Elina Iordanova Schistad

Pain Intensity the First Year after Lumbar Disc Herniation Is Associated with the A118G Polymorphism in the Opioid Receptor Mu 1 Gene: Evidence of a Sex and Genotype Interaction

Earlier studies have shown that the single nucleotide polymorphism (SNP) A118G (rs1799971) in the opioid receptor mu 1 (OPRM1) gene may affect pain sensitivity. In the present study we investigated whether the A118G SNP could predict clinical outcome regarding progression of pain intensity and disability in patients with low back pain and sciatica after lumbar disc herniation. Patients (n = 258) with lumbar disc herniation and sciatic pain, all European-Caucasian, were recruited from two hospitals in Norway. Pain and disability were rated on a visual analog scale (VAS), by McGill Sensory Questionnaire and by Oswestry Disability Index (ODI) over a 12 months period. The data revealed a significant interaction between sex and A118G genotype regarding the pain intensity during the 12 months (VAS, p = 0.002; McGill, p = 0.021; ODI, p = 0.205, repeated-measures ANOVA). We found that */G women had a slower recovery rate than the */G men. Actually, the */G women had 2.3 times as much pain as the */G men 12 months after the disc herniation (VAS, p = 0.043, one-way ANOVA; p = 0.035, Tukey HSD). In contrast, the A/A women and A/A men seemed to have almost exactly the same recovery rate. The present data suggest that OPRM1 G allele increases the pain intensity in women, but has a protective effect in men the first year after disc herniation.

The COMT rs4680 Met allele contributes to long-lasting low back pain, sciatica and disability after lumbar disc herniation.

The COMT enzyme metabolizes catecholamines and thus modulates adrenergic, noradrenergic and dopaminergic signaling. A functional polymorphism in the gene encoding this enzyme, i.e. the COMT Val158Met SNP that reduces enzyme activity, has previously been linked to pain sensitivity.

Serum levels of the pro-inflammatory interleukins 6 (IL-6) and -8 (IL-8) in patients with lumbar radicular pain due to disc herniation: A 12-month prospective study

Earlier studies indicate that lumbar radicular pain after disc herniation may be associated with a local inflammation induced by leakage of nucleus pulposus (NP) into the spinal canal and neuroforamen. In the present study we addressed the role of two interleukins, IL-6 and IL-8 in such long-lasting lumbar radicular pain. All 127 patients were recruited from Oslo University Hospital, Ullevål, Norway. At inclusion, 6weeks and 12months, serum concentrations of IL-6 and IL-8 were analyzed by enzyme-linked immunosorbent assay (ELISA) and pain intensity was reported on a 0-10cm visual analog scale (VAS). Significantly higher levels of IL-6 and IL-8 in serum were found in patients with VAS ⩾3 at 12months, than in patient with VAS <3 at 12months (p⩽0.01, test of between-subjects effect, repeated measures ANOVA, covariates for IL-6: age, smoking; covariates for IL-8: smoking, treatment). For the first time we show that chronic lumbar radicular pain may be associated with a persistent increase of the pro-inflammatory substances IL-6 and IL-8 in serum after disc herniation.

Association between baseline IL-6 and 1-year recovery in lumbar radicular pain

In the present study, the influence of cytokines on 1‐year recovery in lumbar radicular pain was examined.

The MMP1 rs1799750 2G allele is associated with increased low back pain, sciatica, and disability after lumbar disk herniation.

Objectives:Previous studies indicate that genetic variants in genes encoding proteins like matrix metalloproteinase (MMP) enzymes may affect degeneration of the intervertebral disk. One such genetic variant is a single nucleotide polymorphism insertion in the promoter region of the MMP1 gene, that is, the MMP1 rs1799750 2G allele, which increases the MMP1 expression in vitro. In this study, we examined whether the MMP1 rs1799750 2G allele might be associated with disk degeneration and clinical outcome after lumbar disk herniation. Materials and Methods:A total of 260 patients with lumbar disk herniation and sciatic pain were included in this study and genotyped for the MMP1 rs1799750 2G allele. Results:The present data showed no differences in the frequency of the MMP1 2G allele in patients recently diagnosed with disk herniation compared with pain-free controls. Moreover, in the patients, the MMP1 2G allele was not directly related to the disk degeneration. However, our data demonstrated that the MMP1 2G allele was associated with both pain and disability, that is, increased visual analog scale score, McGill Pain Questionnaire score, and Oswestry Disability Index score. Clearly, the patients homozygous for the 2G allele had more pain and reduced function compared with those carrying the 1G allele. Discussions:Our findings suggest that the MMP1 rs1799750 2G/2G genotype may contribute to low back pain, sciatica, and disability after lumbar disk herniation.

The interleukin-1α gene C>T polymorphism rs1800587 is associated with increased pain intensity and decreased pressure pain thresholds in patients with lumbar radicular pain.

Objectives:Previous studies have suggested that many inflammatory cytokines, including interleukin (IL)-1&agr;, may be associated with lumbar radicular pain after disk herniation. In the present study, we examined how variability of the IL-1&agr; gene affects pain intensity and the pressure pain threshold (PPT) in patients with symptomatic disk herniation. Materials and Methods:A total of 121 patients with lumbar radicular pain due to disk herniation were recruited from Oslo University Hospital, Norway, and followed up at 6 weeks and 12 months. The primary outcome measures were pain intensity scores for the lower back and legs using a visual analog pain scale (VAS) and PPT for the gluteal muscles. Genotyping was carried out using a predesigned TaqMan assay for IL-1&agr; rs1800587. The effect of the IL-1&agr; genotype on the VAS and PPT was analyzed by repeated measure analyses of variance. Results:The IL-1&agr; gene C>T polymorphism rs1800587 affected VAS and PPT scores in patients with symptomatic disk herniation. Patients with the CT/TT genotype reported a higher VAS leg pain intensity (P=0.002) and also a lower PPT in the gluteal muscles (left P=0.016; right P=0.016) compared with patients with the CC genotype during 1 year of follow-up. Discussion:The present data show that the IL-1&agr; CT/TT genotype rs1800587 may be associated with increased pain intensity and corresponding reduced PPT during the first year after disk herniation.

Role of IL1A rs1800587, IL1B rs1143627 and IL1RN rs2234677 Genotype Regarding Development of Chronic Lumbar Radicular Pain; a Prospective One-Year Study

Previous studies indicate that lumbar radicular pain following disc herniation may be associated with release of several pro-inflammatory mediators, including interleukin-1 (IL1). In the present study, we examined how genetic variability in IL1A (rs1800587 C>T), IL1B (rs1143627 T>C) and IL1RN (rs2234677 G>A) influenced the clinical outcome the first year after disc herniation. Patients (n = 258) with lumbar radicular pain due to disc herniation were recruited from two hospitals in Norway. Pain and disability were measured by visual analogue scale (VAS) and Oswestry Disability Index (ODI) over a 12 month period. The result showed that patients with the IL1A T allele, in combination with the IL1RN A allele had more pain and a slower recovery than other patients (VAS p = 0.049, ODI p = 0.059 rmANOVA; VAS p = 0.003, ODI p = 0.050 one-way ANOVA at 12 months). However, regarding the IL1B/IL1RN genotype, no clear effect on recovery was observed (VAS p = 0.175, ODI p = 0.055 rmANOVA; VAS p = 0.105, ODI p = 0.214 one-way ANOVA at 12 months). The data suggest that the IL1A T/IL1RN A genotype, but not the IL1B T/IL1RN A genotype, may increase the risk of a chronic outcome in patients following disc herniation.

C-reactive protein and cold-pressor tolerance in the general population: the Tromsø Study

Abstract The aim of this study was to examine whether increases in severity of subclinical inflammation, measured by high-sensitivity C-reactive protein (hs-CRP), increased experimental pain sensitivity, measured by cold-pressor tolerance, and to test whether this relationship is independent of chronic pain. A large population-based study from 2007 to 2008, the sixth Tromsø Study, provided data from 12,981 participants. For the present analysis, complete data for 10,274 participants (age: median 58 years) were available. The main outcome measure was cold-pressor tolerance, tested by placing the dominant hand in circulating cold water (3°C) for a maximum of 106 seconds. Cox proportional hazard models, treating hand withdrawal during the cold-pressor test as the event and enduring the full test time as censored data, were used to investigate the relationship between hs-CRP levels (⩽3 or >3 mg/L) and cold-pressure tolerance. The fully adjusted model was controlled for age, sex, education, body mass index, smoking status, alcohol consumption, emotional distress, statin usage, and self-reported presence of chronic pain. Additional analysis was performed in participants without chronic pain. Higher levels of hs-CRP were negatively related to cold-pressor tolerance (hazard ratio [HR] = 1.24, 95% confidence interval [CI], 1.12-1.37, P < 0.001), adjusted for age and sex. This relationship remained essentially unaltered after controlling for potential confounders (HR = 1.22, 95% CI, 1.09-1.36, P < 0.001), as well as for the presence of chronic pain (HR = 1.22, 95% CI, 1.09-1.36, P < 0.001). The present data show that subclinical inflammation is related to increased pain sensitivity, suggesting a potential role of inflammation in experimental pain which may be of importance for the development of clinical pain.

Genetic predictors of recovery in low back and lumbar radicular pain

Abstract Previous data suggest that persistent back pain may be associated with genetic variability. In this study, we assessed the correlation between 8 genetic polymorphisms (VDR, COL11, MMP1, MMP9, IL-1&agr;, IL-1RN, OPRM1, COMT) and pain recovery in patients with low back pain (LBP) and lumbar radicular pain (LRP). In total, 296 patients with LBP or LRP were followed for 5 years. The patients underwent standardized clinical examination and completed pain and function questionnaires. Univariate linear regression associations with P values <0.1 were included in the multivariable analysis, adjusting for pain intensity at baseline, age, sex, smoking, body mass index, and LBP or LRP. Pain intensity at 5-year follow-up was associated with VDR rs731236 (B = −0.5, 95% confidence interval [CI] −0.9 to −0.1, P = 0.017), MMP9 rs17576 (B = 0.5, 95% CI 0.1-0.9, P = 0.022), and OPRM1 rs1799971 (B = −0.8, 95% CI −1.4 to −0.2, P = 0.006) in the univariate analyses. MMP9 rs17576 and OPRM1 rs1799971 remained significant (B = 0.4, 95% CI 0.05-0.8, P = 0.026 and B = −0.8, 95% CI −1.3 to −0.2, P = 0.007) in the multivariable model. Thus, the data demonstrated that the rare allele of MMP9 rs17576 was associated with poor pain recovery, whereas the rare allele of OPRM1 rs1799971 was associated with better pain recovery at 5-year follow-up in the LBP and LRP patients. In particular, the present study suggested that the OPRM1 rs179971 A>G in men was associated with better long-term pain recovery. In men, the OPRM1 rs1799971 explained 4.7% of the variance of pain intensity. We conclude that the MMP9 rs17576 and OPRM1 rs1799971 genotypes may affect 5-year recovery in patients with LBP and LRP.

Local up-regulation of interferon-γ (IFN-γ) following disc herniation is involved in the inflammatory response underlying acute lumbar radicular pain

&NA; Lumbar radicular pain after disc herniation may be associated with release of pro‐inflammatory cytokines from nucleus pulposus (NP) tissue. In the present study we examined the role of interferon‐&ggr; (IFN‐&ggr;) and cluster of differentiation 68 (CD68) in the acute phase of this process. First, in an animal model mimicking the clinical situation after disc herniation, the role of IFN‐&ggr; close to the dorsal nerve roots was studied. Next, in patients with lumbar radicular pain due to disc herniation, we examined how two single nucleotide polymorphisms (SNPs; rs2069705 and rs2069718) are important for the IFN‐&ggr; expression influenced the pain behavior. The animal data demonstrated a significant increase in the nociceptive activity at the spinal level after local application of NP and IFN‐&ggr; onto the dorsal nerve roots. A positive correlation between IFN‐&ggr; and CD68 in the NP tissue was also demonstrated. In the patients, a significant increase in Oswestry Disability Index (ODI) score was observed in carriers of the IFN‐&ggr; SNPs; rs2069705 A and rs2069718 G alleles. The present data suggest that IFN‐&ggr; close to the dorsal nerve roots may contribute to the pathogenesis, the nociceptive activity and the pain behavior following lumbar disc herniation.