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Neuropathic pain is a debilitating and commonly treatment-refractory condition requiring novel therapeutic options. Accumulating preclinical studies indicate that the potassium channel Slack (K1.1) contributes to the processing of neuropathic pain, and that Slack activators, when injected into mice, ameliorate pain-related hypersensitivity. However, whether Slack activation might reduce neuropathic pain in humans remains elusive. Here, we evaluated the tolerability and analgesic efficacy of loxapine, a first-generation antipsychotic drug and Slack activator, in neuropathic pain patients. We aimed to treat 12 patients with chronic chemotherapy-induced, treatment-refractory neuropathic pain (pain severity ≥ 4 units on an 11-point numerical rating scale) in a monocentric, open label, proof-of-principle study. Patients received loxapine orally as add-on analgesic in a dose-escalating manner (four treatment episodes for 14 days, daily dose: 20, 30, 40, or 60 mg loxapine) depending on tolerability and analgesic efficacy. Patient-reported outcomes of pain intensity and/or relief were recorded daily. After enrolling four patients, this study was prematurely terminated due to adverse events typically occurring with first-generation antipsychotic drugs that were reported by all patients. In two patients receiving loxapine for at least two treatment episodes, a clinically relevant analgesic effect was found at a daily dose of 20-30 mg of loxapine. Another two patients tolerated loxapine only for a few days. Together, our data further support the hypothesis that Slack activation might be a novel strategy for neuropathic pain therapy. However, loxapine is no valid treatment option for painful polyneuropathy due to profound dopamine and histamine receptor-related side effects. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02820519.
Learn More >Reduction in pain following multidisciplinary treatment is most often associated with a reduction in disability. To further elaborate the relationship between pain intensity and disability, the present study investigated three main questions: first, whether multidisciplinary treatment leads to a significant improvement in pain, disability and psychological variables (depression, pain acceptance and catastrophizing). Second, it was examined whether pain reduction may account for significant changes in the psychological variables (pre- to follow-up change scores). Finally, it was analyzed whether the psychological changes mediate the association between reduction in pain and in disability after controlling for age, sex and pain history.
Learn More >This paper aims to determine if hypnotic analgesia suggestion and transcranial direct-current stimulation (tDCS) have a differential effect on pain perception. We hypothesized that transcranial direct-current stimulation would be more effective than hypnotic analgesia suggestion at changing the descending pain modulating system, whereas the hypnotic suggestion would have a greater effect in quantitative sensory testing. This is a randomized, double blind and crossover trial. All stages of this clinical trial were performed at the Laboratory of Pain and Neuromodulation of the Hospital de Clínicas de Porto Alegre. Were included 24 healthy females aged from 18 to 45 years old, with a high susceptibility to hypnosis, according to the Waterloo-Stanford Group Scale of Hypnotic Susceptibility, Form C (15). The subjects received a random and crossover transcranial direct-current stimulation over the dorsolateral prefrontal cortex (2 mA for 20 min) and hypnotic analgesia (20 min). Only hypnotic suggestion produced changes that are statistically significant from pre- to post-intervention in the following outcomes measures: heat pain threshold, heat pain tolerance, cold pressure test, and serum brain-derivate-neurotrophic-factor. The analysis showed a significant main effect for treatment ( = 4.32; = 0.04) when we compared the delta-(Δ) of conditioned pain modulation task between the transcranial direct-current stimulation and hypnotic suggestion groups. Also, the change in the brain-derivate-neurotrophic-factor was positively correlated with the conditioned pain modulation task. The results confirm a differential effect between hypnotic suggestion and transcranial direct-current stimulation on the pain measures. They suggest that the impact of the interventions has differential neural mechanisms, since the hypnotic suggestion improved pain perception, whereas the transcranial direct-current stimulation increased inhibition of the descending pain modulating system. www.ClinicalTrials.gov, identifier NCT03744897. These findings highlight the effect of hypnotic suggestion on contra-regulating mechanisms involved in pain perception, while the transcranial direct-current stimulation increased inhibition of the descending pain modulating system. They could help clinicians comprehend the mechanisms involved in hypnotic analgesia and transcranial direct-current stimulation and thus may contribute to pain and disability management.
Learn More >Pain management with conventional opioids can be challenging due to dose-limiting adverse events (AEs), some of which may be related to the simultaneous activation of β-arrestin (a signaling pathway associated with opioid-related AEs) and G-protein pathways. The investigational analgesic oliceridine is a G-protein-selective agonist at the µ-opioid receptor with less recruitment of β-arrestin. The objective of this phase 3, open-label, multi-center study was to evaluate the safety and tolerability, of IV oliceridine for moderate to severe acute pain in a broad, real-world patient population, including postoperative surgical patients and non-surgical patients with painful medical conditions.
Learn More >Oxaliplatin is the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. Oxaliplatin, however, has been associated with acute and chronic peripheral neuropathies. Despite the awareness of these side-effects, the underlying mechanisms are yet to be clearly established. Therefore, in this study, we aimed to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We established a rat model of oxaliplatin-induced neuropathic pain (4 mg kg-1 intraperitoneally). The paw withdrawal thresholds were assessed at different time-points after the treatment, and a significant decrease was observed 3 and 4 weeks after oxaliplatin treatment as compared to the vehicle treatment (4.4 ± 1.0 vs. 16.0 ± 4.1 g; P < 0.05 and 4.4 ± 0.7 vs. 14.8 ± 3.1 g; P < 0.05, respectively). We further evaluated the role of different mitogen-activated protein kinases (MAPKs) pathways in the pathophysiology of neuropathic pain. Although the levels of total extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglia (DRG) were not different between oxaliplatin and vehicle treatment groups, phosphorylated ERK (p-ERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 μg day-1 intrathecally) inhibited oxaliplatin-induced ERK phosphorylation and neuropathic pain. Therefore, upregulation of p-ERK by oxaliplatin in rat DRG and inhibition of mechanical allodynia by an ERK inhibitor in the present study may provide a better understanding of intracellular molecular alterations associated with oxaliplatin-induced neuropathic pain and help in the development of potential therapeutics.
Learn More >Neuropathic pain with complications greatly affects patients worldwide. High mobility group box 1 (HMGB1) has been shown to contribute to the pathogenesis of neuropathic pain; thus, suppression of HMGB1 may provide a novel therapeutic option for neuropathic pain. Electroacupuncture (EA) has been indicated to be effective in attenuating neuropathic pain, but the underlying mechanism remains to be fully clarified. We aim to explore whether 2Hz EA stimulation regulates the spinal HMGB1/NF-κB signaling in neuropathic pain induced by spared nerve injury (SNI).
Learn More >Intranasal lidocaine has been shown to be effective in treating patients with acute migraines; however, its efficacy is still controversial. In this study, we intend to assess the efficacy and safety of intranasal lidocaine compared with a placebo or an active comparator for the treatment of migraines.
Learn More >Unresolved inflammation is a significant predictor for developing chronic pain, and targeting the mechanisms underlying inflammation offers opportunities for therapeutic intervention. During inflammation, matrix metalloproteinase (MMP) activity contributes to tissue remodeling and inflammatory signaling, and is regulated by tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 and -2 have known roles in pain, but only in the context of MMP inhibition. However, TIMP-1 also has receptor-mediated cell signaling functions that are not well understood. Here, we examined how TIMP-1-dependent cell signaling impacts inflammatory hypersensitivity and ongoing pain. We found that hindpaw injection of complete Freund's adjuvant (CFA) increased cutaneous TIMP-1 expression that peaked prior to development of mechanical hypersensitivity, suggesting that TIMP-1 inhibits the development of inflammatory hypersensitivity. To examine this possibility, we injected TIMP-1 knockout (T1KO) mice with CFA and found that T1KO mice exhibited rapid onset thermal and mechanical hypersensitivity at the site of inflammation that was absent or attenuated in WT controls. We also found that T1KO mice exhibited hypersensitivity in adjacent tissues innervated by different sets of afferents, as well as skin contralateral to the site of inflammation. Replacement of recombinant murine (rm)TIMP-1 alleviated hypersensitivity when administered at the site and time of inflammation. Administration of either the MMP inhibiting N-terminal or the cell signaling C-terminal domains recapitulated the antinociceptive effect of full-length rmTIMP-1, suggesting that rmTIMP-1inhibits hypersensitivity through MMP inhibition and receptor-mediated cell signaling. We also found that hypersensitivity was not due to genotype-specific differences in MMP-9 activity or expression, nor to differences in cytokine expression. Administration of rmTIMP-1 prevented mechanical hypersensitivity and ongoing pain in WT mice, collectively suggesting a novel role for TIMP-1 in the attenuation of inflammatory pain.
Learn More >Previous studies suggested that both maladaptive stress response and circadian dysregulation might have a role in the background of migraine. However, effects of circadian genes on migraine have not been tested yet. In the present study, we investigated the main effect of rs10462028 of the circadian locomotor output cycles kaput () gene and its interaction with different stress factors on migraine. In our cross-sectional study 2,157 subjects recruited from Manchester and Budapest completed the ID-Migraine questionnaire to detect migraine type headaches (migraineID). Additional stress factors were assessed by a shortened version of the Childhood Trauma Questionnaire, the List of Threatening Experiences questionnaire, and a validated questionnaire to identify financial difficulties. Rs10462028 showed no main genetic effect on migraineID. However, chronic stress indexed by financial difficulties showed a significant interaction effect with rs10462028 ( = 0.006 in recessive model) on migraineID. This result remained significant after correction for lifetime bipolar and unipolar depression and was replicated in both subsamples, although only a trend effect was reached after Bonferroni-correction, which is the strictest correction not considering interdependences. Childhood adversity (CHA) and Recent negative life events (RLE) showed no significant gene × stress interaction with rs10462028. In addition, analysis demonstrated that the genetic region tagged by rs10462028 alters the binding of several miRNAs. Our exploratory study suggests that variations in the gene, with moderating effect on gene function through miRNA binding, in interaction with financial difficulties might influence the risk of migraine-type headaches. Thus, financial hardship as a chronic stress factor may affect migraine through altering circadian rhythms.
Learn More >Children and adolescents with primary headache are at risk of persistent somatic symptoms and reduced quality of life (Qol) due to pain and pain-related behaviors, such as avoiding school and activities. Sleep is essential to health, and children and adolescents with primary headaches have more sleep complaints than do healthy controls. A treatment approach that addresses multifactorial causes is likely important. Nonpharmacological interventions seem promising. However, knowledge about effective strategies is limited. The objective of this review is to assess the effect of nonpharmacological interventions in randomized controlled trials (RCTs) among children and adolescents with primary headache in order to identify useful strategies.
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