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.publishedVersio

Amoxicillin did not Reduce Modic Change Oedema 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.publishedVersio

Amoxicillin did not Reduce Modic Change Oedema 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. To assess the effect of amoxicillin versus placebo in reducing Modic change (MC) oedema in patients with chronic low back pain (LBP). Summary of Background Data. The AIM study showed a small, clinically insignificant effect of amoxicillin on pain-related disability in patients with chronic LBP and MC type 1 (oedema type) on magnetic resonance imaging (MRI). Methods. A total of 180 patients were randomised to receive 100 days of amoxicillin or placebo. MC oedema was assessed on MRI at baseline and one-year follow-up. Per-protocol analyses were conducted in subgroups with MC oedema on short tau inversion recovery (STIR) or T1/T2-weighted MRI at baseline. MC oedema reductions (yes/no) in STIR and T1/T2-series were analysed separately. The effect of amoxicillin in reducing MC oedema was analysed using logistic regression adjusted for prior disc surgery. To assess the effect of amoxicillin versus placebo within the group with the most abundant MC oedema 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 oedema reduction). Results. Compared to placebo, amoxicillin did not reduce MC oedema on STIR (volume/intensity) in the total sample with oedema on STIR at baseline (odds ratio 1.0, 95% confidence interval (95%CI) [0.5, 2.0]; n=141) or within the STIR3 group (probability of oedema 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 oedema in T1/T2-series (volume of the type 1 part of MCs) (odds ratio 1.0, 95%CI [0.5, 2.3], n=104). Oedema declined in >50% of patients in both treatment groups. Conclusions. From baseline to one-year follow-up, amoxicillin did not reduce MC oedema compared with placebo. Level of Evidence. Level 2

Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement

Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifiable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood. We explored the pathobiology of these lesions using profiling of gene expression in blood, coupled with an edema-sensitive MRI technique known as short tau inversion recovery (STIR) imaging. STIR images and total RNA from blood were collected from 96 patients with chronic LBP and MC type I, the most inflammatory MC state. We found the expression of 37 genes significantly associated with STIR signal volume, ten genes with edema abundancy (a constructed combination of STIR signal volume, height, and intensity), and one gene with expression levels significantly associated with maximum STIR signal intensity. Gene sets related to interferon signaling, mitochondrial metabolism and defense response to virus were identified as significantly enriched among the upregulated genes in all three analyses. Our results point to inflammation and immunological defense as important players in MC biology in patients with chronic LBP.publishedVersio

Post-covid medical complaints following infection with SARS-CoV-2 Omicron vs Delta variants

The SARS-CoV-2 Omicron (B.1.1.529) variant has been associated with less severe acute disease, however, concerns remain as to whether long-term complaints persist to a similar extent as for earlier variants. Studying 1 323 145 persons aged 18-70 years living in Norway with and without SARS-CoV-2 infection in a prospective cohort study, we found that individuals infected with Omicron had a similar risk of post-covid complaints (fatigue, cough, heart palpitations, shortness of breath and anxiety/depression) as individuals infected with Delta (B.1.617.2), from 14 to up to 126 days after testing positive, both in the acute (14 to 29 days), sub-acute (30 to 89 days) and chronic post-covid (≥90 days) phases. However, at ≥90 days after testing positive, individuals infected with Omicron had a lower risk of having any complaint (43 (95%CI = 14 to 72) fewer per 10,000), as well as a lower risk of musculoskeletal pain (23 (95%CI = 2-43) fewer per 10,000) than individuals infected with Delta. Our findings suggest that the acute and sub-acute burden of post-covid complaints on health services is similar for Omicron and Delta. The chronic burden may be lower for Omicron vs Delta when considering musculoskeletal pain, but not when considering other typical post-covid complaints

Post-covid medical complaints following infection with SARS-CoV-2 Omicron vs Delta variants

The SARS-CoV-2 Omicron (B.1.1.529) variant has been associated with lesssevere acute disease, however, concerns remain as to whether long-termcomplaints persist to a similar extent as for earlier variants. Studying 1 323 145persons aged 18-70 years living in Norway with and without SARS-CoV-2infection in a prospective cohort study, we found that individuals infected withOmicron had a similar risk of post-covid complaints (fatigue, cough, heartpalpitations, shortness of breath and anxiety/depression) as individualsinfected with Delta (B.1.617.2), from 14 to up to 126 days after testing positive,both in the acute (14 to 29 days), sub-acute (30 to 89 days) and chronic post-covid (≥90 days) phases. However, at ≥90 days after testing positive, indivi-duals infected with Omicron had a lower risk of having any complaint (43 (95%CI = 14 to 72) fewer per 10,000), as well as a lower risk of musculoskeletal pain(23 (95%CI = 2-43) fewer per 10,000) than individuals infected with Delta. Ourfindings suggest that the acute and sub-acute burden of post-covid complaintson health services is similar for Omicron and Delta. The chronic burden may belower for Omicron vs Delta when considering musculoskeletal pain, but notwhen considering other typical post-covid complaints

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

Clinical effect modifiers of antibiotic treatment in patients with chronic low back pain and Modic changes - secondary analyses of a randomised, placebocontrolled 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

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