher in MC type 1 (oedema type) vs type 3 (sclerotic type) vs type 2 (fatty type). Accordingly, the purpose of this study was to evaluate ADC values in MCs for interobserver reproducibility and relation to MC type. METHODS: We used ADC maps (b 50, 400, 800 s/mm2) from 1.5 T lumbar spine MRI of 90 chronic low back pain patients with MCs in the AIM (Antibiotics In Modic changes)-study. Two radiologists independently measured ADC in fixed-sized regions of interests. Variables were MC-ADC (ADC in MC), MC-ADC% (0% = vertebral body, 100% = cerebrospinal fluid) and MC-ADC-ratio (MC-ADC divided by vertebral body ADC). We calculated mean difference between observers ± limits of agreement (LoA) at separate endplates. The relation between ADC variables and MC type was assessed using linear mixed-effects models and by calculating the area under the receiver operating characteristic curve (AUC). RESULTS: The 90 patients (mean age 44 years; 54 women) had 224 MCs Th12-S1 comprising type 1 (n = 111), type 2 (n = 91) and type 3 MC groups (n = 22). All ADC variables had higher predicted mean for type 1 vs 3 vs 2 (p < 0.001 to 0.02): MC-ADC (10- 6 mm2/s) 1201/796/576, MC-ADC% 36/21/14, and MC-ADC-ratio 5.9/4.2/3.1. MC-ADC and MC-ADC% had moderate to high ability to discriminate between the MC type groups (AUC 0.73-0.91). MC-ADC-ratio had low to moderate ability (AUC 0.67-0.85). At L4-S1, widest/narrowest LoA were for MC-ADC 20 ± 407/12 ± 254, MC-ADC% 1.6 ± 18.8/1.4 ± 10.4, and MC-ADC-ratio 0.3 ± 4.3/0.2 ± 3.9. Difference between observers > 50% of their mean value was less frequent for MC-ADC (9% of MCs) vs MC-ADC% and MC-ADC-ratio (17-20%). CONCLUSIONS: The MC-ADC variable (highest mean ADC in the MC) had best interobserver reproducibility, discriminated between MC type groups, and may be used in further research. ADC values differed between MC types as expected from previously reported MC histology.

Strategies to manage auxiliary pain medications in chronic pain trials: a topical review.

Chronic pain trials commonly allow auxiliary pain medications such as rescue and concomitant analgesics in addition to the randomized treatment. Changes in auxiliary pain medications after randomization represent intercurrent events that may affect either the interpretation or the existence of the measurements associated with the clinical question of interest, complicating the assessment of treatment efficacy. In chronic pain trials, pain intensity typically varies and patients may take the auxiliary medications 1 day but not the next or increase and decrease the dosages temporarily while continuing their randomized study medication. This distinctive feature of auxiliary pain medications as an intercurrent event has received little attention in the literature. Further clarifications on how to manage these issues are therefore pressing. Here we provide perspectives on issues related to auxiliary pain medication-related intercurrent events in randomized controlled chronic pain trials considering the strategies suggested in the E9(R1) addendum to the ICH guideline on statistical principles for clinical trials.

NSAIDs in sciatica (NIS): study protocol for an investigator-initiated multicentre, randomized placebo-controlled trial of naproxen in patients with sciatica.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat sciatica, despite insufficient evidence from placebo-controlled trials. NSAIDs may cause serious side effects; hence, there is a strong need to clarify their potential beneficial effects in patients with sciatica. METHODS: This is a multicentre, randomized, placebo-controlled, parallel-group superiority trial. Participants will be recruited among sciatica patients referred to outpatient clinics at hospitals in Norway who have radiating pain below the knee with a severity score of ≥ 4 on a 0-10 numeric rating scale and clinical signs of nerve root or spinal nerve involvement. The intervention consists of oral naproxen 500 mg or placebo twice daily for 10 days. Participants will report the outcomes and adverse events daily using an electronic case report form. The primary endpoint is change in leg pain intensity from baseline to day 10 based on daily observations. The secondary outcomes are back pain intensity, disability, sciatica symptom severity, rescue medication (paracetamol) consumption, opioid use, ability to work or study, 30% and 50% improvement in leg pain, and global perceived change of sciatica/back problem. The outcomes will be analysed using mixed effects models for repeated measurements. The total duration of follow-up is 12 (± 2) days. DISCUSSION: This trial aims to evaluate the benefits of naproxen, a non-selective NSAID, in patients with sciatica. No important differences in efficacy have been demonstrated between different NSAIDs in the management of musculoskeletal disorders; hence, the results of this trial will likely be applicable to other NSAIDs. TRIAL REGISTRATION: ClinicalTrials.gov NCT03347929 . Registered on November 20, 2017.

Impact of rescue medication in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back pain.

ABSTRACT: Rescue medication (RM) consumption is commonly used as a secondary outcome in placebo-controlled trials of chronic pain, but its validity has yet to be established. If participants randomized to placebo take more RM than those randomized to an active drug, the difference in pain between the 2 groups may be reduced, potentially masking effects of the active drug. This study assessed proportional RM consumption in the placebo and active groups according to results of 42 randomized controlled trials of neuropathic pain (NeP), and 29 trials of low back pain, which were included in 2 systematic reviews and meta-analyses. Trial results were assessed based on effect size, statistical significance, and whether the drug was recommended as first-line treatment by the systematic reviews. In trials indicating effect of the investigational drug, RM consumption was generally higher in the placebo groups than in the active groups. In trials reporting a small or a medium effect size of the investigational drug, subjects receiving placebo consumed 17% to 30% more RM than subjects receiving active drug, potentially leading to underestimation of the effects of the investigational drugs. Few trials reported a large effect size. Differences in RM consumption between participants receiving placebo and those receiving active drug were seldom taken in account by the individual trials and not at all by the systemic reviews when making treatment recommendations for NeP or low back pain. Elaboration on analytical methods to assess treatment effects in chronic pain trials using RM is warranted.

Pinprick and Light Touch Are Adequate to Establish Sensory Dysfunction in Patients with Lumbar Radicular Pain and Disc Herniation.

BACKGROUND: The frequency with which sensory disturbances occur in patients with radicular leg pain and disc herniation is not well known, and the efficacy of tests to identify such changes are not firmly established. The presence of sensory disturbances is a key sign of nerve root involvement and may contribute to the diagnosis of a lumbar disc herniation, identify patients for referral to spinal imaging and surgery, and improve disease classification. QUESTIONS/PURPOSES: In this study, we sought: (1) to determine the frequency with which abnormal sensory findings occur in patients with lumbar disc herniation-related radicular pain, using a standard neurological sensory examination; (2) to determine what particular standard sensory test or combination of tests is most effective in establishing sensory dysfunction; and (3) to determine whether a more detailed in-depth sensory examination results in more patients being identified as having abnormal sensory findings. METHODS: Between October 2013 and April 2016, 115 patients aged 18 to 65 years referred to secondary health care with radicular leg pain and disc herniation were considered potentially eligible for inclusion in the study. Based on these inclusion criteria, 79% (91) were found eligible. Ten percent (11) were excluded because of other illness that interfered with the study purpose, 3% (3) because of cauda equina syndrome, 2% (2) because of spinal stenosis, 2% (2) because of prior surgery at the same disc level, and 2% (2) because of poor Norwegian language skills. Three percent (4) of the patients did not want to participate in the study. Of the 91 eligible patients, 56% (51) consented to undergo a comprehensive clinical examination and were used for analysis here. The sample for the purposes of the present study was predetermined at 50. These patients were first examined by a standard procedure, including sensory assessment of light touch, pinprick, vibration, and warmth and cold over the back and legs. Second, an in-depth semiquantitative sensory testing procedure was performed in the main pain area to assess sensory dysfunction and improve the detection of potential positive sensory signs, or sensory gain of function more precisely. Sensory loss was defined as sensations experienced as distinctly reduced in the painful side compared with the contralateral reference side. In contrast, sensory gain was defined as sensations experienced as abnormally strong, unpleasant, or painful and distinctly stronger than the contralateral side. Ambiguous test results were coded as a normal response to avoid inflating the findings. The proportions of abnormal findings were calculated for each sensory modality and for all combinations of the standard examination tests. RESULTS: The standard examination identified at least one abnormal finding in 88% (45 of 51) of patients. Sensory loss was present in 80% (41), while sensory gain was present in 35% (18). The combination of pinprick and light touch identified all patients who were classified as having abnormal findings by the full standard examination. The semiquantitative procedure identified an additional three patients with an abnormal finding. CONCLUSION: We suggest that the combination of pinprick and light touch assessment is an adequate minimal approach for diagnostic and classification purposes in patients with lumbar radicular pain. LEVEL OF EVIDENCE: Level I, diagnostic study.

Oedema on STIR modified the effect of amoxicillin as treatment for chronic low back pain with Modic changes-subgroup analysis of a randomized trial.

OBJECTIVE: To evaluate potential MRI-defined effect modifiers of amoxicillin treatment in patients with chronic low back pain and type 1 or 2 Modic changes (MCs) at the level of a previous lumbar disc herniation (index level). METHODS: In a prospective trial (AIM), 180 patients (25-64 years; mean age 45; 105 women) were randomised to receive amoxicillin or placebo for 3 months. Primary outcome was the Roland-Morris Disability Questionnaire (RMDQ) score (0-24 scale) at 1 year. Mean RMDQ score difference between the groups at 1 year defined the treatment effect; 4 RMDQ points defined the minimal clinically important effect. Predefined baseline MRI features of MCs at the index level(s) were investigated as potential effect modifiers. The predefined primary hypothesis was a better effect of amoxicillin when short tau inversion recovery (STIR) shows more MC-related high signal. To evaluate this hypothesis, we pre-constructed a composite variable with three categories (STIR1/2/3). STIR3 implied MC-related STIR signal increases with volume ≥ 25% and height > 50% of vertebral body and maximum intensity increase ≥ 25% and presence on both sides of the disc. As pre-planned, interaction with treatment was analysed using ANCOVA in the per protocol population (n = 155). RESULTS: The STIR3 composite group (n = 41) and STIR signal volume ≥ 25% alone (n = 45) modified the treatment effect of amoxicillin. As hypothesised, STIR3 patients reported the largest effect (- 5.1 RMDQ points; 95% CI - 8.2 to - 1.9; p for interaction = 0.008). CONCLUSIONS: Predefined subgroups with abundant MC-related index-level oedema on STIR modified the effect of amoxicillin. This finding needs replication and further support. KEY POINTS: • In the primary analysis of the AIM trial, the effect of amoxicillin in patients with chronic low back pain and type 1 or 2 MCs did not reach the predefined cut-off for clinical importance. • In the present MRI subgroup analysis of AIM, predefined subgroups with abundant MC-related oedema on STIR reported an effect of amoxicillin. • This finding requires replication and further support.

The effect of infliximab in patients with chronic low back pain and Modic changes (the BackToBasic study): study protocol of a randomized, double blind, placebo-controlled, multicenter trial.

BACKGROUND: Low back pain is common and a significant number of patients experience chronic low back pain. Current treatment options offer small to moderate effects. Patients with vertebral bone marrow lesions visualized as Modic changes on magnetic resonance imaging may represent a subgroup within the low back pain population. There is evidence for inflammatory mediators being involved in development of Modic changes; hence, suppression of inflammation could be a treatment strategy for these patients. This study examines the effect of anti-inflammatory treatment with the TNF-α inhibitor infliximab in patients with chronic low back pain and Modic changes. METHODS/DESIGN: The BackToBasic trial is a multicenter, double blind, randomized controlled trial conducted at six hospitals in Norway, comparing intravenous infusions with infliximab with placebo. One hundred twenty-six patients aged 18-65 with chronic low back pain and type 1 Modic changes will be recruited from secondary care outpatients' clinics. The primary outcome is back pain-specific disability at day 154 (5 months). The study is designed to detect a difference in change of 10 (SD 18) in the Oswestry Disability Index at day 154/ 5 months. The study also aims to refine MRI-assessment, investigate safety and cost-effectiveness and explore the underlying biological mechanisms of Modic changes. DISCUSSION: Finding treatments that target underlying mechanisms could pose new treatment options for patients with low back pain. Suppression of inflammation could be a treatment strategy for patients with low back pain and Modic changes. This paper presents the design of the BackToBasic study, where we will assess the effect of an anti-inflammatory treatment versus placebo in patients with chronic low back pain and type 1 Modic changes. The study is registered at ClinicalTrials.gov under the identifier NCT03704363 . The EudraCT Number: 2017-004861-29.

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).

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.

Association of Modic change types and their short tau inversion recovery signals with clinical characteristics- a cross sectional study of chronic low back pain patients in the AIM-study.

BACKGROUND: Modic Changes (MCs, magnetic resonance imaging (MRI) signal changes in the vertebral bone marrow extending from the vertebral endplate) may represent a subgroup of nonspecific chronic low back pain that could benefit from a specific management. The primary aim was to compare clinical characteristics between patients with type 1 versus type 2 MCs. The secondary aim was to explore associations between clinical characteristics and MC related short tau inversion recovery (STIR) signals. METHODS: This cross-sectional study used baseline data prospectively collected between 2015 and 2017 on the 180 patients included in the AIM-study (Antibiotics In Modic changes), a randomized controlled trial in a Norwegian hospital out-patient setting of patients with chronic low back pain, a lumbar disc herniation within the last 2 years, low back pain intensity score ≥ 5 (on a 0-10 scale) and current type 1 or type 2 MCs at the previously herniated lumbar disc level. We used prespecified clinical characteristics including self-report measures, physiologic measures and functional measures from clinical history and examination. The diagnostic accuracy of various clinical characteristics to discriminate between patients with type 1 MCs (with or without additional type 2 MCs) and patents with type 2 MCs only (not type 1) were assessed by calculating the area under the receiver-operating curve. We assessed the correlations of clinical characteristics with details of MC related STIR signal increase. RESULTS: No clinical characteristic differed between patients with type 1 (n = 118) versus type 2 (but not type 1) (n = 62) MCs. The clinical characteristics showed no/minor differences or no/weak correlations with MC related STIR signal increase. Patients with a positive Springing test (at any lumbar level) had slightly less volume of STIR signal increase than those with a negative test (mean difference 1.3 on a 0-48 scale, 95% CI 0.3 to 2.3). CONCLUSION: Clinical characteristics were similar for patients with type 1 MCs and patients with type 2 MCs, and showed no clinically relevant correlations with MC related STIR signal increase. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323412, First registered 23 December 2014.

Cost-utility analysis of antibiotic treatment in patients with chronic low back pain and Modic changes: results from a randomised, placebo-controlled trial in Norway (the AIM study).

OBJECTIVE: To evaluate the cost-utility of 100 days of antibiotics in patients with chronic low back pain (LBP) and type I or II Modic changes included in the Antibiotic treatment In patients with chronic low back pain and Modic changes (AIM) study. DESIGN: A cost-utility analysis from a societal and healthcare perspective alongside a double-blinded, parallel group, placebo, multicentre trial. SETTING: Hospital outpatient clinics at six hospitals in Norway. The main results from the AIM study showed a small effect in back-related disability in favour of the antibiotics group, and slightly larger in those with type I Modic changes, but this effect was below the pre-defined threshold for clinically relevant effect. PARTICIPANTS: 180 patients with chronic LBP, previous disc herniation and Modic changes type I (n=118) or type II (n=62) were randomised to antibiotic treatment (n=89) or placebo-control (n=91). INTERVENTIONS: Oral treatment with either 750 mg amoxicillin or placebo three times daily for 100 days. MAIN OUTCOME MEASURES: Quality-adjusted life years (QALYs) by EuroQoL-5D over 12 months and costs for healthcare and productivity loss measured in Euro (€1=NOK 10), in the intention-to-treat population. Cost-utility was expressed in incremental cost-effectiveness ratio (ICER). RESULTS: Mean (SD) total cost was €21 046 (20 105) in the amoxicillin group and €19 076 (19 356) in the placebo group, mean difference €1970 (95% CI; -3835 to 7774). Cost per QALY gained was €24 625. In those with type I Modic changes, the amoxicillin group had higher healthcare consumption than the placebo group, resulting in €39 425 per QALY gained. Given these ICERs and a willingness-to-pay threshold of €27 500 (NOK 275 000), the probability of amoxicillin being cost-effective was 51%. Even when the willingness-to-pay threshold increased to €55 000, the probability of amoxicillin being cost-effective was never higher than 53%. CONCLUSIONS: Amoxicillin treatment showed no evidence of being cost-effective for people with chronic LBP and Modic changes during 1-year follow-up. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02323412.

Association between vitamin D and fatigue in patients with rheumatoid arthritis: a cross-sectional study.

OBJECTIVES: In rheumatoid arthritis (RA), fatigue is an important complaint with a significant impact on quality of life. Vitamin D has modulatory effects on cells of the immune system and may potentially affect RA disease activity and thereby RA-related fatigue. The purpose of this study was to explore associations between fatigue and vitamin D status in patients with RA. DESIGN: Hypothesis-generating cross-sectional study. SETTING: Scheduled follow-up visits at a hospital-based general rheumatology clinic. PARTICIPANTS: Patients (n=169) with established RA. PRIMARY OUTCOME MEASURES AND ANLYSES: Fatigue, assessed by the Chalder fatigue questionnaire, and serum concentrations of 25-hydroxyvitamin D (25(OH)D), assessed by liquid chromatography-tandem mass spectrometry. Associations were analysed by correlation, and multivariate linear regression with adjustments for age, sex, body mass index, RA disease activity as measured by the Disease Activity Score 28-joint count C reactive protein (DAS28-CRP), psychological distress, pain and sleep. Fatigue was also compared across four groups based on the levels of serum 25(OH)D with cut points at 30, 50 and 75 nmol/L using one-way analysis of variance. RESULTS: Two-thirds of the patients (116/169, 69%) were classified with low RA disease activity, that is, a DAS28-CRP score below 3.2. Their mean (SD) serum 25(OH)D concentration was 56.3 (21.2) nmol/L, with 77 (45.6%) having values below 50 nmol/L and 12 patients (7.1%) below 30 nmol/L. The correlation between fatigue and serum concentrations of 25(OH)D was weak and not statistically significant, r = -0.14 (95% CI: -0.29 to 0.03, p=0.08). In the multivariate model, fatigue was significantly associated with RA disease activity, psychological distress and pain, but not with serum 25(OH)D. Fatigue did not differ across groups with varying levels of serum 25(OH)D. CONCLUSION: This cross-sectional study found no evidence of association between vitamin D and fatigue in patients with RA.

New insight to the characteristics and clinical course of clusters of patients with imaging confirmed disc-related sciatica.

BACKGROUND: Referral to secondary care is common for a considerable proportion of patients with persistent sciatica symptoms. It is unclear if information from clinical assessment can further identify distinct subgroups of disc-related sciatica, with perhaps different clinical courses. AIMS: This study aims to identify and describe clusters of imaging confirmed disc-related sciatica patients using latent class analysis, and compare their clinical course. METHODS: The study population were 466 patients with disc-related sciatica. Variables from clinical assessment were included in the analysis. Characteristics of the identified clusters were described and their clinical course over 2 years was compared. RESULTS: A four-cluster solution was optimal. Cluster 1 (n = 110) had mild back and leg pain; cluster 2 (n = 59) had moderate back and leg pain; cluster 3 (n = 158) had mild back pain and severe leg pain; cluster 4 (n = 139) had severe back and leg pain. Patients in cluster 4 had the most severe profile in terms of disability, distress and comorbidity and the lowest reported global change and the smallest proportion of patients with a successful outcome at 2 years. Of the 135 patients who underwent surgery, 42% and 41% were in clusters 3 and 4, respectively. CONCLUSIONS: Using a strict diagnosis of sciatica, this work identified four clusters of patients primarily differentiated by back and leg pain severity. Patients with severe back and leg pain had the most severe profile at baseline and follow-up irrespective of intervention. This simple classification system may be useful when considering prognosis and management with sciatica patients. SIGNIFICANCE: Using data from a large observational prospective study, this work identifies four distinct clusters of patients with imaging confirmed disc-related sciatica. This classification could be used when considering prognosis and management with sciatica patients at their initial consultation.