Linda M. Pedersen

Codeine plus paracetamol versus paracetamol in longer-term treatment of chronic pain due to osteoarthritis of the hip. A randomised, double-blind, multi-centre study

&NA; This randomized, double‐blind, multi‐centre study was undertaken to evaluate the efficacy and safety of treatment for 4 weeks with codeine plus paracetamol versus paracetamol in relieving chronic pain due to osteoarthritis of the hip. A total of 158 outclinic patients entered the study. Eighty‐three patients (mean age 66 years) were treated with codeine 60 mg plus paracetamol 1 g 3 times daily, and 75 patients (mean age 67 years) with paracetamol 1 g 3 times daily. Ibuprofen 400 mg was prescribed as rescue medication. Due to an unexpected high rate of adverse drug reactions, the study was closed before the planned 400 patients had entered. Over weeks 1–4, 87%, 64%, 61% and 52% of patients in the codeine plus paracetamol group, and 38%, 31%, 22% and 29% of patients in the paracetamol group had one or more adverse drug reactions. Significantly more patients in the codeine plus paracetamol group had adverse drug reactions in each of the 4 weeks. Nausea, dizziness, vomiting and constipation were predominant adverse reactions in the codeine plus paracetamol group. During the first week of treatment, 30 patients (36%) in the codeine plus paracetamol group and 9 (12%) in the paracetamol group dropped out. As evaluated from patients completing the first week of treatment, the pain intensity during that week compared to their baseline pain was significantly lower in the codeine plus paracetamol group than in the paracetamol group. Moreover, during the first week the paracetamol group received rescue medicine significantly more frequently. In conclusion, when evaluated after 7 days of treatment, the daily addition of codeine 180 mg to paracetamol 3 g significantly reduced the intensity of chronic pain due to osteoarthritis of the hip joint. However, several adverse drug reactions, mainly of the gastrointestinal tract, and the larger number of patients withdrawing from treatment means that the addition of such doses of codeine cannot be recommended for longer‐term treatment of chronic pain in elderly patients.

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.

Spinal cord long-term potentiation (LTP) is associated with increased dorsal horn gene expression of IL-1β, GDNF and iNOS

Previous data show that spinal cord long‐term potentiation (LTP) can be induced by electrical high‐frequency stimulation (HFS) conditioning applied to the sciatic nerve. It has been suggested that the cellular events leading to this form of plasticity may contribute to central hyperalgesia. In the present study, extracellular recordings from single dorsal horn neurons and quantitative real‐time reverse‐transcriptase polymerase chain reaction (RT‐PCR) on rat dorsal horn tissue were used to examine whether maintenance of spinal LTP is associated with changes in gene expression of the proinflammatory interleukin‐1β (IL‐1β), glial cell‐line derived neurotrophic factor (GDNF), inducible nitric oxide synthase (iNOS), p38 mitogen‐activated protein kinase (p38 MAPK), cyclooxygenase 2 (COX2) and tumor necrosis factor α (TNFα). The data demonstrated that the HFS conditioning induced a robust increase in the dorsal horn C‐fibre responses, which outlasted the duration of the experiments of 6 h (p < 0.05, HFS vs. control). Moreover, a significant increase in the expression of mRNA for IL‐1β, GDNF and iNOS were observed 6 h following the HFS conditioning (p < 0.05, HFS vs. control). For the first time we show that spinal cord LTP is associated with an increased dorsal horn expression of the genes for IL‐1β, GDNF and iNOS.

Spinal cord long-term potentiation is attenuated by the NMDA-2B receptor antagonist Ro 25-6981

Aim:  The NR2B‐containing N‐methyl‐d‐aspartate (NMDA) receptors may be involved in a variety of phenomena including synaptic plasticity, memory formation and pain perception. Here we used the NMDA‐2B receptor antagonist Ro 25‐6981 to investigate the role of the NR2B‐containing NMDA receptors in spinal nociception.

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.

Induction of long-term potentiation in single nociceptive dorsal horn neurons is blocked by the CaMKII inhibitor AIP

Neuronal events leading to development of long-term potentiation (LTP) in the nociceptive pathways may be a cellular mechanism underlying central hyperalgesia. Here, we examine whether induction of LTP in nociceptive dorsal horn neurons at depths of 80-500 microm from the cord surface can be affected by spinal application of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. Extracellular recordings from single neurons in intact urethane anesthetized Sprague-Dawley rats were performed, and the neuronal A-fiber and C-fiber responses after sciatic nerve test pulses were defined according to latencies. A clear LTP of the nociceptive transmission following sciatic nerve high-frequency stimulation (HFS) was observed in single neurons in laminae I-IV of the dorsal horn. The increase in the C-fiber response after HFS was blocked in the presence of 2.0 mM AIP (P < 0.05 HFS group versus AIP + HFS group 2 h after conditioning). However, the C-fiber response was not affected by 2.0 mM AIP alone or by vehicle. Thus, our data show that the neuronal process leading to the induction of LTP in the dorsal horn induced by HFS is clearly inhibited by the specific CaMKII inhibitor AIP. It is concluded that CaMKII may be important for the induction of LTP in single nociceptive dorsal horn neurons.

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.

Catechol-O-methyltransferase (COMT) inhibition reduces spinal nociceptive activity.

Several variants of the catechol-O-methyltransferase (COMT) gene have recently been linked to pain sensitivity. In the present study, electrophysiological field potential recordings from the dorsal horn in rats were used to examine the spinal effect of reduced COMT activity. The data demonstrated that 30 mg/kg of the COMT inhibitor OR 486 reduced spinal nociceptive responses to painful stimuli (p<or=0.01, OR 486 vs. vehicle) and attenuated the expression of spinal long-term potentiation (LTP), an often studied model for central sensitization (p<or=0.01, HFS vs. HFS+OR 486). Our findings suggest that low COMT activity may have an antinociceptive effect in the spinal cord.

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.