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Chronic postsurgical pain (CPSP) is a significant detriment to post-surgical recovery and a risk factor for prolonged opioid use. Emerging evidence suggests the estimated heritability for chronic pain is 45% and that genetic factors partially explain individual susceptibility to CPSP. The aim of this study was to systematically review, assess quality and summarize the studies in humans that have investigated genetic factors associated with CPSP. We also conducted a meta-analysis to derive a single effect size for evaluable genetic associations with CPSP. Our comprehensive literature search included review of 21 full-text articles evaluating variants of 69 genes for association with CPSP. We found significant gene variant associations reported for variants/haplotypes of 26 genes involved in neurotransmission, pain signaling, immune responses and neuroactive ligand-receptor interaction, with CPSP. Six variants of five genes (COMT: rs4680 and rs6269, OPRM1: rs1799971, GCH1: rs3783641, KCNS1: rs734784 and TNFA: rs1800629), were evaluated by more than one study and were included in the meta-analysis. At rs734784 (A>G) of KCNS1, presence of G allele marginally increased risk of CPSP (Additive genetic model; Odds ratio: 1.511; 95% CI 1 to 2.284; p-value 0.050), while the other variants did not withstand meta-analyses criteria. Our findings demonstrate the role of genetic factors with different functions in CPSP, and also emphasize that single genetic factors have small effect sizes in explaining complex conditions like CPSP. Heterogeneity in surgical cohorts, population structure and outcome definitions, as well as small number of available studies evaluating same variants, limit the meta-analysis. There is a need for large-scale, homogenous, replication studies to validate candidate genes, and understand the underlying biological networks underpinning CPSP. Perspective: Our systematic review comprehensively describes 21 studies evaluating genetic association with CPSP, and limitations thereof. A meta-analysis of 6 variants (5 genes) found marginally increased risk for CPSP associated with rs734784 A>G of the potassium voltage-gated channel gene (KCNS1). Understanding genetic predisposition for CPSP will enable prediction and personalized management.
Learn More >Preoperative anxiety is common in patients undergoing elective surgery and is closely related to postoperative hyperalgesia. In this study, a single prolonged stress (SPS) model was used to induce preoperative anxiety-like behavior in rats 24h before the surgery. We found that SPS exacerbated the postoperative pain and elevated the level of serum corticosterone (CORT). Previous studies have shown that glucocorticoid (GC) is associated with synaptic plasticity, and decreased spinal GABAergic activity can cause hyperalgesia in rodents. Here, SPS rats lumbar spinal cord showed reduced glutamic acid decarboxylase-65 (GAD65), glutamic acid decarboxylase-67 (GAD67), GABA type A receptor alpha 1 subunit (GABAA α1), and GABA type A receptor gamma 2 subunit (GABAA γ2) , indicating an impairment of GABAergic system. Furthermore, Neuronal PAS domain protein 4 (Npas4) was also reduced in rats after SPS stimulation, which has been reported to promote GABAergic synapse development. Then intraperitoneal injection of RU486 (a glucocorticoid receptor antagonist) rather than spironolactone (a mineralocorticoid receptor antagonist) was found to relieve SPS induced hyperalgesia and reverse Npas4 reduction and the impairment of GABAergic system. Further over-expressing Npas4 could also restore the damage of GABAergic system caused by SPS while interfering with Npas4 caused an opposite effect. Finally, after stimulation of rat primary spinal cord neurons with exogenous CORT in vitro, Npas4 and GABAergic markers were also down-regulated, and RU486 reversed that. Together, our results demonstrated that preoperative anxiety led to GABAergic system impairment in spinal cord and thus caused hyperalgesia due to glucocorticoid-induced down-regulation of Npas4.
Learn More >Structural and functional analyses of the human claustrum, a poorly understood telencephalic gray matter structure, are hampered by its sheet-like anatomical arrangement. Here, we first describe a functional magnetic resonance imaging (fMRI) method to reveal claustrum signal with no linear relationship with adjacent regions in human subjects. We applied this approach to resting state functional connectivity (RSFC) analysis of the claustrum at high resolution (1.5 mm isotropic voxels) using a 7T dataset (n = 20) and a separate 3T dataset for replication (n = 35). We then assessed claustrum activation during performance of a cognitive task, the multi-source interference task, at 3T (n = 33). Extensive functional connectivity was observed between claustrum and cortical regions associated with cognitive control, including anterior cingulate, prefrontal and parietal cortices. Cognitive task performance was associated with widespread activation and deactivation that overlapped with the cortical areas showing functional connectivity to the claustrum. Furthermore, during high cognitive conflict conditions of the task, the claustrum was significantly activated at the onset of the task, but not during the remainder of the difficult condition. Both of these findings suggest that the human claustrum can be functionally isolated with fMRI, and that it may play a role in cognitive control, and specifically task switching, independent of sensorimotor processing.
Learn More >Trigeminal neuralgia (TN) commonly results in pain behaviors and cognitive impairment. Convincing evidence suggests that TWIK-related spinal cord K+ (TRESK) exerts antinociceptive and neuroprotective effects. However, its possible potentials in TN remain unclear. TN model was established in rats by generating an infraorbital nerve chronic constriction injury (ION-CCI), and rats received intrathecal injections of TRESK overexpressing lentivirus (LV-TRESK) and siRNA expression vector targeted against TRESK (si-TRESK) into the trigeminal ganglions. Mechanical allodynia was evaluated by mechanical withdrawal threshold (MWT). Cognitive capacity was tested using Morris water maze (MWM). The TRESK expression was determined by quantitative real-time PCR (qRT-PCR) and western blotting. Results showed that the mRNA and protein levels of TRESK were significantly downregulated in trigeminal ganglions in injured rats. Intrathecal treatment with TRESK reduced mechanical allodynia and relieved learning and memory deficits in TN rats, while si-TRESK injection caused neuropathic pain and cognitive deficits. In summary, the present study concluded that TRESK ameliorated pain-associated behaviors and cognitive deficits, which was useful as an alternative approach in management of TN.
Learn More >The ACCURATE randomized, controlled trial compared outcomes of dorsal root ganglion (DRG) stimulation versus tonic spinal cord stimulation (SCS) in 152 subjects with chronic lower extremity pain due to complex regional pain syndrome (CRPS) type I or II. This ACCURATE sub-study was designed to evaluate whether therapy habituation occurs with DRG stimulation as compared to SCS through 12-months. A modified intention-to-treat analysis was performed to assess percentage pain relief (PPR) and responder rates at follow-up visits (end-of-trial, 1, 3, 6, 9, 12-months post-permanent implant) for all subjects that completed trial stimulation (DRG:N=73, SCS_N=72). For both groups, mean PPR was significantly greater at end-of-trial (DRG:82.2%, SCS:77.0%) than all other follow-ups. Following permanent DRG system implantation, none of the time points were significantly different from one another in PPR (range:69.3-73.9%). For the SCS group, PPR at 9-months (58.3%) and 12-months (57.9%) was significantly less than at 1-month (66.9%). The responder rate also decreased for the SCS group from 1-month (68.1%) to 12-months (61.1%). After stratifying by diagnosis, it was found that only the CRPS-I population had diminishing pain relief with SCS. DRG stimulation resulted in more stable pain relief through 12-months, while tonic SCS demonstrated therapy habituation at 9- and 12-months. Trial Registration: The ACCURATE study was registered at ClinicalTrials.gov with Identifier NCT01923285. Perspective: This article reports on an ACCURATE sub-study, which found that long-term therapy habituation occurred at 12-months with SCS, but not DRG stimulation, in patients with CRPS. The underlying mechanisms of action for these results remain unclear, although several lines of inquiry are proposed.
Learn More >The Hospital Anxiety and Depression Scale (HADS) is a scale originally developed for the assessment of anxiety and depression in hospitalized patients. Despite its wide diffusion, the HADS factorial structure has displayed inconsistent results, leaving doubts about its use in chronic musculoskeletal pain. The purpose of this study was to thoroughly assess the factorial structure of the HADS in patients with chronic pain and to give guidance for a potential refinement. Data from 2522 patients with chronic pain from the Amsterdam Pain (AMS-PAIN) cohort were analyzed through: (1) exploratory bifactor analysis based on a Schmid-Leiman orthogonalization, (2) confirmatory factor analysis comparing a unidimensional model, the original correlated factors model and a bifactor model, (3) item response theory (IRT) analysis based on the graded response model. The results of the confirmatory factor analysis and of the IRT analysis were then cross – validated in an independent sample of patients with chronic pain (n = 8604). Both exploratory and confirmatory analyses revealed the presence of a strong general emotional distress factor, suggesting that the HADS can be used as a unidimensional scale. The IRT analysis led to the exclusion of three items and to the recoding of one item. The refined 11-item HADS scale was successfully cross-validated and confirmed as a unidimensional, locally independent, monotonic and reliable scale. Perspective: An 11-item shorter version of the HADS could be used to measure emotional distress in patients with chronic musculoskeletal pain. Given its unidimensionality, the use of its total score seems appropriate.
Learn More >A descriptive analysis of secondary data.
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