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Failed back surgery syndrome (FBSS) is a pain condition refractory to therapy, and is characterised by persistent low back pain after spinal surgery. FBSS is associated with severe disability, low quality of life and high unemployment. We are currently unable to identify patients who are at risk of developing FBSS. Patients with chronic low back pain may display signs of central hypersensitivity as assessed by quantitative sensory tests (QST). This can contribute to the risk of developing persistent pain after surgery.
Learn More >How obesity exacerbates migraine and other pain disorders remains unknown. Trigeminal nociceptive processing, crucial in migraine pathophysiology, is abnormal in mice with diet induced obesity. However, it is not known if this is also true in genetic models of obesity. We hypothesized that obese mice, regardless of the model, have trigeminal hyperalgesia. To test this, we first evaluated trigeminal thermal nociception in leptin deficient (ob/ob) and control mice using an operant thermal assay. Unexpectedly, we found significant hypoalgesia in ob/ob mice. Because thermal hypoalgesia also occurs in mice lacking the transient receptor potential vanilloid 1 channel (TRPV1), we tested capsaicin-evoked trigeminal nociception. Ob/ob and control mice had similar capsaicin-evoked nocifensive behaviors, but ob/ob mice were significantly less active after a facial injection of capsaicin than were diet-induced obese mice or lean controls. Conditioned place aversion in response to trigeminal stimulation with capsaicin was similar in both genotypes, indicating normal negative affect and pain avoidance. Supporting this, we found no difference in TRPV1 expression in the trigeminal ganglia of ob/ob and control mice. Finally, we assessed the possible contribution of hyperphagia, a hallmark of leptin deficiency, to the behavior observed in the operant assay. Ob/ob and lean control mice had similar reduction of intake when quinine or capsaicin was added to the sweetened milk, excluding a significant contribution of hyperphagia. In summary, ob/ob mice, unlike mice with diet-induced obesity, have trigeminal thermal hypoalgesia but normal responses to capsaicin, suggesting specificity in the mechanisms by which leptin acts in pain processing.
Learn More >The mechanisms underlying inter-individual variability in analgesic efficacy of non-steroidal anti-inflammatory drugs are not well understood. Therefore, we performed pain phenotyping, functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, inflammation biomarkers, and gene expression profiling in healthy subjects who underwent surgical extraction of bony impacted third molars and were treated with ibuprofen (400 mg; N=19) or placebo (N=10). Analgesic efficacy was not associated with demographic or clinical characteristics, ibuprofen pharmacokinetics, or the degree of cyclooxygenase inhibition by ibuprofen. Compared to partial responders to ibuprofen (N=9, required rescue medication within the dosing interval), complete responders (N=10, no rescue medication) exhibited greater induction of urinary prostaglandin metabolites and serum tumor necrosis factor-α and interleukin-8. Differentially expressed genes in peripheral blood mononuclear cells were enriched for inflammation-related pathways. These findings suggest that a less pronounced activation of the inflammatory prostanoid system is associated with insufficient pain relief on ibuprofen alone and the need for additional therapeutic intervention. This article is protected by copyright. All rights reserved.
Learn More >Implantable Motor Cortex Stimulation (iMCS) has been performed for over 25 years to treat various intractable pain syndromes. Its effectiveness shows to be highly variable and although various studies revealed predictive variables, none of these were found repeatedly. This study uses neural network analysis (NNA) to identify predictive factors of iMCS treatment of intractable pain. A systematic review provided a database of patient data on an individual level of patients who underwent iMCS to treat refractory pain between 1991 and 2017. Responders were defined as patients with a pain relief >40% as measured by numerical rating scale (NRS) score. NNA was carried out to predict outcome of iMCS and to identify predictive factors that impacted the outcome of iMCS. The outcome prediction value of the NNA was expressed as mean accuracy, sensitivity and specificity. The NNA furthermore provided the mean weight of predictive variables, which shows the impact of the predictive variable on the prediction. The mean weight was converted into the mean relative influence (M), a value that varies between 0-100%. A total of 358 patients were included (202 males (56.4%); mean age: 54.2 ±13.3), 201 of which were responders to iMCS. NNA had a mean accuracy of 66.3% and a sensitivity and specificity of 69.8% and 69.4%, respectively. NNA further identified six predictive variables that had a relatively high M: 1) the sex of the patients (M=19.7%); 2) the origin of the lesion (M=15.1%); 3) the preoperative NRS score (M= 9.2%); 4) preoperative use of rTMS (M=7.3%); 5) preoperative intake of opioids (M=7.1%) and; 6) the follow-up period (M= 13.1%). The results from the present study show that these six predictive variables influence the outcome of iMCS and that based on these variables, a fair prediction model can be built to predict outcome after iMCS surgery. PERSPECTIVE: The presented neural network analysis (NNA) analyzed the functioning of computational models and modeled non-linear statistical data. Based on this NNA, six predictive variables were identified which are suggested to be of importance in the improvement of future implantable motor cortex stimulation (iMCS) to treat chronic pain.
Learn More >Atopic dermatitis (AD) is an inflammatory skin disease with a chronic, relapsing course. Clinical features of AD vary by age, duration, and severity but can include papules, vesicles, erythema, exudate, xerosis, scaling, and lichenification. However, the most defining and universal symptom of AD is pruritus. Pruritus or itch, defined as an unpleasant urge to scratch, is problematic for many reasons, particularly its negative impact on quality of life. Despite the profoundly negative impact of pruritus on patients with AD, clinicians and researchers lack standardized and validated methods to objectively measure pruritus. The purpose of this review is to discuss emerging methods to assess pruritus in AD by describing objective patient-centered tools developed or enhanced over the last decade that can be utilized by clinicians and researchers alike.
Learn More >To investigate whether people with chronic low back pain (LBP) show dysfunctional exercise induced hypoalgesia (EIH) in response to repeated contractions of their back muscles during a lifting task.
Learn More >Kappa opioid receptor (KOR) agonists show promise in ameliorating disorders, such as addiction and chronic pain, but are limited by dysphoric and aversive side effects. Clinically beneficial effects of KOR agonists (e.g., analgesia) are predominantly mediated by heterotrimeric G protein signaling, whereas β-arrestin signaling is considered central to their detrimental side effects (e.g., dysphoria/aversion). Here we show that Regulator of G protein Signaling-12 (RGS12), via independent signaling mechanisms, simultaneously attenuates G protein signaling and augments β-arrestin signaling downstream of KOR, exhibiting considerable selectivity in its actions for KOR over other opioid receptors. We previously reported that RGS12-null mice exhibit increased dopamine transporter-mediated dopamine (DA) uptake in the ventral (vSTR), but not dorsal striatum (dSTR), as well as reduced psychostimulant-induced hyperlocomotion; in the current study, we found that these phenotypes are reversed following KOR antagonism. Fast-scan cyclic voltammetry studies of dopamine (DA) release and reuptake suggest that striatal disruptions to KOR-dependent DAergic neurotransmission in RGS12-null mice are restricted to the nucleus accumbens. In both ventral striatal tissue and transfected cells, RGS12 and KOR are seen to interact within a protein complex. Ventral striatal-specific increases in KOR levels and KOR-induced G protein activation are seen in RGS12-null mice, as well as enhanced sensitivity to KOR agonist-induced hypolocomotion and analgesia-G protein signaling-dependent behaviors; a ventral striatal-specific increase in KOR levels was also observed in β-arrestin-2-deficient mice, highlighting the importance of β-arrestin signaling to establishing steady-state KOR levels in this particular brain region. Conversely, RGS12-null mice exhibited attenuated KOR-induced conditioned place aversion (considered a β-arrestin signaling-dependent behavior), consistent with the augmented KOR-mediated β-arrestin signaling seen upon RGS12 over-expression. Collectively, our findings highlight a role for RGS12 as a novel, differential regulator of both G protein-dependent and -independent signaling downstream of KOR activation.
Learn More >To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine.
Learn More >To investigate suicidality related to cluster headache and factors associated with increased suicidality in cluster headache patients.
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